Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). It is indicated to treat obsessive-compulsive disorder (OCD) in adult and pediatric patients 8 years and older. An extended-release formulation was indicated for the treatment of social anxiety disorder in adults as well, but the manufacturer asked for the voluntary removal of this indication. Unlike other SSRIs, fluvoxamine is not approved to treat major depression; however, the drug is used off-label for this condition in adults. Other off-label uses in adults include generalized anxiety disorder (GAD), premenstrual dysphoric disorder (PMDD), post-traumatic stress disorder, and panic disorder. Limited data suggest efficacy in children as young as 6 years old for various childhood anxiety disorders. Fluvoxamine has the shortest half-life of all the SSRIs. Sedation appears to be more common with fluvoxamine than with some other SSRIs in adults. However, activation symptoms have been frequently observed in pediatric patients; therefore, close monitoring is recommended for early identification of increased motor activity and behavioral activation symptoms in children and adolescents receiving fluvoxamine. Product labels for all antidepressants contain a boxed warning related to an increased risk of suicidality in children, adolescents, and young adults during the initial stages of therapy when treating depression or other conditions; therefore, the necessity of pharmacologic therapy versus the potential risks should be carefully considered in these populations.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer without regard to meals.
Oral Solid Formulations
-Immediate-release tablets: To minimize side effects, administer at bedtime. Administer doses > 100 mg/day (or > 50 mg/day in pediatric patients 8-17 years) in two divided doses; if doses are not equal, give the larger dose at bedtime.
-Extended-release capsules: Do not crush or chew. To minimize side effects, administer at bedtime. A combination of the 100 mg and 150 mg capsules may be required to attain the appropriate titration or maintenance dose. Once stabilized, prescribe the smallest combination of capsules needed to achieve the total daily dose.
During clinical trials in adults, the following gastrointestinal (GI) effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: nausea (34% to 40%), diarrhea (11% to 18%), constipation (4% to 10%), dyspepsia (8% to 10%), anorexia (6% to 14%), vomiting (5% to 6%), flatulence (4%), tooth disorder (2% to 3%), dysphagia (2%), xerostomia (10 to 14%), abdominal pain (5%), elevated hepatic enzymes (2%), gingivitis (2%), and weight loss (2%). Nausea usually subsides after a few weeks of therapy and may potentially be minimized by the administration of the drug with food. The overall adverse effect profile in pediatric patients was similar to that observed in adult trials. Weight loss was reported more frequently in patients receiving fluvoxamine compared to those receiving placebo during pediatric clinical trials. During other clinical trial evaluation, weight gain was reported in at least 1% of patients but at rates similar to placebo. Melena, colitis, esophagitis, gastritis, gastroenteritis, peptic ulcer, glossitis, hemorrhoids, stomatitis, eructation, and hypersalivation were reported in 0.1% to 1% of patients. Biliary pain, cholecystitis, cholelithiasis, fecal incontinence, hematemesis, GI obstruction, and jaundice were reported rarely (less than 0.1%). Hepatitis, ileus, gastroesophageal reflux, glossodynia, and pancreatitis have been reported postmarketing.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and major depressive disorder (MDD), the following centrally-mediated effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: insomnia (21% to 35%), drowsiness (22% to 27%), dizziness (11% to 15%), headache (22% to 35%), tremor (5% to 8%), hypertonia (2%), paresthesias (3%), abnormal dreams (3%), twitching (2%), and CNS stimulation (2%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adult trials. During other clinical trial evaluation, hyperkinesis, myoclonia, and hypokinesia were reported in at least 1% of patients. Akathisia, ataxia, CNS depressive symptoms, dyskinesia, dystonic reaction, extrapyramidal syndrome, unsteady gait, hemiplegia, hypersomnia, hypotonia, muscle paralysis, stupor, vertigo, incoordination, and sleep disorder were reported in 0.1 to 1% of patients. Rare events (less than 0.1%) included akinesia, coma, fibrillations, mutism (aphonia), hyporeflexia, dysarthria, tardive dyskinesia, torticollis, and trismus. Teeth grinding (bruxism), dysarthria, pseudoparkinsonism, gait disturbance, loss of consciousness, and shock have been reported during postmarketing use.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and depression, the following psychiatric effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: nervousness (10% to 12%), anxiety (5% to 8%), agitation (2% to 3%), apathy (3%), abnormal thinking (3%), and neurosis (2%). During other clinical trial evaluation, mania, psychosis, and amnesia were reported in at least 1% of patients. Euphoria, confusion, agoraphobia, delirium, delusions, depersonalization, emotional lability, hallucinations, hostility, hypochondriasis, hysteria, paranoia, and phobia were reported in 0.1% to 1% of patients. The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adults; emotional lability and manic reaction were reported more frequently in pediatric patients receiving immediate-release fluvoxamine than with placebo. Obsessions were reported rarely (less than 0.1%) in adults. Aggression, feeling drunk (impaired cognition), feeling jittery, homicidal ideation, impulsive behavior, irritability, self-injurious behavior, anger, and activation syndrome have been reported postmarketing. All effective antidepressants can transform depression into mania or hypomania in predisposed individuals (including those with depression or bipolar disorder). If a manic reaction occurs, the antidepressant should be held and appropriate therapy to treat the manic symptoms initiated.
Monitor all antidepressant-treated patients for any indication for worsening of depression or the treated condition for the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. During clinical trials in adults for conditions including but not limited to major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), depression was reported in 2% of patients receiving fluvoxamine and more frequently than in patients receiving placebo. Suicidal tendencies, suicide attempt, and overdose were reported in 0.1% to 1% of patients. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation during fluvoxamine treatment.
Platelet dysfunction (i.e., impaired platelet aggregation) may occur during treatment with selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematoma, petechiae, hemorrhage). During clinical trials in adults for obsessive-compulsive disorder (OCD), ecchymosis was reported in 4% and epistaxis occurred in 2% of patients receiving extended-release fluvoxamine and at a rate twice that of placebo. Events occurring during fluvoxamine clinical trials in 0.1 to 1% of patients receiving active drug included anemia, GI bleeding (i.e., hemorrhage), rectal hemorrhage, vaginal hemorrhage, leukocytosis, lymphadenopathy, and thrombocytopenia. Less than 0.1% of patients experienced leukopenia or purpura. During clinical trials in pediatric patients, ecchymosis and epistaxis occurred more frequently in the group receiving fluvoxamine than those on placebo. Purpura, aplastic anemia, agranulocytosis, and porphyria have been reported postmarketing, however causality to the drug has not been established. An increased risk of bleeding complications is possible in patients receiving antiplatelet or anticoagulant medications concurrently with fluvoxamine.
Selective serotonin reuptake inhibitors (SSRIs) may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Elderly patients, those receiving diuretics, those prone to becoming dehydrated, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of fluvoxamine, as well as implementation of the appropriate medical interventions. SIADH has been reported during postmarket use of fluvoxamine, although the frequency is unknown.
Seizures occur infrequently with fluvoxamine. During premarketing studies with immediate-release fluvoxamine, seizures were reported in 0.2% of fluvoxamine-treated patients. Fluvoxamine should be discontinued in any patient who develops seizures or an increase in seizure frequency while on therapy.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and depression, the following cardiovascular effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: palpitations (3%), peripheral vasodilation (2%), chest pain (unspecified) (3%), and hypertension (2%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adult trials. During other clinical trial evaluation, syncope and hypotension were reported in at least 1% of patients. Infrequent (0.1% to 1%) cardiac or peripheral vascular events included angina, bradycardia, cardiomyopathy, cold extremities, conduction delay, myocardial infarction, pallor, irregular pulse, and ST-T wave changes. Rare effects (less than 0.1%) included AV block, stroke, embolus, pericarditis, phlebitis, pulmonary infarction, and supraventricular extrasystoles. Vasculitis, QT prolongation, ventricular arrhythmia, ventricular tachycardia (including torsade de pointes, TdP), sinus tachycardia, and cardio-pulmonary arrest (cardiac arrest) have occurred postmarketing; although the incidences are unknown. There is a report of QTc prolongation occurring in an adolescent with no apparent risk factors using a therapeutic dose of fluvoxamine (i.e., 75 mg/day), with resolution of the cardiac effect after a dose reduction to 50 mg/day. Fluvoxamine use has been associated with TdP under certain conditions, especially when used in excessive doses or with drugs that prolong the QT interval. Some cases of fluvoxamine overdose (single or multiple dose) have included bradycardia, cardiac arrest, QT prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm. However, the majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, use of fluvoxamine is not a significant risk factor for the development of QT prolongation.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and depression, the following general effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: asthenia (14% to 26%) chills (2%), pain (10%), and accidental injury (5%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adults. During other clinical trial evaluation, malaise was reported in at least 1% of patients. Neck pain and neck rigidity were reported in 0.1% to 1% of patients. Sudden death occurred rarely (less than 0.1%). Fatigue, lethargy, and falls have been reported during postmarketing.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and depression, the following dermatologic effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: hyperhidrosis (6 to 7%) acne vulgaris (2%), and vasodilation such as flushing (3%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adults; however, rash (unspecified) was reported more frequently in fluvoxamine-treated pediatric patients than with placebo. During other clinical trial evaluation, urticaria, photosensitivity reaction, alopecia, xerosis, exfoliative dermatitis, furunculosis, seborrhea, skin discoloration, and atopic dermatitis were reported in 0.1 to 1% of patients. Bullous rash, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), anaphylactoid reactions, and angioedema have occurred during postmarket use.
The following respiratory effects or infections were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo during clinical trials: influenza (3%), viral infection (2%), upper respiratory infection (9%), dyspnea (2%), yawning (2 to 5%), pharyngitis (6%), laryngitis (3%), and bronchitis (2%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adult trials. In pediatric patients treated with immediate-release fluvoxamine, cough increase and sinusitis were reported at higher rates than with placebo. During other clinical trial evaluation, increased cough and sinusitis were reported in at least 1% of patients. Infrequent events (0.1 to 1%) included asthma (bronchospasm), hoarseness, and hyperventilation. Hemoptysis, laryngismus (laryngospasm), apnea, upper airway congestion, hiccups (singultus), obstructive pulmonary disease, and pneumonia were reported rarely (less than 0.1%). Interstitial lung disease and fever have been reported during postmarket use.
During clinical trials in adults for conditions including but not limited to obsessive-compulsive disorder (OCD) and depression, the following genitourinary (GU) effects were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: ejaculation dysfunction (8 to 11%), increased urinary frequency (3%), impotence (erectile dysfunction) (2%), urinary retention (1%), menorrhagia (3%), urinary tract infection (2%), polyuria (2%), libido decrease in males (6%), libido decrease in females (4%), sexual dysfunction in males (2 to 4%), sexual dysfunction in females (3%), orgasm dysfunction in males (4%), and orgasm dysfunction in females (5%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adult trials. In pediatric patients treated with immediate-release fluvoxamine dysmenorrhea reported at higher rates than with placebo; in adults, this adverse event was reported at a rate similar to placebo. During other clinical trial evaluation, hematuria, anuria, cystitis, delayed menstruation, dysuria, galactorrhea, libido increase, menopause, metrorrhagia, nocturia, premenstrual syndrome, impaired urination, vaginitis, and vaginal bleeding (hemorrhage) were reported in 0.1 to 1% of patients. Hematospermia, nephrolithiasis, and oliguria were reported rarely (less than 0.1%). Acute renal failure (unspecified), renal impairment (unspecified), and amenorrhea have occurred during postmarket use. As with other SSRIs, cases of priapism have been reported during fluvoxamine therapy which have been reversible upon discontinuation of the drug.
During clinical trials in adults, the following special senses adverse reactions were reported more frequently in patients receiving immediate-release or extended-release fluvoxamine than placebo: amblyopia (2 to 3%) and dysgeusia (2 to 3%). The overall adverse effect profile in pediatric patients with OCD was similar to that observed in adults. During other clinical trial evaluation, abnormal accomodation (blurred vision), conjunctivitis, diplopia, ocular pain, mydriasis, otitis media, parosmia, visual field defect (visual impairment), xerophthalmia, photophobia, and taste loss were reported in 0.1 to 1% of patients. Corneal ulcer was reported rarely (less than 0.1%). In postmarketing experience, anosmia and hyposmia have also been reported.
During clinical trials in adults for obsessive-compulsive disorder (OCD), myalgia was reported in 5% of patients receiving extended-release fluvoxamine and 2% of patients receiving placebo. Musculoskeletal effects reported in 0.1% to 1% of patients receiving fluvoxamine included arthralgia, arthritis, bursitis, generalized muscle spasm, and myasthenia. Myopathy was reported rarely (less than 0.1%). Rhabdomyolysis has been reported during postmarket use.
During clinical trial evaluation, edema was reported in at least 1% of patients receiving fluvoxamine. Infrequently reported (0.1% to 1%) metabolic and nutritional effects included dehydration and hypercholesterolemia. Rare events (less than 0.1%) included diabetes mellitus, hyperglycemia, hyperlipidemia, hypoglycemia, hypokalemia, and increased lactate dehydrogenase. Increased blood glucose has been reported postmarketing.
During clinical trial evaluation, hypothyroidism was reported in 0.1% to 1% of patients receiving fluvoxamine. Goiter was reported rarely (less than 0.1%).
Serotonin syndrome has been reported during use of SSRIs alone, during concurrent use of other medications known to increase CNS or peripheral serotonin levels, or during SSRI overdose. Close monitoring of the patient is essential in the initial stages of fluvoxamine therapy when a combination of serotonergic agents is used. Initiate therapy with a low dose and titrate dose upwards as clinically indicated. If serotonin syndrome becomes evident during treatment, the SSRI and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated. A drug discontinuation syndrome, resembling serotonin syndrome, has been reported in neonates exposed to SSRIs or SNRIs late in the third trimester.
Use selective serotonin reuptake inhibitors (SSRIs) with caution in patients with osteopenia or risk factors for osteopenia. Epidemiological studies suggest an association between the use of SSRIs and bone fractures. Some data suggest that chronic treatment with SSRIs, such as fluvoxamine, may be associated with reduced bone density. Serotonin (5-HT) receptors and the serotonin reuptake transporter (5-HTT) have been found in osteoblasts and osteoclasts, and 5-HT functioning appears to be involved in bone architecture, bone mass, and bone density. Results of one observational retrospective study assessing the association between the degree of 5-HTT inhibition among antidepressants and the risk of osteoporotic and non-osteoporotic fractures indicated that use of antidepressants considered to have a high affinity for 5-HTT was associated with a higher risk of osteoporotic fractures than antidepressants with a moderate or low affinity for 5-HTT (OR 1.86, CI 1.63 to 2.13). There was no trend with increasing affinity for 5-HTT in non-osteoporotic fractures, although antidepressant use in general resulted in a 50% increase in this fracture type. In a separate prospective population-based cohort study, the risk of non-vertebral fractures was 2.35 in users of SSRIs compared to nonusers of antidepressants. A sub-analysis was conducted, which included current and prior antidepressant users only. The results showed that current users of SSRIs had a 2.07-fold increased risk of fracture compared to past users of tricyclic antidepressants or SSRIs, and this risk further increased with prolonged use.
Withdrawal symptoms have been reported with abrupt or rapid discontinuation of short-acting SSRIs such as fluvoxamine. During clinical trial evaluation of fluvoxamine, a withdrawal syndrome was reported in less than 0.1% of patients. The most commonly reported withdrawal symptoms include fatigue, abdominal pain or nausea, dizziness/light-headedness, tremor, chills, diaphoresis, and incoordination. Other reported symptoms include impaired memory, insomnia, shock sensations, headache, agitated state, or aggression. Withdrawal symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and remit within 1 to 2 weeks. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of withdrawal symptoms.
A neonatal abstinence syndrome has been reported in infants exposed to serotonergic agents in utero. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. Other symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, and constant crying. Serum concentrations of the serotonergic agent were measurable in the infants affected. Several other symptoms (bloody stools, necrotizing enterocolitis) may have been attributable to rebound platelet activation on withdrawal of the exposure to the SSRI. Neonatal symptoms generally improved over several days. A cohort study of 55 women revealed that 22% (12/55) of neonates exposed to an SSRI in the third trimester had complications requiring treatment or extended hospitalization compared with 6% in comparison groups. Complications included respiratory distress (n = 9), hypoglycemia (n = 2), and jaundice (n = 1). The incidence of prematurity in the third trimester SSRI group was significant at 20% vs. 3.7% of controls. These features are consistent with either a direct toxic effect of serotonergic agents, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with an SSRI or other serotonergic agent during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, tapering of fluvoxamine prior to delivery may be considered as an alternative. A case-controlled epidemiologic report has been published that suggests the significant association between maternal use of SSRIs after 20 weeks of pregnancy and the development of persistent pulmonary hypertension of the newborn (PPHN) (odds ratio (OR) 5.1; 95% CI, 1.9 to 13.3). The study population consisted of 377 women whose infants had PPHN and 836 matched control women and their infants. There was no increased risk of PPHN when SSRI use was restricted to the first half of the pregnancy (OR = 0.3; 95% CI, 0.1 to 1.1). Additionally, the use of non-SSRI antidepressant drugs at any time during pregnancy was not associated with an increased risk of PPHN. The SSRIs that were used by women > 20 weeks gestation in the study included fluoxetine, paroxetine, and sertraline. However, the numbers were too small to permit examination of the effects of dose size, specific SSRI used, or reduction of the length of exposure before delivery. Neonatal somnolence has been reported during post-market use.
As with other SSRIs, decreased weight gain has been observed in children and adolescents receiving fluvoxamine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition, but height and weight should be monitored periodically throughout therapy. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.
Fluvoxamine is contraindicated in those patients with a hypersensitivity to fluvoxamine or any of the product formulation components.
Abrupt discontinuation of any SSRI should be avoided if possible. Gradual tapering is recommended during discontinuation of fluvoxamine to decrease or prevent the occurrence of potential discontinuation symptoms. The most frequent SSRI discontinuation symptoms include dizziness, vertigo, nausea, vomiting, flu-like symptoms, sensory disturbances (e.g., paresthesias, electric shock sensation), sleep disturbances, irritability, anxiety, and/or agitation. Discontinuation symptoms are more likely to occur after withdrawal of SSRIs with a short half-life such as fluvoxamine than SSRIs with a long half-life such as fluoxetine.
The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, fluvoxamine should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality.
Fluvoxamine is not FDA-approved for use in pediatric patients except for the treatment of obsessive-compulsive disorder. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. Prescribe fluvoxamine in the smallest quantity consistent with good patient management to reduce the risk of overdose. Monitor all patients receiving antidepressants for any indication closely for clinical worsening, suicidal ideation, and unusual behavioral changes, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, especially during the first few months of therapy and after any dosage adjustment. Instruct caregivers and patients to immediately notify the prescriber of changes in behavior or suicidal ideation. Consider changing the therapeutic regimen or discontinuing the medication in patients with persistent or worrisome symptoms, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. In a pooled analysis of placebo-controlled trials of antidepressants (n = more than 4,400 pediatric patients and 77,000 adult patients), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults older than 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide. It is unknown if the suicidality risk extends to long-term use (i.e., more than 4 months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression, a known risk factor for suicidal thoughts and behaviors. In addition to suicide risk, monitor pediatric patients for the potential for growth inhibition during SSRI therapy. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving SSRIs. Monitor height and weight periodically while the patient is receiving fluvoxamine. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.
Fluvoxamine is contraindicated for concomitant use in patients receiving monoamine oxidase inhibitor therapy (MAOI therapy). The use of MAOIs intended to treat psychiatric disorders with fluvoxamine or within 14 days of stopping treatment with fluvoxamine is contraindicated because of an increased risk of serotonin syndrome. The use of fluvoxamine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting fluvoxamine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue, which also have MAOI activity, is also contraindicated because of an increased risk of serotonin syndrome. Other medications when combined with fluvoxamine may increase the risk for serotonin syndrome. Serotonin syndrome has been reported with SSRIs, including fluvoxamine, both when taken alone, but especially when co-administered with other serotonergic agents including serotonin agonists (triptans), tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort. If such symptoms occur, discontinue fluvoxamine and initiate supportive treatment.
Fluvoxamine's effects during electroconvulsive therapy (ECT) have not been systematically evaluated in clinical studies.
During premarketing studies with fluvoxamine, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of a seizure disorder. Fluvoxamine should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.
Selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Older patients (65 years and older), those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of fluvoxamine, as well as implementation of the appropriate medical interventions.
QT prolongation and torsade de pointes (TdP) have been reported with fluvoxamine use in clinical practice and postmarketing. Fluvoxamine has been associated with conditional risk of TdP, which occurs under certain conditions, especially when used in excessive doses or with drugs that prolong the QT interval; avoid use in patients with a history of congenital long QT syndrome. However, the majority of available evidence indicates that at therapeutic doses, and in the absence of risk factors, use of fluvoxamine is not a significant risk factor for the development of QT prolongation. Use fluvoxamine with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Fluvoxamine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable cardiac disease.
Fluvoxamine should be used with caution in patients with hepatic disease because decreased clearance occurs. Modified dosing and titration may be necessary. Fluvoxamine is also known to inhibit hepatic CYP450 isoenzymes, which may lead to clinically significant drug interactions. The use of certain medications with fluvoxamine is contraindicated; patient profiles should be carefully reviewed to determine drug interactions.
Monitor patients taking fluvoxamine for signs and symptoms of bleeding. Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). In published observational studies, pregnant patients taking SSRIs, particularly in the month before obstetric delivery, were at an increased risk of postpartum hemorrhage. Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase the risk of bleeding complications. Patients should be instructed to promptly report any bleeding events to their health care provider.
SSRIs and other medications used to treat major depressive disorder have been associated with closed-angle glaucoma; therefore, caution is recommended when using fluvoxamine in patients with this condition. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.
Because any psychoactive drug may impair judgment, thinking, or motor skills, patients should use caution when driving or operating machinery, until they are reasonably certain that fluvoxamine does not affect them adversely. As with other psychotropic medications, patients should be advised to avoid ethanol ingestion while taking fluvoxamine.
Sexual dysfunction can occur in individuals taking fluvoxamine. For males, these effects may present as ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Females may experience decreased libido and delayed or absent orgasm. Prescribers should discuss sexual function prior to initiating treatment with fluvoxamine and throughout treatment and obtain a detailed history and timeline of any changes in sexual function to determine whether the changes are medication-related or may be attributed to the underlying psychiatric disorder. Clinicians should also discuss management strategies and treatment options with patients.
Use selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, with caution in patients with osteoporosis. Epidemiological studies on bone fracture risk following exposure to SSRIs have reported an association between SSRI treatment and bone fractures. It is unknown to what extent fracture risk is directly attributable to SSRI treatment. If a SSRI-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising, consider the possibility of a fragility fracture. Patients at risk for osteoporosis, such as postmenopausal females, may benefit from more frequent monitoring of bone density during long-term use of an SSRI.
There are no adequate and well-controlled studies of fluvoxamine use during pregnancy; use in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. There are risks to the mother associated with untreated psychiatric conditions (e.g., relapse) and a potential risk due to SSRI exposure of persistent pulmonary hypertension of the newborn (PPHN). Some neonates exposed to SSRIs late in the third trimester have experienced poor neonatal adaptation resulting in complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with direct SSRI toxicity, serotonin syndrome, or a drug discontinuation syndrome. Data from published observational studies have also reported that exposure to SSRIs, particularly in the month before obstetric delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Animal teratology studies with fluvoxamine did not show an increased risk of fetal malformations at doses twice the maximum human daily dose (MHDD) on a BSA basis; in some studies, decreased pup birth weight and survival have been noted at doses near the normal MHDD on a BSA basis. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to fluvoxamine; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry/antidepressants or by calling 1-866-961-2388.
Consider the benefits of breast-feeding, the risk of fluvoxamine exposure to the infant, and the risk of an untreated or inadequately treated condition. Fluvoxamine is secreted into breast milk. Relative to other SSRIs, however, infant concentrations when fluvoxamine is used are among the lower in the group. Based on plasma and breast milk concentrations from 2 mothers taking fluvoxamine, it was estimated that the infants would receive 0.8% to 1.38% of the maternal weight-adjusted dose; in this report, fluvoxamine concentrations were not detectable in either infant and no adverse events in the infants were observed. Other SSRIs have been reported to induce changes in sleeping or eating patterns in the breast-fed infant. Patients should advise their physicians of their intention to breast-feed. If breast-feeding is continued, the infant should be observed for evidence of adverse effects, and breast-feeding should be avoided at times of peak serum concentrations. Alternatives may also be considered. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.
The selective serotonin reuptake inhibitors (SSRIs) are often a preferred antidepressant group for treatment of various psychiatric indications in the geriatric adult, including patients with dementia. Data indicate that fluvoxamine clearance is reduced by about 50% in the older adult, although no differences in safety relative to younger adults has been recorded. Careful initial dosing and slow titration are recommended. Selective serotonin reuptake inhibitors (SSRIs) may cause hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH); older adults appear to be at higher risk. According to the Beers Criteria, SSRIs are considered potentially inappropriate medications (PIMs) in older adults with a history of falls or fractures; SSRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an SSRI must be used, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk. Also, SSRIs may cause hyponatremia and SIADH; closely monitor sodium concentrations when initiating treatment or changing doses in older adults. The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). When used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the antidepressant as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Dosages and durations of treatment used in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines.
Tobacco smoking increases the metabolism of fluvoxamine. Smokers have a 25% increase in metabolism over non-smokers; however, no dosage adjustments are recommended in this patient population.
For the treatment of obsessive-compulsive disorder (OCD):
Oral dosage (immediate-release tablets):
Adults: Initially, 50 mg PO at bedtime, then adjust as needed. Consider lower doses and slower dose titration in geriatric adults. Dose adjustments in increments of 50 mg can be made every 4 to 7 days until therapeutic benefit is reached. Usual dose is 100 to 200 mg/day (range: 50 to 300 mg/day). Administer total daily doses more than 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime.
Children and Adolescents 12 years and older: 25 mg PO at bedtime. May titrate by 25 mg increments every 4 to 7 days based on efficacy and tolerability. Max: 300 mg/day PO. Daily doses more than 50 mg should be divided.
Children 8 to 11 years: 25 mg PO at bedtime. May titrate by 25 mg increments every 4 to 7 days based on efficacy and tolerability. Max: 200 mg/day PO. Daily doses more than 50 mg should be divided.
Oral dosage (extended-release capsules, e.g., Luvox CR):
Adults: Initially, 100 mg PO once daily at bedtime. Titrate as needed and tolerated in increments of 50 mg per week to a target range of 100 to 300 mg/day. During the titration phase, both the 100 mg and the 150 mg capsules may be needed to supply the daily dose; once stabilized, use the lowest effective daily dose. Max: 300 mg/day PO. Some patients taking immediate-release fluvoxamine may be switched to extended-release, at a similar total daily dosage.
Children and Adolescents 12 years and older: Initially, 100 mg PO once daily at bedtime. Titrate as needed and tolerated in increments of 50 mg per week to a target range of 100 to 300 mg/day. During the titration phase, both the 100 mg and the 150 mg capsules may be needed to supply the daily dose; once stabilized, use the lowest effective daily dose. Max: 300 mg/day PO. Dosage data are derived from the use of immediate-release products in pediatric populations. Physicians should consider that the lowest available dose of the extended-release capsules may not be appropriate for pediatric patients who are naive to fluvoxamine, as lower initiation doses are recommended (see immediate-release dosage). Some pediatric patients taking immediate-release fluvoxamine may be switched to extended-release, at a similar total daily dosage.
Children 8 to 11 years: Initially, 100 mg PO once daily at bedtime. Titrate as needed and tolerated in increments of 50 mg per week; use the lowest effective daily dose. Max for this age group: 200 mg/day PO. Dosage data are derived from the use of immediate-release products in this pediatric population. Physicians should consider that the lowest available dose of the extended-release capsules may not be appropriate for pediatric patients who are naive to fluvoxamine, as lower initiation doses are recommended (see immediate-release dosage).
For the treatment of generalized anxiety disorder (GAD)*:
Oral dosage (immediate-release tablets):
Adults: Initially, 50 mg PO at bedtime, then adjust as needed. Geriatric adults may need lower initial doses and slower dose titration. Dose adjustments in increments of up to 50 mg can be made every 4 to 7 days as needed until therapeutic benefit is reached. Mean effective dose based on limited clinical trials is 200 mg/day, with a range of 50 to 300 mg/day. Give total daily doses more than 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime.
Children and Adolescents 6 years and older: Initiate at a low dose (e.g., 25 mg/day PO at bedtime) to minimize side effects. In one short-term, placebo-controlled study (n = 128) including pediatric patients with social phobia, separation anxiety, and/or generalized anxiety disorder, fluvoxamine was titrated by 50 mg/week to an effective dose. The average dose of all participants (6 to 17 years of age) was 2.9 mg/kg/day +/- 1.3 PO. Max (12 years and older): 300 mg/day PO. Max (6 to 11 years): 250 mg/day PO. The fluvoxamine group had a greater mean decrease in anxiety symptoms than those receiving placebo (p < 0.001). Significant differences were observed by week 3 and increased through week 6. On the CGI-Improvement scale, 76% of fluvoxamine-treated participants had a response compared to 29% of those receiving placebo (p < 0.001). Effectiveness was sustained in an open-label 6-month follow up study. Patients should be periodically reassessed to determine the need for ongoing maintenance treatment.
For the treatment of social phobia (social anxiety disorder)*:
Oral dosage (extended-release capsules; e.g., Luvox CR):
Adults: Initially, 100 mg PO at bedtime. Titrate as needed and tolerated in increments of 50 mg per week to a target range of 100 to 300 mg/day. During the titration phase, both the 100 mg and the 150 mg capsules may be needed to supply the daily dose; once stabilized, use the lowest effective total daily dose. Max: 300 mg/day. NOTE: Fluvoxamine CR was previously FDA-approved for social anxiety disorder in 2008, but the manufacturer petitioned for voluntary removal of the indication from the product label in 2011, and the FDA-approval for the indication was removed.
Oral dosage (immediate-release tablets):
Adults: Initially, 50 mg PO at bedtime, then adjust as needed. Geriatric patients may require a reduced initial dose and slower titration. Titrate in 50 mg increments every 4 to 7 days as needed until therapeutic benefit is reached. Mean effective dose per limited clinical trials is 200 mg/day, with a range of 50 mg/day to 300 mg/day PO. Total daily doses higher than 100 mg/day should be given in divided doses; if doses are unequal, give the larger dose at bedtime.
Children and Adolescents 6 years and older: Initiate at a low dose (e.g., 25 mg/day PO at bedtime) to minimize side effects. In one short-term, placebo-controlled study (n = 128) including pediatric patients with social phobia, separation anxiety, and/or generalized anxiety disorder, fluvoxamine was titrated by 50 mg/week to an effective dose. The average dose of all participants (6 to 17 years of age) was 2.9 mg/kg/day +/- 1.3 PO. Max (12 years and older): 300 mg/day PO. Max (6 to 11 years): 250 mg/day PO. The fluvoxamine group had a greater mean decrease in anxiety symptoms than those receiving placebo (p < 0.001). Significant differences were observed by week 3 and increased through week 6. On the CGI-Improvement scale, 76% of fluvoxamine-treated participants had a response compared to 29% of those receiving placebo (p < 0.001). Effectiveness was sustained in an open-label 6-month follow up study. Patients should be periodically reassessed to determine the need for ongoing maintenance treatment.
For the treatment of panic disorder*:
Oral dosage (immediate-release tablets):
Adults: Initially, 50 mg PO at bedtime for the first 4 to 7 days, then titrate by 25 to 50 mg/dose every 4 to 7 day as needed to reach a therapeutic dose. Geriatric patients may require a reduced initial dose and slower titration. Usual dose is 150 to 300 mg/day in single or divided doses for 6 to 8 weeks. Give total daily doses greater than 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime.
For the treatment of posttraumatic stress disorder (PTSD)*:
Oral dosage (immediate-release tablets):
Adults: Initially, 25 to 50 mg PO at bedtime for the first 4 to 7 days, then titrate by 25 to 50 mg/dose every 4 to 7 days as needed to reach a therapeutic dose. Geriatric patients may require a lower initial dose as well as slower titration. Usual dosage range 25 to 300 mg/day in single or divided doses for 3 to 12 weeks. Fluvoxamine has been effective for a wide variety of traumatic stressors, including combat. Give total daily doses greater than 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime.
For the treatment of major depression*:
Oral dosage (immediate-release tablets e.g., Luvox):
Adults: Initiate with 50 mg/day PO once daily at bedtime. Increase at weekly intervals by 50 mg/day according to response and tolerability. Geriatric patients may require a reduced initial dose and slower titration. The average effective dose in clinical trials was approximately 100 mg/day. Doses of 150 mg/day or more may reduce tolerability without an increase in benefit. Administer total daily doses greater than 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime. Generally, acute episodes of depression require several months of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to that needed for maintenance is unknown. Study results indicate that fluvoxamine is at least as effective as fluoxetine and paroxetine in the acute treatment of major depressive disorder (MDD), and similar to sertraline in recurrence rates. When compared to paroxetine, fluvoxamine was initiated at 50 mg/day PO with weekly increases of 50 mg/day permitted up to a maximum of 150 mg/day. Paroxetine was initiated at 20 mg/day with titration up to a maximum dose of 50 mg/day. The mean doses at study end for fluvoxamine and paroxetine were 102 mg/day +/- 44 mg, and 36 mg/day +/-13 mg, respectively. More patients in the fluvoxamine group than the paroxetine group required the maximum permitted dosage for optimal efficacy (53% vs. 33%). In the fluoxetine comparison trial, fluvoxamine was initiated at 50 mg/day and increased to 100 mg/day after 1 week, while the fluoxetine dose was maintained at 20 mg/day. After 2 weeks, significantly more patients in the fluvoxamine group were responders than in the fluoxetine group (29% vs. 16%); however, at study end, the percentage of responders was similar (about 60%). In a 48-month comparison of recurrence rates between sertraline and fluvoxamine, the recurrence rates over the 48-month period were similar (31.2% vs. 34.3%, respectively).
For the treatment of bulimia nervosa*:
Oral dosage (immediate-release tablets):
Adults: Initially, 50 mg PO at bedtime for 4-7 days, then titrate by 25-50 mg/dose every 4-7 days as needed until therapeutic response is reached; usual dose is 50-200 mg/day in single or divided doses for 4-12 weeks. Give total daily doses > 100 mg/day in divided doses; if the doses are unequal, give the larger dose at bedtime. Limited data exist with mixed clinical efficacy results. Some data indicate a high placebo response rate; other data indicate a statistically significant reduction in binge-eating and purging episodes relative to placebo.
For the treatment of separation anxiety disorder*:
Oral dosage (immediate-release tablets):
Children and Adolescents 6 years and older: Initiate at a low dose (e.g., 25 mg/day PO at bedtime) to minimize side effects. In one short-term, placebo-controlled study (n = 128) including pediatric patients with social phobia, separation anxiety, and/or generalized anxiety disorder, fluvoxamine was titrated by 50 mg/week to an effective dose. The average dose of all participants (6 to 17 years of age) was 2.9 mg/kg/day +/- 1.3 PO. Max (12 years and older): 300 mg/day PO. Max (6 to 11 years): 250 mg/day PO. The fluvoxamine group had a greater mean decrease in anxiety symptoms than those receiving placebo (p < 0.001). Significant differences were observed by week 3 and increased through week 6. On the CGI-Improvement scale, 76% of fluvoxamine-treated participants had a response compared to 29% of those receiving placebo (p < 0.001). Effectiveness was sustained in an open-label 6-month follow up study. Periodically reassess to determine the need for ongoing treatment.
Maximum Dosage Limits:
-Adults
300 mg/day PO.
-Geriatric
300 mg/day PO; however, lower dosages are effective and may be better tolerated due to decreased drug clearance.
-Adolescents
300 mg/day PO. Safety and efficacy of extended-release capsules have not been established.
-Children
12 years: 300 mg/day PO.
8 to 11 years: 200 mg/day PO for OCD; doses up to 250 mg/day PO have been used off-label for anxiety disorders.
6 to 7 years: Safety and efficacy have not been established; however, doses up to 250 mg/day PO have been used off-label for anxiety disorders. Do not use extended-release capsules.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Because fluvoxamine is significantly metabolized in the liver, a lower initial dose and a slower rate of upward dosage titration are advisable; however, quantitative guidelines are not available.
Patients with Renal Impairment Dosing
CrCl more than 45 mL/minute: No dosage adjustment needed.
CrCl 5 to 45 mL/minute: No accumulation occurs and no dosage adjustments are needed.
CrCl less than 5 mL/minute: Specific guidelines are not available; it appears that no dosage adjustments are needed.
Intermittent hemodialysis
Specific guidelines for fluvoxamine dosage adjustments are not available; it appears that no dosage adjustments are needed. Fluvoxamine is unlikely to be removed by hemodialysis given its extensive tissue distribution.
*non-FDA-approved indication
Abciximab: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor closely for signs and symptoms of bleeding.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with fluvoxamine is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Abiraterone: (Moderate) Monitor for an increase in fluvoxamine-related adverse reactions if coadministration with abiraterone is necessary. Fluvoxamine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. While none of the drugs studied for interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study in CYP2D6 poor metabolizers (PM) demonstrated altered pharmacokinetic properties compared to extensive metabolizers (EM), with the Cmax, AUC, and half-life of fluvoxamine increased by 52%, 200%, and 62%, respectively. The manufacturer recommends caution in patients receiving concomitant drugs known to inhibit CYP2D6.
Abrocitinib: (Major) Do not exceed an initial abrocitinib dose of 50 mg PO once daily or a maximum dose of 100 mg PO once daily if coadministered with fluvoxamine. Concurrent use may increase the combined exposure of abrocitinib and its 2 active metabolites; monitor closely for adverse reactions. Abrocitinib is a CYP2C19 substrate and fluvoxamine is a strong CYP2C19 inhibitor.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fluvoxamine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use of dihydrocodeine with fluvoxamine may increase dihydrocodeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fluvoxamine is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fluvoxamine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fluvoxamine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Acetaminophen; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluvoxamine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluvoxamine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Concomitant use of adagrasib and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ado-Trastuzumab emtansine: (Moderate) If coadministration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Fluvoxamine is a moderate CYP3A4 inhibitor and plasma exposure to DM1, the cytotoxic small molecule of ado-trastuzumab emtansine, may be increased. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and fluvoxamine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as fluvoxamine, may decrease systemic clearance of alfentanil leading to increased or prolonged effects.
Alfuzosin: (Moderate) Use fluvoxamine with caution in combination with alfuzosin as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering almotriptan with fluvoxamine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluvoxamine and almotriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Alosetron: (Contraindicated) The combined use of fluvoxamine and alosetron is contraindicated. Fluvoxamine has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6-fold and prolong the half-life by approximately 3-fold. Elevated serum concentrations of alosetron may result in severe constipation. Fluvoxamine is a strong inhibitor of CYP1A2 and inhibits CYP3A4 and CYP2C9. Alosetron is primarily metabolized by CYP1A2 with minor contributions from CYP3A4 and CYP2C9.
Alprazolam: (Major) Avoid coadministration of alprazolam and fluvoxamine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with fluvoxamine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with fluvoxamine increased alprazolam exposure by 1.96-fold.
Alteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Amiloride: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Amiodarone: (Major) Concomitant use of amiodarone and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other amiodarone-related adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with fluvoxamine. Amisulpride causes dose- and concentration- dependent QT prolongation. QT prolongation and TdP have been reported during fluvoxamine postmarketing use.
Amitriptyline: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as amitriptyline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, several isoenzymes have been identified in the metabolism of amitriptyline including CYP2D6 (primary), CYP2C19, CYP1A2, CYP3A4, and CYP2C9. Fluvoxamine is a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP3A4. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by the SSRI fluoxetine. Patients receiving a TCA should be monitored closely for toxicity if fluvoxamine is added.
Amlodipine: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Amlodipine; Atorvastatin: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Amlodipine; Benazepril: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Amlodipine; Celecoxib: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals. (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Amlodipine; Olmesartan: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Amlodipine; Valsartan: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals. (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Amoxicillin; Clarithromycin; Omeprazole: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
Amphetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Amphetamine; Dextroamphetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Amphetamines: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Anagrelide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and anagrelide. Coadminister with caution. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as needed. Platelet aggregation may be impaired by fluvoxamine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking fluvoxamine with an antiplatelet medication and to promptly report any bleeding events to the practitioner. Lastly, anagrelide is partially metabolized by CYP1A2, and it also has demonstrated some inhibitory activity of CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as fluvoxamine, patients should be monitored for increased adverse effects of either drug.
Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with fluvoxamine since concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of fluvoxamine with aprepitant, fosaprepitant due to the potential for substantially increased exposure of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant. Fluvoxamine is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold.
Argatroban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Aripiprazole: (Major) Concomitant use of aripiprazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients and increases aripiprazole exposure and risk for side effects. An aripiprazole dosage reduction is necessary; management recommendations vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Additionally, consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Aripiprazole is CYP2D6 and CYP3A substrate, fluvoxamine is a weak CYP2D6 and moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Moderate) Concomitant use of aripiprazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT prolongation such as fluvoxamine. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrocardiograms. Torsade de Pointes (TdP), QT prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as fluvoxamine. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, artemether and lumefantrine are CYP3A substrates and fluvoxamine is a moderate CYP3A4 inhibitor while lumefantrine is a CYP2D6 inhibitor and fluvoxamine is a CYP2D6 substrate. Concomitant use may lead to increased artemether; lumefantrine or fluvoxamine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Asenapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and asenapine. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have these effects. In addition, fluvoxamine is a potent inhibitor of CYP1A2 and a moderate CYP3A4 inhibitor and asenapine is a primary substrate of CYP1A2 with a lesser contribution by CYP3A4. Coadministration may result in increased asenapine exposure. In one trial, coadministration of fluvoxamine 25 mg twice daily resulted in a marginal increase in asenapine exposure; full therapeutic doses of fluvoxamine would be expected to further increase asenapine exposure.
Aspirin, ASA: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluvoxamine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Omeprazole: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluvoxamine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluvoxamine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Atazanavir: (Minor) Fluvoxamine is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
Atazanavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Minor) Fluvoxamine is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
Atenolol; Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Atomoxetine: (Minor) Coadminister atomoxetine and fluvoxamine with caution as concurrent use may increase the risk of QT prolongation. There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of these medications. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. QT prolongation and TdP have been reported during post-marketing use of fluvoxamine.
Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including fluvoxamine, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Avapritinib: (Major) Avoid coadministration of avapritinib with fluvoxamine due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Azilsartan; Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Azithromycin: (Major) Avoid coadministration of azithromycin with fluvoxamine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. QT prolongation and TdP have been reported during fluvoxamine postmarketing use.
Bedaquiline: (Major) Coadministration of fluvoxamine and bedaquiline may result in additive or synergistic prolongation of the QT interval. Coadminister with caution. Bedaquiline has been reported to prolong the QT interval. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluvoxamine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluvoxamine is a CYP2C19 inhibitor.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Bendamustine: (Major) Consider the use of an alternative therapy if fluvoxamine treatment is needed in patients receiving bendamustine. Fluvoxamine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and fluvoxamine is a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with fluvoxamine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of fluvoxamine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Fluvoxamine is an inhibitor of CYP3A4. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and fluvoxamine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with IV methylene blue, fluvoxamine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of methylene blue. MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Benzphetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Bivalirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluvoxamine is a moderate inhibitor of both CYP2C9 and CYP3A4 pathways. Concomitant therapy with fluvoxamine may increase the plasma concentrations of bosentan. Monitor for potential adverse effects of bosentan during coadministration; excessive dosage may result in hypotension or elevated hepatic enzymes.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Fluvoxamine is a moderate inhibitor of CYP3A4. If fluvoxamine is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with fluvoxamine if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of fluvoxamine, resume the brigatinib dose that was tolerated prior to initiation of fluvoxamine. Brigatinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, limit the dose of bromocriptine (Cycloset) to 1.6 mg/day during coadministration of moderate CYP3A4 inhibitors such as fluvoxamine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and fluvoxamine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and fluvoxamine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and fluvoxamine if possible due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bumetanide: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluvoxamine increases lidocaine exposure by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine plasma clearance is decreased by 41% to 60% and the mean half-life prolonged by 1 hour when used in combination with fluvoxamine. Lidocaine is a CYP1A2 and CYP3A4 substrate; fluvoxamine inhibits both of these hepatic isoenzymes. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluvoxamine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Buprenorphine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome during concurrent use of fluvoxamine and buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as fluvoxamine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a moderate CYP3A4 inhibitor such as fluvoxamine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If coadministration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Buprenorphine; Naloxone: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome during concurrent use of fluvoxamine and buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as fluvoxamine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a moderate CYP3A4 inhibitor such as fluvoxamine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If coadministration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Bupropion: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluvoxamine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion.
Bupropion; Naltrexone: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluvoxamine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion.
Buspirone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering buspirone and fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Butalbital; Acetaminophen; Caffeine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Cabotegravir; Rilpivirine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Caffeine: (Moderate) Inhibitors of CYP1A2, such as fluvoxamine, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced. (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Caffeine; Sodium Benzoate: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Cangrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cangrelor). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Capivasertib: (Major) Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off if coadministration with fluvoxamine is necessary; monitor for adverse reactions. Concomitant use may increase capivasertib exposure which may increase the risk for capivasertib-related adverse effects. Capivasertib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.5-fold.
Capsaicin; Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Carbamazepine: (Moderate) Carbamazepine is metabolized by CYP3A4 and fluvoxamine is known to inhibit this enzyme. Serum carbamazepine concentrations should be monitored closely if fluvoxamine is added during carbamazepine therapy. It may be necessary to reduce the dose of carbamazepine in this situation. At least one case is noted where carbamazepine serum concentrations increased substantially when fluvoxamine was added, accompanied by signs of carbamazepine toxicity.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluvoxamine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Celecoxib; Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluvoxamine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ceritinib: (Major) Avoid coadministration of ceritinib with fluvoxamine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during postmarketing experience with fluvoxamine.
Chlordiazepoxide: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation, including chlordiazepoxide.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as amitriptyline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, several isoenzymes have been identified in the metabolism of amitriptyline including CYP2D6 (primary), CYP2C19, CYP1A2, CYP3A4, and CYP2C9. Fluvoxamine is a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP3A4. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by the SSRI fluoxetine. Patients receiving a TCA should be monitored closely for toxicity if fluvoxamine is added. (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation, including chlordiazepoxide.
Chlordiazepoxide; Clidinium: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation, including chlordiazepoxide.
Chloroquine: (Major) Avoid coadministration of chloroquine with fluvoxamine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. QT prolongation and TdP has been reported during fluvoxamine postmarketing use.
Chlorothiazide: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Chlorpheniramine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fluvoxamine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fluvoxamine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Chlorpromazine: (Major) Coadministration may increase the risk of QT prolongation, torsade de pointes (TdP), and elevated chlorpromazine concentrations. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a mild inhibitor of CYP2D6, the primary isoenzyme responsible for the metabolism of chlorpromazine. Decreased metabolism of chlorpromazine may lead to clinically important adverse reactions such as QT prolongation or TdP. Serum concentrations of thioridazine, a phenothiazine that is also highly dependent on CYP2D6 for its metabolism, increased three-fold during coadministration with fluvoxamine.
Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Cilostazol: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with fluvoxamine. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; fluvoxamine is a moderate inhibitor of CYP3A4. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased cilostazol Cmax by 94% and AUC by 117%.
Cimetidine: (Moderate) Cimetidine may inhibit the metabolism of fluvoxamine.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of cisapride and fluvoxamine is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, cisapride is metabolized by CYP3A4 and fluvoxamine is a moderate CYP3A4 inhibitor. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported when inhibitors of CYP3A4 are coadministered with cisapride.
Citalopram: (Contraindicated) Due to the similarity in pharmacology of citalopram and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, QT prolongation, and torsade de pointes (TdP), these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both citalopram and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Clarithromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Clobazam: (Moderate) A dosage reduction of clobazam and/or fluvoxamine may be necessary during co-administration of clobazam and fluvoxamine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluvoxamine is a potent inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluvoxamine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam.
Clofazimine: (Moderate) Concomitant use of clofazimine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clomipramine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as clomipramine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, clomipramine is a primary substrate of CYP2D6 with a lesser contribution by CYP1A2. Fluvoxamine is a potent CYP1A2 inhibitor and a mild CYP2D6 inhibitor. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving clomipramine should be monitored closely for toxicity if fluvoxamine is added.
Clonazepam: (Moderate) Clonazepam is a substrate of CYP3A4. In theory, co-administration of clonazepam and a potent CYP3A4 inhibitor, such as fluvoxamine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. Fluoxetine, another CYP3A4 inhibitor, does not affect the pharmacokinetics of clonazepam. Monitor patients closely for excessive clonazepam side effects, including changes in psychomotor performance and sedation.
Clopidogrel: (Major) Consider an alternative antidepressant to fluvoxamine if possible in patients receiving clopidogrel. If coadministration is necessary, monitor patients for reduced clopidogrel effectiveness and signs and symptoms of bleeding. Fluvoxamine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. Additionally, selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Clorazepate: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation, including clorazepate.
Clozapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clozapine. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death, especially at high dosages. In addition, if coadministration of clozapine and a potent inhibitor of CYP1A2 such as fluvoxamine is necessary, the manufacturer of clozapine recommends using one-third of the usual clozapine dose. If the inhibitor is discontinued, increase the clozapine dose based on clinical response. In one study, the mean concentrations of clozapine and its metabolites were increased about 3-fold compared to baseline values. Up to a 10-fold increase in plasma concentrations of clozapine and its metabolites have been noted in other evaluations. Fluvoxamine is also a moderate CYP3A4 inhibitor and a mild CYP2D6 inhibitor. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP3A4, or CYP2D6 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects.
Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cobimetinib: (Major) When a patient taking full dose cobimetinib receives a moderate inhibitor of CYP3A4 for 14 days or less, reduce cobimetinib to 20 mg; resume 60 mg when the inhibitor is discontinued. Do not use a moderate CYP3A4 inhibitor, such as fluvoxamine, in patients receiving a reduced dose of cobimetinib.
Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as SSRIs, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. Additionally, citalopram causes dose-dependent QT interval prolongation. Local anesthetics (e.g., cocaine) are associated with a possible risk for QT prolongation and according to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Guaifenesin: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Phenylephrine; Promethazine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Concomitant use of promethazine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use of codeine with fluvoxamine may increase codeine plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Concomitant use of promethazine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Colchicine: (Major) Avoid concomitant use of colchicine and fluvoxamine due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Coadministration of medroxyprogesterone, a CYP3A substrate, with fluvoxamine, a moderate CYP3A inhibitor, may result in an increase in concentrations of medroxyprogesterone. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via CYP3A4 in vitro.
Crizotinib: (Major) Avoid coadministration of crizotinib with fluvoxamine due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions; also, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Fluvoxamine is a moderate CYP3A4 inhibitor that has had postmarketing reports of QT prolongation and torsade de pointes (TdP).
Cyclobenzaprine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of cyclobenzaprine with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
Cyclosporine: (Moderate) Fluvoxamine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity or require the downward dosage adjustment of cyclosporine. Until more data are available, cyclosporine concentrations should be monitored very carefully any time fluvoxamine is prescribed.
Cyproheptadine: (Moderate) Cyproheptadine is a serotonin antagonist in the CNS and can oppose the pharmacologic actions of selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine.
Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dalteparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and fluvoxamine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as fluvoxamine.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with fluvoxamine. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Dasatinib: (Moderate) Use dasatinib with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with fluvoxamine. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; fluvoxamine is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving fluvoxamine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Desflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Desipramine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as desipramine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, several isoenzymes have been identified in the metabolism of desipramine including CYP2D6 (primary), CYP2C19 (primary), CYP3A4, and CYP2C9. Fluvoxamine is a strong inhibitor of CYP2C19 and a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
Desmopressin: (Minor) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia, which may include monitoring serum sodium or electrolytes periodically. Ensure the patient is compliant with fluid restrictions and intake.
Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like desvenlafaxine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Discontinuation symptoms have been reported when switching from other antidepressants to desvenlafaxine. It may be advisable to taper the previous antidepressant to minimize discontinuation symptoms.
Deutetrabenazine: (Minor) Use fluvoxamine with caution in combination with deutetrabenazine. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine postmarketing use. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dexlansoprazole: (Moderate) Fluvoxamine is a major inhibitor of the cytochrome P450 enzyme (CYP) 2C19. Several proton pump inhibitors (PPIs), including dexlansoprazole, are primary substrates of the CYP2C19 enzyme. Reduced metabolism and resulting elevated plasma concentrations of these PPIs may occur if combined with fluvoxamine. A single-dose pharmacokinetic study has shown that the mean AUC of omeprazole 40 mg was increased 2- to 6-fold when given after fluvoxamine 50 mg/day for 6 days. Monitor patients for PPI toxicity, such as headache or GI distress if these drugs are combined.
Dexmedetomidine: (Minor) QT/QTc prolongation can occur with concomitant use of dexmedetomidine and fluvoxamine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Dexmethylphenidate: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Dextroamphetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluvoxamine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Quinidine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or elevated plasma concentrations of either quinidine or fluvoxamine during coadministration. Quinidine administration is associated with QT prolongation and TdP. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate CYP3A4 inhibitor and the metabolism of CYP3A4 substrates such as quinidine may be reduced. In a small open-label study (n = 6), fluvoxamine 100 mg/day decreased the total oral clearance of quinidine by 29%. Conversely, quinidine is a CYP2D6 inhibitor and CYP2D6 is partially responsible for fluvoxamine metabolism, which may lead to elevated fluvoxamine concentrations. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Diazepam: (Major) Fluvoxamine decreases the oxidative hepatic metabolism of diazepam. Diazepam is metabolized by CYP2C19 and CYP3A4 and fluvoxamine inhibits these CYP isoenzymes and appears to have a significant effect on diazepam exposure, clearance, and elimination half-life. Monitor the patient closely for sedation, CNS depression, and prolonged benzodiazepine effects. Dose reduction may be necessary. In a study with healthy volunteers, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/mL, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (significant difference, p less than 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p less than 0.01). N-Desmethyldiazepam AUC values were also significantly increased. These data suggest the interaction is likely to have clinical significance.
Diclofenac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diclofenac; Misoprostol: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diflunisal: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, serotonin syndrome, and symptoms of serotonin excess, such as weakness, hyperreflexia, and incoordination, during concomitant use of ergotamine and fluvoxamine. Concomitant use may increase ergotamine exposure and both medications enhance serotonergic activity. Ergotamine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Diltiazem: (Moderate) Fluvoxamine may decrease the clearance of calcium-channel blockers, including diltiazem, via inhibition of CYP3A4 metabolism. Bradycardia has been reported when fluvoxamine has been added to a stable diltiazem regimen.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diphenhydramine; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Disopyramide: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or elevated disopyramide concentrations during concurrent use of fluvoxamine and disopyramide. Disopyramide is associated with QT prolongation and TdP. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, CYP3A4 inhibitors such as fluvoxamine may increase plasma concentrations of disopyramide, a CYP3A4 substrate. Caution should be used when CYP3A4 inhibitors are coadministered with disopyramide; monitor clinical response and serum disopyramide concentrations.
Diuretics: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Docetaxel: (Minor) Docetaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit CYP3A enzymes, such as fluvoxamine, can significantly reduce the metabolism of docetaxel. Use docetaxel cautiously when administered concurrently with inhibitors of CYP3A enzymes.
Dofetilide: (Major) Coadministration of dofetilide and fluvoxamine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have also been reported during fluvoxamine postmarketing use. Additionally, fluvoxamine is also an inhibitor of CYP3A4, which could increase dofetilide exposure, further increasing the risk of cardiac events.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation; the risk of serotonin syndrome may also increase. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. If serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
Dolutegravir; Rilpivirine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Donepezil: (Moderate) Use donepezil with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Doxepin: (Moderate) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as doxepin may increase the risk of serotonin syndrome. In addition, doxepin is a primary substrate of CYP2C19 and CYP2D6, and is metabolized to a lesser extent by CYP1A2 and CYP2C9. Fluvoxamine is a strong inhibitor of CYP2C19 and CYP1A2 and a mild inhibitor of CYP2D6. Increased doxepin exposure is possible. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome or doxepin-related side effects, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of fluvoxamine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluvoxamine is a CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of fluvoxamine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Fluvoxamine is a CYP3A4 inhibitor, and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) Use caution if coadministration of dronabinol with fluvoxamine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fluvoxamine is a moderate inhibitor of CYP3A4 and a weak CYP2C9 inhibitor. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of dronedarone and fluvoxamine is contraindicated. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is about 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, dronedarone is metabolized by CYP3A and fluvoxamine is a moderate inhibitor of CYP3A4. Concomitant use of dronedarone with fluvoxamine may increase dronedarone concentrations.
Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as fluvoxamine. If coadministration cannot be avoided, use extreme caution. Initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Drospirenone: (Minor) Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors, such as fluvoxamine, are coadministered with drospirenone; estradiol. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Estetrol: (Minor) Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors, such as fluvoxamine, are coadministered with drospirenone; estradiol. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Estradiol: (Minor) Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors, such as fluvoxamine, are coadministered with drospirenone; estradiol. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Ethinyl Estradiol: (Minor) Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors, such as fluvoxamine, are coadministered with drospirenone; estradiol. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take CYP3A4 inhibitors long-term and concomitantly.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when CYP3A4 inhibitors, such as fluvoxamine, are coadministered with drospirenone; estradiol. In addition, drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take CYP3A4 inhibitors long-term and concomitantly.
Duloxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, when fluvoxamine, a potent CYP1A2 inhibitor, was coadministered with duloxetine to male subjects (n=14) the duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine half-life was increased approximately 3-fold. The increased duloxetine exposure induced by fluvoxamine would potentially increase the risk of serotonin-related adverse effects; therefore, the manufacturer recommends avoiding concurrent use of these agents.
Dutasteride; Tamsulosin: (Moderate) Tamsulosin should be used with caution in combination with moderate inhibitors of CYP3A4 such as fluvoxamine. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are responsible for the extensive metabolism of tamsulosin. Strong inhibitors of CYP3A4 are known to increase the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. No studies have been performed with moderate CYP3A4 inhibitors. As with other alpha adrenergic blocking agents there is a potential risk of syncope with tamsulosin, particularly if serum concentrations are elevated. Monitor blood pressure and observe for symptoms of orthostasis.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib if coadministered with fluvoxamine. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; fluvoxamine is a moderate CYP3A inhibitor.
Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with fluvoxamine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been reported with the use of efavirenz. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with fluvoxamine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been reported with the use of efavirenz. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with fluvoxamine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been reported with the use of efavirenz. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Elacestrant: (Major) Avoid concomitant use of elacestrant and fluvoxamine due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with fluvoxamine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluvoxamine is a moderate inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering eletriptan with fluvoxamine; eletriptan exposure may also increase. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluvoxamine and eletriptan and initiate symptomatic treatment if serotonin syndrome occurs. Eletriptan is a substrate for CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with fluvoxamine; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); fluvoxamine is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with fluvoxamine; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; fluvoxamine is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) Fluvoxamine is a moderate CYP3A4 inhibitor and the manufacturer of eliglustat recommends against use with moderate CYP3A4 inhibitors due to the potential for increased eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 poor and intermediate metabolizers because a larger portion of the eliglustat dose is metabolized via CYP3A. In addition, QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine which may further increase the risk of QT prolongation with eliglustat. Because eliglustat is a CYP2D6 inhibitor, coadministration with CYP2D6 substrates such as fluvoxamine may result in increased concentrations of the concomitant drug. If combination therapy cannot be avoided, monitor patients closely for adverse events, and use the lowest effective dosages of each drug.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inhibitors of CYP1A2, such as fluvoxamine, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Encorafenib: (Major) Avoid concomitant use of encorafenib with fluvoxamine due to the risk for increased encorafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Encorafenib is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Enoxaparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Entrectinib: (Major) Avoid concomitant use of entrectinib with fluvoxamine due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, fluvoxamine is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Fluvoxamine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Eptifibatide: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Ergoloid Mesylates: (Minor) Monitor for symptoms of serotonergic toxicity during concomitant use of ergoloid mesylates (co-dergocrine mesylate) and a selective serotonin reuptake inhibitor (SSRI). Serotonin receptor agonist and antagonist activity has been observed with ergoloid mesylates. Concomitant use may increase the risk for serotonin syndrome in some patients.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, serotonin syndrome, and symptoms of serotonin excess, such as weakness, hyperreflexia, and incoordination, during concomitant use of ergotamine and fluvoxamine. Concomitant use may increase ergotamine exposure and both medications enhance serotonergic activity. Ergotamine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, serotonin syndrome, and symptoms of serotonin excess, such as weakness, hyperreflexia, and incoordination, during concomitant use of ergotamine and fluvoxamine. Concomitant use may increase ergotamine exposure and both medications enhance serotonergic activity. Ergotamine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Eribulin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and eribulin. Eribulin has been associated with QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. If eribulin and fluvoxamine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Erlotinib: (Major) Avoid coadministration of erlotinib with fluvoxamine if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Fluvoxamine is a CYP3A4 and CYP1A2 inhibitor. Coadministration with another moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
Erythromycin: (Major) Concomitant use of erythromycin and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Due to the similarity in pharmacology of fluvoxamine and escitalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluvoxamine and escitalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Esomeprazole: (Minor) Fluvoxamine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
Estazolam: (Moderate) In patients receiving moderate CYP3A4 inhibitors, such as fluvoxamine, estazolam should be used with caution and with consideration of appropriate dosage reduction. Monitor for excessive sedation or next-day drowsiness. The metabolism of estazolam to the major circulating metabolite 4-hydroxy-estazolam is catalyzed by CYP3A. Fluvoxamine may inhibit the oxidative metabolism of estazolam to some extent, and has been shown to increase the exposure to other benzodiazepines metabolized by the CYP450 system.
Ethacrynic Acid: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Ethanol: (Major) As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine. Studies involving single 40 gram doses of alcohol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine (50 mg twice daily) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. Multiple doses have not been studied. It is possible that ethanol may adversely affect mood or behavior.
Etodolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Etonogestrel: (Minor) Co-administration of etonogestrel and moderate CYP3A4 inhibitors, such as fluvoxamine, may increase the serum concentrations of progestins, including etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Minor) Co-administration of etonogestrel and moderate CYP3A4 inhibitors, such as fluvoxamine, may increase the serum concentrations of progestins, including etonogestrel.
Etrasimod: (Major) Avoid concomitant use of etrasimod and fluvoxamine in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluvoxamine is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Coadministration of fluvoxamine (CYP3A4 inhibitor) and simvastatin (CYP3A4 substrate) would be expected to result in an increase in simvastatin serum concentrations. Elevation of simvastatin serum concentrations can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Monitor patients receiving concomitant simvastatin and fluvoxamine closely for muscle pain or weakness.
Fedratinib: (Moderate) Closely monitor for an increase in fedratinib-related adverse effects if coadministered with fluvoxamine. Coadministration may increase fedratinib exposure. Fedratinib is a CYP3A and CYP2C19 substrate; fluvoxamine is an inhibitor of both CYP3A and CYP2C19. Coadministration with another dual CYP3A and CYP2C19 inhibitor increased fedratinib exposure by approximately 1.5-fold at steady-state.
Felodipine: (Moderate) Fluvoxamine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism. Caution should be used when CYP3A4 inhibitors are co-administered with felodipine; a conservative approach to dosing felodipine should be taken.
Fenfluramine: (Major) Concomitant use of fenfluramine and fluvoxamine may increase fenfluramine plasma concentrations and the risk of adverse reactions, including serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary. If concomitant use is unavoidable, do not exceed a maximum dose of fenfluramine 20 mg/day PO if coadministered with fluvoxamine and 17 mg/day PO if patient is also receiving stiripentol plus clobazam. Fenfluramine is a CYP1A2 substrate and fluvoxamine is a strong CYP1A2 inhibitor. Coadministration with fluvoxamine increased fenfluramine overall exposure by 102% and decreased norfenfluramine overall exposure by 22%.
Fenoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fluvoxamine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexinidazole: (Major) Concomitant use of fexinidazole and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and fluvoxamine is a moderate CYP3A inhibitor.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and fluvoxamine is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; fluvoxamine is a strong CYP1A2 inhibitor. Concomitant use increased fezolinetant overall exposure by 840%.
Finasteride; Tadalafil: (Major) Avoid coadministration of fluvoxamine and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72 hours of fluvoxamine for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as fluvoxamine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or fluvoxamine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with fluvoxamine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Flecainide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and flecainide. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and fluvoxamine is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of fluvoxamine, start flibanserin at least 2 weeks after the last dose of fluvoxamine. If initiating fluvoxamine following flibanserin use, start fluvoxamine at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
Fluconazole: (Minor) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluconazole and fluvoxamine. Fluconazole has been associated with QT prolongation and rare cases of TdP. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Fluoxetine: (Major) Due to the similarity in pharmacology of fluoxetine and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Fluphenazine: (Minor) Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of fluvoxamine and fluphenazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Fluphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Flurazepam: (Moderate) In patients receiving moderate CYP3A4 inhibitors, such as fluvoxamine, flurazepam should be used with caution and with consideration of appropriate dosage reduction. Monitor for excessive sedation or next-day drowsiness. The metabolism of flurazepam to the major active metabolites N-desalkylflurazepam and N-1-hydroxyethylflurazepam appears to be catalyzed by CYP3A. Fluvoxamine may inhibit the oxidative metabolism of flurazepam to some extent, and has been shown to increase the exposure to other benzodiazepines metabolized by the CYP450 system.
Flurbiprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluvoxamine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Food: (Major) Use together is not recommended; advise patients not to use cannabis without the advice of their health care professional. Cannabis smoking induces CYP1A2 through activation of the aromatic hydrocarbon receptor, in a manner that is similar to tobacco smoking, which is known to increase fluvoxamine elimination by about 25%. Fluvoxamine is an inhibitor of CYP2C9 and CYP3A4, 2 isoenzymes responsible for the metabolism of cannabis's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). Of the over 70 phytocannabinoids in cannabis, delta-9-tetrahydrocannabinol (9THC), cannabidiol (CBD) and cannibinol are the 3 main constituents, regardless of the route of administration (e.g., inhaled, ingested). Any changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered cannabis effect profile. In addition, the additive pharmacodynamic effects of these 2 agents have not been studied and there may be additive effects on CNS function.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with fluvoxamine. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Foscarnet: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and foscarnet. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet. Because of these reports, avoid the use of foscarnet with other drugs known to prolong the QT interval. If coadministration is necessary, monitor ECG and serum electrolytes.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Fosphenytoin: (Major) Hydantoin anticonvulsant clearance can be decreased by drugs that inhibit the cytochrome P450 2C subset of isoenzymes, including fluvoxamine. Phenytoin, ethotoin or fosphenytoin dosage adjustments may be necessary in some patients who receive fluvoxamine concurrently; monitor for signs of hydantoin toxicity.
Fostemsavir: (Moderate) Use fluvoxamine and fostemsavir together with caution due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Furosemide: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Gemifloxacin: (Moderate) Use fluvoxamine with caution in combination with gemifloxacin as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and fluvoxamine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use.
Gilteritinib: (Major) Avoid coadministration of fluvoxamine with gilteritinib if possible due to the potential for decreased response to fluvoxamine and additive QT prolongation. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluvoxamine that target these receptors. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
Glasdegib: (Major) Avoid coadministration of glasdegib with fluvoxamine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Glimepiride: (Moderate) Fluvoxamine should be used cautiously with glimepiride. The combination of fluvoxamine and glimepiride has resulted in a 43% increase in glimepiride peak plasma concentrations and an increase in glimepiride half-life in healthy volunteers; blood glucose response may be altered in diabetic patients. The mechanism of this interaction is unclear. Blood glucose concentrations should be monitored during coadministration of fluvoxamine.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
Granisetron: (Moderate) Use granisetron with caution in combination with fluvoxamine due to increased the risk of serotonin syndrome, QT prolongation, and torsade de pointes. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Granisetron has been associated with QT prolongation.
Grapefruit juice: (Moderate) Patients who are stabilized on a fluvoxamine regimen should not significantly alter their consumption of grapefruit juice and patients starting fluvoxamine should limit or avoid grapefruit juice intake. The mean peak and AUC of fluvoxamine were increased in a study where patients were given grapefruit juice 3 times a day for 5 days prior to receiving fluvoxamine. Altered P-glycoprotein-mediated transport, initiated by grapefruit juice, is the suspected mechanism of action. Sporadic case reports of this potential interaction have appeared in the literature.
Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Caffeine is a substrate of CYP1A2. Fluvoxamine is a strong CYP1A2 inhibitor and it reduces hepatic oxidative metabolism of caffeine. In patients who complain of caffeine related side effects, the ingestion of caffeine containing products such as green tea may need to be reduced.
Guanfacine: (Major) Fluvoxamine may significantly increase plasma concentrations of guanfacine, a primary CYP3A4 substrate. FDA-approved labeling for extended-release (ER) guanfacine recommends that if taken with a moderate CYP3A4 inhibitor, such as fluvoxamine, the guanfacine dosage be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If fluvoxamine is discontinued, the guanfacine ER dosage should be increased back to the recommended dose.
Halogenated Anesthetics: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Haloperidol: (Moderate) Use fluvoxamine with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. Fluvoxamine is a moderate CYP3A4 inhibitor that has been associated with a risk of QT prolongation and torsade de pointes (TdP). Haloperidol is a CYP3A4 substrate; QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fluvoxamine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fluvoxamine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fluvoxamine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fluvoxamine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fluvoxamine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fluvoxamine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with IV methylene blue, fluvoxamine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of methylene blue. MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Ibrutinib: (Major) If ibrutinib is coadministered with fluvoxamine, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluvoxamine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Famotidine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluvoxamine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluvoxamine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibutilide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and ibutilide. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Ibutilide can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluvoxamine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated iloperidone concentrations during concurrent use of fluvoxamine and iloperidone. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. According to the manufacturer of iloperidone, the drug should be avoided in combination with other agents also known to have this effect. In addition, fluvoxamine is a moderate CYP3A4 inhibitor, which may result in decreased clearance of CYP3A4 substrates including iloperidone. Decreased metabolism of iloperidone may lead to clinically important adverse reactions such as extrapyramidal symptoms, QT prolongation, and TdP.
Imipramine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as imipramine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, imipramine is a primary substrate of CYP2D6, and is metabolized to a lesser extent by CYP3A4, CYP2C9, and CYP2C19. Fluvoxamine is a strong inhibitor of CYP2C19 and CYP1A2, a moderate inhibitor of CYP3A4, and a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
Indapamide: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Indomethacin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Infigratinib: (Major) Avoid concomitant use of infigratinib and fluvoxamine. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with fluvoxamine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Inotuzumab has been associated with QT prolongation. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment.
Iobenguane I 123: (Major) Discontinue medications that decrease norepinephrine uptake, such as selective serotonin reuptake inhibitors (SSRIs), for at least 5 biological half-lives prior to iobenguane I 123 administration. Consider medication tapering or additional supportive therapy as appropriate to minimize the risk for precipitating SSRI withdrawal symptoms. Medications that decrease the uptake of norepinephrine can cause false negative imaging results. Increasing the dose of iobenguane I 123 will not overcome any potential uptake limiting effect of this medication.
Ioflupane I 123: (Moderate) Selective serotonin reuptake inhibitors (SSRIs) may interfere with dopamine transporter (DAT) imaging that utilizes radiolabeled ioflupane. Observed changes in striatal tracer binding have generally been small and inconsistent. These changes are unlikely to affect the interpretation of visual assessments in routine clinical practice but may be relevant in the research setting.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with fluvoxamine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; fluvoxamine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Isoflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Isoniazid, INH: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isradipine: (Moderate) Caution should be used when CYP3A4 inhibitors, such as fluvoxamine, are co-administered with calcium-channel blockers, CYP3A4 substrates.
Itraconazole: (Moderate) Use caution as there may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and itraconazole. Itraconazole has been associated with prolongation of the QT interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Ivabradine: (Moderate) Coadministration may increase the plasma concentrations of ivabradine, potentially increasing the risk for bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and fluvoxamine is a moderate CYP3A4 inhibitor.
Ivacaftor: (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with fluvoxamine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Fluvoxamine is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of fluvoxamine is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluvoxamine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Ketoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ketorolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Lansoprazole: (Moderate) Fluvoxamine is a major inhibitor of the cytochrome P450 enzyme 2C19. Several proton pump inhibitors, including lansoprazole, are primary substrates of the CYP2C19 enzyme. Reduced metabolism and resulting elevated plasma concentrations of these PPIs may occur if combined with fluvoxamine. Monitor patients for PPI toxicity, such as headache or GI distress if these drugs are combined.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. (Moderate) Fluvoxamine is a major inhibitor of the cytochrome P450 enzyme 2C19. Several proton pump inhibitors, including lansoprazole, are primary substrates of the CYP2C19 enzyme. Reduced metabolism and resulting elevated plasma concentrations of these PPIs may occur if combined with fluvoxamine. Monitor patients for PPI toxicity, such as headache or GI distress if these drugs are combined.
Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with fluvoxamine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. QT prolongation and TdP have also been reported during fluvoxamine post-marketing use.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with fluvoxamine is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and selective serotonin reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Lefamulin: (Major) Avoid coadministration of lefamulin with fluvoxamine as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fluvoxamine is a moderate CYP3A4 that has been associated with QT prolongation and torsade de pointes (TdP) during postmarketing use.
Lemborexant: (Major) Avoid coadministration of lemborexant and fluvoxamine as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; fluvoxamine maleate is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with fluvoxamine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported during fluvoxamine in postmarketing experience.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
Levamlodipine: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluvoxamine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluvoxamine increases lidocaine exposure by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine plasma clearance is decreased by 41% to 60% and the mean half-life prolonged by 1 hour when used in combination with fluvoxamine. Lidocaine is a CYP1A2 and CYP3A4 substrate; fluvoxamine inhibits both of these hepatic isoenzymes.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and fluvoxamine increases lidocaine exposure by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine plasma clearance is decreased by 41% to 60% and the mean half-life prolonged by 1 hour when used in combination with fluvoxamine. Lidocaine is a CYP1A2 and CYP3A4 substrate; fluvoxamine inhibits both of these hepatic isoenzymes.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and fluvoxamine increases lidocaine exposure by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine plasma clearance is decreased by 41% to 60% and the mean half-life prolonged by 1 hour when used in combination with fluvoxamine. Lidocaine is a CYP1A2 and CYP3A4 substrate; fluvoxamine inhibits both of these hepatic isoenzymes.
Linezolid: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with linezolid, fluvoxamine should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with fluvoxamine can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
Lisdexamfetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Lithium: (Moderate) Concomitant use of fluvoxamine and lithium may increase the risk of serotonin syndrome and QT prolongation. Lithium has been associated with QT prolongation and there are reports of QT prolongation and TdP during postmarketing use of fluvoxamine. Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has central serotonin-enhancing effects and may increase the risk of serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine. Inform patients of the possible increased risk and monitor for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and symptomatic treatment should be initiated.
Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with fluvoxamine due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. QT prolongation and TdP have been reported during fluvoxamine postmarketing use.
Lomitapide: (Contraindicated) Concomitant use of lomitapide, a CYP3A4 substrate, and moderate inhibitors of CYP3A4, such as fluvoxamine, is contraindicated due to the potential for lomitapide toxicity.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and fluvoxamine is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and CYP2C9 substrate; fluvoxamine is a moderate CYP3A4 inhibitor and a weak CYP2C9 inhibitor.
Loperamide: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Loperamide; Simethicone: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and loperamide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with fluvoxamine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported with postmarketing use of fluvoxamine. (Moderate) Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of one or both drugs. Fluvoxamine is partially metabolized by CYP2D6 and ritonavir is a weak CYP2D6 inhibitor. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Losartan: (Moderate) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluvoxamine, have the potential to inhibit the conversion of losartan, a prodrug, to its active metabolite. No specific management recommendations are currently available. Monitor therapeutic response to individualize losartan dosage to desired blood pressure or other therapeutic goals.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluvoxamine, have the potential to inhibit the conversion of losartan, a prodrug, to its active metabolite. No specific management recommendations are currently available. Monitor therapeutic response to individualize losartan dosage to desired blood pressure or other therapeutic goals. (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Low Molecular Weight Heparins: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Lumacaftor; Ivacaftor: (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of fluvoxamine is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) Fluvoxamine is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and fluvoxamine due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as fluvoxamine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine postmarketing use.
Macitentan; Tadalafil: (Major) Avoid coadministration of fluvoxamine and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72 hours of fluvoxamine for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as fluvoxamine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Maprotiline: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and maprotiline. In addition, these medications may be duplicate treatment for some conditions. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with elevated serum concentrations from high dose therapy. Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in commonly prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT prolonging drugs. Therefore, coadministration with fluvoxamine should be avoided if possible. In addition, fluvoxamine is a CYP2D6 inhibitor and maprotiline is a substrate for CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when selective serotonin reuptake inhibitors (SSRIs) and cyclic antidepressants were used together. Patients receiving maprotiline should be monitored closely for toxicity if fluvoxamine is added.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with fluvoxamine due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and fluvoxamine is a strong CYP2C19 inhibitor and a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Meclofenamate Sodium: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Medroxyprogesterone: (Moderate) Coadministration of medroxyprogesterone, a CYP3A substrate, with fluvoxamine, a moderate CYP3A inhibitor, may result in an increase in concentrations of medroxyprogesterone. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via CYP3A4 in vitro.
Mefenamic Acid: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving fluvoxamine as concurrent use may increase the risk of QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Melatonin: (Major) Concurrent use of fluvoxamine and melatonin should be avoided if possible. Melatonin appears to be primarily metabolized by CYP1A2, with lesser contributions by CYP1A1, CYP2C9 and CYP2C19. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, and possibly a weak inhibitor of 2C9. In several healthy volunteers, fluvoxamine induced an increase in the melatonin AUC by 23-fold and peak melatonin concentrations by12-fold, respectively after the co-administration of a 5-mg melatonin dose. The interaction may increase the sedative and other CNS effects of melatonin.
Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of fluvoxamine is necessary; if fluvoxamine is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Concomitant use with fluvoxamine can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and fluvoxamine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as fluvoxamine.
Methadone: (Major) Coadministration may increase the risk of serotonin syndrome, QT prolongation, or torsade de pointes (TdP). Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although there are reports in patients receiving doses commonly used for maintenance treatment of opioid addiction. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, both fluvoxamine and methadone have central serotonergic properties and serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Lastly, fluvoxamine is a potent inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4, two of the isoenzymes responsible for the metabolism of methadone. In a small number of patients receiving methadone for opiate dependence, the addition of fluvoxamine produced a substantial increase in methadone serum concentrations. Clinical symptoms of methadone excess have resulted from concurrent use.
Methamphetamine: (Moderate) Coadministration of selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with IV methylene blue, fluvoxamine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of methylene blue. MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Methylene Blue: (Contraindicated) According to the manufacturer of fluvoxamine, treatment initiation with fluvoxamine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluvoxamine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluvoxamine and requiring urgent treatment with IV methylene blue, fluvoxamine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluvoxamine may be re-initiated 24 hours after the last dose of methylene blue. MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Methylergonovine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of methylergonovine and fluvoxamine. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Methylphenidate: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Metoclopramide: (Moderate) Concomitant use of metoclopramide and selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary. In rare cases postmarketing, NMS-like symptoms, which may overlap with serotonin syndrome symptoms, have been reported with metoclopramide when used with serotonergic agents.
Metolazone: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Metoprolol: (Moderate) Fluvoxamine may potentiate the clinical effects of metoprolol, which is suspected to be due inhibition of metoprolol metabolism via CYP2D6.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Fluvoxamine may potentiate the clinical effects of metoprolol, which is suspected to be due inhibition of metoprolol metabolism via CYP2D6. (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Metronidazole: (Moderate) Concomitant use of metronidazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mexiletine: (Major) Fluvoxamine appears to decrease the hepatic clearance of mexiletine. The mechanism of this interaction is most likely due to fluvoxamine inhibition of the CYP1A2 isoenzyme and a resultant 38% reduction in the clearance of mexiletine. If fluvoxamine and mexiletine are co-administered, serum mexiletine levels should be monitored and the patient closely observed.
Midazolam: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation like midazolam.
Midostaurin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and midostaurin. QT prolongation was reported in patients who received midostaurin in clinical trials. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Consider obtaining electrocardiograms to monitor the QT interval midostaurin is used with other drugs that prolong the QT interval.
Mifepristone: (Moderate) Coadministration of drugs that have been associated with QT prolongation, such as mifepristone and fluvoxamine, may increase the risk of QT prolongation or torsade de pointes. In addition, mifepristone is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor, which may further increase the risk of QT prolongation.
Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of milnacipran with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluvoxamine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or serotonin syndrome during concurrent use of mirtazapine and fluvoxamine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. QT prolongation and torsade de pointes have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Case reports suggest that serotonin syndrome is possible during concurrent use of mirtazapine and SSRIs. In addition, mirtazapine is a substrate for CYP2D6, CYP1A2, and CYP3A4. Increased mirtazapine serum concentrations (3 to 4 fold) have been reported following the addition of fluvoxamine, an inhibitor of CYP3A4, CYP1A2, and CYP2D6, to stable mirtazapine regimens. Patients receiving mirtazapine with fluvoxamine should be monitored for the emergence of serotonin syndrome, QT prolongation, or other adverse effects.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with fluvoxamine and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and fluvoxamine; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and fluvoxamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and fluvoxamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Moxifloxacin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and moxifloxacin. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Nabumetone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with fluvoxamine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and fluvoxamine due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of fluvoxamine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Naproxen; Esomeprazole: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Minor) Fluvoxamine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
Naproxen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering naratriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with fluvoxamine is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and fluvoxamine is a CYP2C9 inhibitor.
Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Neratinib: (Major) Avoid concomitant use of fluvoxamine with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of neratinib with a strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with moderate inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluvoxamine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nilotinib: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval, such as fluvoxamine. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use.
Niraparib; Abiraterone: (Moderate) Monitor for an increase in fluvoxamine-related adverse reactions if coadministration with abiraterone is necessary. Fluvoxamine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. While none of the drugs studied for interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study in CYP2D6 poor metabolizers (PM) demonstrated altered pharmacokinetic properties compared to extensive metabolizers (EM), with the Cmax, AUC, and half-life of fluvoxamine increased by 52%, 200%, and 62%, respectively. The manufacturer recommends caution in patients receiving concomitant drugs known to inhibit CYP2D6.
Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of one or both drugs. Fluvoxamine is partially metabolized by CYP2D6 and ritonavir is a weak CYP2D6 inhibitor. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and fluvoxamine due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with fluvoxamine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and fluvoxamine is a CYP3A4 inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nortriptyline: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as nortriptyline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, nortriptyline is metabolized by CYP2D6 and CYP3A4. Fluvoxamine is a moderate inhibitor of CYP3A4 and a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
Olanzapine; Fluoxetine: (Major) Due to the similarity in pharmacology of fluoxetine and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
Olanzapine; Samidorphan: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
Olaparib: (Major) Avoid coadministration of olaparib with fluvoxamine due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after fluvoxamine is discontinued. Olaparib is a CYP3A substrate and fluvoxamine is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and fluvoxamine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and fluvoxamine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If fluvoxamine is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals. (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and fluvoxamine. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
Ondansetron: (Major) Concomitant use of fluvoxamine and ondansetron may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, both fluvoxamine and ondansetron have central serotonin enhancing effects; therefore, serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Oritavancin: (Moderate) Fluvoxamine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of fluvoxamine may be reduced if these drugs are administered concurrently.
Osilodrostat: (Minor) Monitor ECGs in patients receiving osilodrostat with fluvoxamine. Osilodrostat is associated with dose-dependent QT prolongation. QT prolongation and torsade de pointes have been reported during fluvoxamine postmarketing use.
Osimertinib: (Major) Avoid coadministration of fluvoxamine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation and TdP has been reported during fluvoxamine post-marketing use.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fluvoxamine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with the use of both drugs in postmarketing experience.
Oxaprozin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased if coadministered with inhibitors of CYP3A4 including fluvoxamine. The manufacturer recommends that caution when oxybutynin is co-administered with CYP3A4 inhibitors.
Oxycodone: (Major) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluvoxamine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluvoxamine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking fluvoxamine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis and serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergic effects. Ozanimod is a monoamine oxidase inhibitor that may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluvoxamine is a serotonergic drug that is associated with QT prolongation and TdP.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Inhibitors of these enzymes, such as fluvoxamine, may increase the serum concentration of paclitaxel. Closely monitor patients for toxicity when administering paclitaxel with fluvoxamine.
Pacritinib: (Major) Avoid concurrent use of pacritinib with fluvoxamine due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Paliperidone: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and paliperidone. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, use of the drug should be avoided with other agents known to prolong the QT interval. However, if concurrent use is necessary and the patient has risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluvoxamine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Palovarotene: (Major) Avoid concomitant use of palovarotene and fluvoxamine due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and panobinostat. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. QT prolongation has been reported with panobinostat and concurrent use with other agents that prolong the QT interval is not recommended.
Paroxetine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and fluvoxamine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and fluvoxamine is a weak CYP2D6 inhibitor.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Pazopanib: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and pazopanib. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Coadministration of pazopanib and other drugs that prolong the QT interval is not advised. If pazopanib and fluvoxamine must be coadministered, closely monitor for QT prolongation.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to fluvoxamine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while fluvoxamine is a CYP2D6 substrate.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and fluvoxamine due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If fluvoxamine is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of fluvoxamine. Pemigatinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and pentamidine. Systemic pentamidine has been associated with QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
Pentosan: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Perindopril; Amlodipine: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Perphenazine: (Minor) Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of fluvoxamine and perphenazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as amitriptyline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, several isoenzymes have been identified in the metabolism of amitriptyline including CYP2D6 (primary), CYP2C19, CYP1A2, CYP3A4, and CYP2C9. Fluvoxamine is a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP3A4. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by the SSRI fluoxetine. Patients receiving a TCA should be monitored closely for toxicity if fluvoxamine is added. (Minor) Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of fluvoxamine and perphenazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and fluvoxamine due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If fluvoxamine is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of fluvoxamine. Pexidartinib is a CYP3A substrate; fluvoxamine is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenelzine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phentermine; Topiramate: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phenytoin: (Moderate) Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including fluvoxamine. Phenytoin dosage adjustments may be necessary in some patients who receive any of these drugs concurrently; monitor for signs of phenytoin toxicity.
Pimavanserin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and pimavanserin. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval.
Pimozide: (Contraindicated) Pimozide is contraindicated for use with selective serotonin reuptake inhibitors (SSRIs) due to an increased risk of QT prolongation and torsade de pointes (TdP). Pimozide is thought to be primarily metabolized through CYP3A4, and to a lesser extent, CYP1A2 and CYP2D6. Elevated plasma concentrations of pimozide occurring through inhibition of one or more of these isoenzymes by SSRIs can lead to QT prolongation, ventricular arrhythmias, and sudden death. Additionally, most SSRIs are also associated with QT prolongation, further increasing the risk of additive QT prolongation.
Pioglitazone; Glimepiride: (Moderate) Fluvoxamine should be used cautiously with glimepiride. The combination of fluvoxamine and glimepiride has resulted in a 43% increase in glimepiride peak plasma concentrations and an increase in glimepiride half-life in healthy volunteers; blood glucose response may be altered in diabetic patients. The mechanism of this interaction is unclear. Blood glucose concentrations should be monitored during coadministration of fluvoxamine.
Pirfenidone: (Major) Discontinue fluvoxamine prior to beginning pirfenidone, and avoid coadministration because it significantly increases exposure to pirfenidone. If fluvoxamine is the only drug of choice, it is recommended that the maintenance dose of pirfenidone be reduced to 267 mg PO 3 times daily. Monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Fluvoxamine is a potent inhibitor of CYP1A2, a potent inhibitor of CYP2C19, and a mild inhibitor of CYP2C9. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In a single-dose study, pirfenidone was coadministered with fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days, and 50 mg in the morning and 100 mg at bedtime for 4 days); an approximate 4-fold increase in pirfenidone exposure in nonsmokers and 7-fold increase in smokers was observed.
Piroxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Pitolisant: (Major) Avoid coadministration of pitolisant with fluvoxamine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
Pomalidomide: (Major) Avoid the concomitant use of pomalidomide and fluvoxamine; significantly increased pomalidomide exposure occurred when these agents were administered together in a drug interaction study. If concomitant use is unavoidable, decrease the pomalidomide dose to 2 mg once daily and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and fluvoxamine is a strong CYP1A2 inhibitor. In healthy volunteers, the AUC value for pomalidomide was increased by 125% when pomalidomide was co-administered with fluvoxamine.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking fluvoxamine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluvoxamine is associated with QT prolongation and TdP.
Posaconazole: (Moderate) Use posaconazole with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes (TdP). QT prolongation and TdP have been reported during fluvoxamine post-marketing use.
Pralsetinib: (Major) Avoid concomitant use of fluvoxamine with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Prasugrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and fluvoxamine due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Procainamide: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and procainamide. Procainamide is associated with a well-established risk of QT prolongation and TdP. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Procarbazine: (Major) Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should avoid the use of selective serotonin reuptake inhibitors (SSRIs) in patients receiving MAOIs. Fatalities have been reported when fluoxetine was administered to patients receiving MAOIs. Confusion, seizures, severe hypertension, and other, less severe symptoms have also been reported with this drug combination. Non-selective MAOIs inhibit both MAO types A and B. Since serotonin is metabolized by MAO type A, it is thought that this drug interaction may lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of therapy with an SSRI except fluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-lives of fluoxetine and its principle metabolite norfluoxetine.
Prochlorperazine: (Minor) Coadministration of fluvoxamine and prochlorperazine may increase the risk of QT prolongation and torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Prochlorperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of promethazine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Propafenone: (Major) Concomitant use of propafenone and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol: (Moderate) Fluvoxamine can also inhibit hepatic cytochrome P-450 isoenzymes and has been shown to interfere with propranolol clearance however clinical symptoms of excessive beta-blocker effects were not seen.
Protriptyline: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as protriptyline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, protriptyline is partially metabolized by CYP2D6 and fluvoxamine is a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
Quazepam: (Moderate) Fluvoxamine inhibits the oxidative metabolism of quazepam to some extent, and has been shown to increase the exposure to other benzodiazepines metabolized by the CYP450 system. Monitor for excessive sedation or next-day drowsiness. In one study, the effect of fluvoxamine on the plasma concentrations of quazepam and its active metabolites 2-oxoquazepam (OQ) and N-desalkyl-2-oxoquazepam (DOQ) was studied in healthy volunteers. Fluvoxamine did not change plasma concentrations of quazepam but significantly decreased those of the OQ and DOQ metabolites. The AUC ratio of OQ to quazepam was significantly lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function in these subjects at most of the time points.
Quetiapine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated quetiapine concentrations during concurrent use of fluvoxamine and quetiapine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. The manufacturer of quetiapine recommends avoiding combined use of quetiapine with drugs known to increase the QT interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, fluvoxamine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as quetiapine. Decreased metabolism of quetiapine may lead to adverse effects such as orthostatic hypotension, sedation, QT prolongation, or extrapyramidal symptoms.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Quinidine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or elevated plasma concentrations of either quinidine or fluvoxamine during coadministration. Quinidine administration is associated with QT prolongation and TdP. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate CYP3A4 inhibitor and the metabolism of CYP3A4 substrates such as quinidine may be reduced. In a small open-label study (n = 6), fluvoxamine 100 mg/day decreased the total oral clearance of quinidine by 29%. Conversely, quinidine is a CYP2D6 inhibitor and CYP2D6 is partially responsible for fluvoxamine metabolism, which may lead to elevated fluvoxamine concentrations.
Quinine: (Major) It is recommended to avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP. Quinine has been associated with QT prolongation and rare cases of torsade de pointes. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Quizartinib: (Major) Concomitant use of quizartinib and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ramelteon: (Contraindicated) Ramelteon is contraindicated for use in combination with fluvoxamine, a strong CYP1A2 inhibitor; CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon. When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose co-administration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased roughly 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone.
Ranolazine: (Major) According to the manufacturer of ranolazine, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving moderate CYP3A inhibitors. Ranolazine is a primary substrate of CYP3A and fluvoxamine is a moderate CYP3A4 inhibitor. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and selective serotonin reuptake inhibitors (SSRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During postmarketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any SSRI. Conversely, when discontinuing an SSRI, it is advisable to wait the length of 4 to 5 half-lives of the individual agent being discontinued prior to initiation with rasagiline. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and initiation of rasagiline. If coadministration of rasagiline and fluvoxamine is required, do not exceed a rasagiline dose of 0.5 mg once daily. Rasagiline is primarily metabolized by CYP1A2; fluvoxamine is a strong CYP1A2 inhibitor. When rasagiline was administered with another strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Relugolix: (Minor) Use fluvoxamine with caution in combination with relugolix. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Minor) Use fluvoxamine with caution in combination with relugolix. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with fluvoxamine due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ribociclib: (Major) Avoid coadministration of ribociclib with fluvoxamine due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and torsade de pointes (TdP) have been reported with fluvoxamine use during postmarketing experience.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with fluvoxamine due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and torsade de pointes (TdP) have been reported with fluvoxamine use during postmarketing experience.
Rilpivirine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Riluzole: (Moderate) Coadministration of riluzole with fluvoxamine may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and fluvoxamine is a CYP1A2 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with fluvoxamine; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
Risperidone: (Moderate) Use risperidone and fluvoxamine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Ritonavir: (Moderate) Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of one or both drugs. Fluvoxamine is partially metabolized by CYP2D6 and ritonavir is a weak CYP2D6 inhibitor. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering rizatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after the initiation of the SSRI or dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Roflumilast: (Moderate) Coadminister fluvoxamine and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Fluvoxamine is an inhibitor of CYP3A4 and CYP1A2; roflumilast is a CYP3A4 and CYP1A2 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of fluvoxamine (50 mg daily for 14 days) with a single oral dose of roflumilast 500 mcg showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in the active metabolite roflumilast N-oxide Cmax and AUC, respectively.
Rolapitant: (Major) Use caution if fluvoxamine and rolapitant are used concurrently, and monitor for fluvoxamine-related adverse effects. Fluvoxamine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated romidepsin concentrations during concurrent use of fluvoxamine and romidepsin. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, consider cardiac monitoring, such as monitoring electrolytes and ECGs at baseline and periodically during treatment. In addition, romidepsin is a substrate for CYP3A4 and fluvoxamine is a moderate inhibitor of CYP3A4. Concurrent administration may cause an increase in systemic romidepsin concentrations. Monitor for romidepsin-related adverse effects.
Ropinirole: (Moderate) Ropinirole is primarily metabolized by cytochrome P450 1A2. Ropinirole concentrations may increase when coadministered with inhibitors of CYP1A2, such as fluvoxamine. If fluvoxamine is initiated or discontinued during treatment with ropinirole, adjustment of the ropinirole dose may be required.
Ropivacaine: (Major) Ropivacaine is metabolized primarily by cytochrome P450 (CYP) isoenzyme 1A2. Agents that are known inhibitors of CYP1A2, such as fluvoxamine, may result in increased systemic levels of ropivacaine when given concurrently, resulting in toxicity. In vivo, the plasma clearance of ropivacaine was reduced by 70% and the half-life doubled during concurrent administration of fluvoxamine.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as fluvoxamine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
Safinamide: (Major) The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is generally avoided; however, the manufacturer of safinamide recommends monitoring for serotonin syndrome and using the lowest effective dose of the SSRI during concurrent use. During clinical trial evaluation of safinamide, 1 case of serotonin syndrome occurred during co-administration with an SSRI. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Salsalate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Saquinavir: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated saquinair concentrations during concurrent use of fluvoxamine and saquinavir boosted with ritonavir. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, both saquinavir boosted with ritonavir and fluvoxamine are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. These drugs used together may result in large increases in saquinavir serum concentrations, which could cause adverse events such as life threatening cardiac arrhythmias.
Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and fluvoxamine are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as fluvoxamine.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and a moderate CYP3A4 inhibitor, such as fluvoxamine may increase the serum concentration of segesterone.
Selegiline: (Contraindicated) Selective serotonin reuptake inhibitors (SSRIs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with an SSRI. With the exception of fluoxetine, a time period equal to 4 to 5 half-lives of the SSRI or any active metabolite should elapse after discontinuing treatment with the SSRI and before starting therapy with selegiline. Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonin-augmenting antidepressants simultaneously. Monitor for serotonergic side effects during therapy transitions.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and fluvoxamine due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If fluvoxamine is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of fluvoxamine. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; fluvoxamine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP) during postmarketing use. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and fluvoxamine due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If fluvoxamine is discontinued, resume the original selumetinib dose after 3 elimination half-lives of fluvoxamine. Selumetinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Sertraline: (Major) Due to the similarity in pharmacology of sertraline and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both sertraline and fluvoxamine have been associated with QT prolongation, which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
Sevoflurane: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Reports of QT prolongation, associated with TdP (in exceptional cases, fatal), have been received. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with fluvoxamine is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration of fluvoxamine increased the sildenafil AUC by 40%.
Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as fluvoxamine may cause significant increases in silodosin plasma concentrations.
Simvastatin: (Moderate) Coadministration of fluvoxamine (CYP3A4 inhibitor) and simvastatin (CYP3A4 substrate) would be expected to result in an increase in simvastatin serum concentrations. Elevation of simvastatin serum concentrations can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. Monitor patients receiving concomitant simvastatin and fluvoxamine closely for muscle pain or weakness.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving fluvoxamine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. QT prolongation and torsade de pointes have been reported during fluvoxamine postmarketing use. Additionally, concomitant use of siponimod and fluvoxamine may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of fluvoxamine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with fluvoxamine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluvoxamine is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with fluvoxamine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluvoxamine is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Solifenacin: (Moderate) Use fluvoxamine with caution with other drugs known to prolong the QT interval. QT prolongation and torsade de pointes (TdP) have been reported for both fluvoxamine and solifenacin with postmarketing use. Solifenacin has been associated with dose-dependent prolongation of the QT interval. In addition, solifenacin is significantly metabolized via the CYP3A4 pathway. Adult patients receiving potent CYP3A4 inhibitors should not receive solifenacin doses greater than 5 mg per day. Patients receiving moderate inhibitors, such as fluvoxamine, have not been assessed. It is possible that some patients taking fluvoxamine concurrently might need lower solifenacin doses.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and fluvoxamine; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Major) Avoid coadministration of sorafenib with fluvoxamine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
Sotalol: (Major) Concomitant use of sotalol and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with fluvoxamine is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
Spironolactone: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering fluvoxamine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Sufentanil: (Major) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if fluvoxamine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluvoxamine has resulted in serotonin syndrome. In addition, sufentanil is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If fluvoxamine is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulindac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Sumatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sumatriptan; Naproxen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with fluvoxamine. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Use fluvoxamine with caution in combination with tacrolimus as concurrent use may increase the risk of QT prolongation; exposure to tacrolimus may also increase. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. Fluvoxamine is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use. Tacrolimus is a sensitive CYP3A4 substrate that also causes QT prolongation.
Tadalafil: (Major) Avoid coadministration of fluvoxamine and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72 hours of fluvoxamine for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as fluvoxamine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tamsulosin: (Moderate) Tamsulosin should be used with caution in combination with moderate inhibitors of CYP3A4 such as fluvoxamine. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are responsible for the extensive metabolism of tamsulosin. Strong inhibitors of CYP3A4 are known to increase the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. No studies have been performed with moderate CYP3A4 inhibitors. As with other alpha adrenergic blocking agents there is a potential risk of syncope with tamsulosin, particularly if serum concentrations are elevated. Monitor blood pressure and observe for symptoms of orthostasis.
Tapentadol: (Moderate) If concomitant use of tapentadol and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP1A2, such as fluvoxamine, should be avoided. Because tasimelteon is partially metabolized via CYP1A2, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of fluvoxamine 50 mg/day for 6 days, the AUC and Cmax of tasimelteon increased by 7-fold and 2-fold, respectively.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with fluvoxamine as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If fluvoxamine is discontinued, wait at least 3 half-lives of fluvoxamine before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and selective serotonin reuptake inhibitors (SSRIs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SSRIs were excluded from clinical trials. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid, which is structurally similar to tedizolid.
Telavancin: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and telavancin. Telavancin has been associated with QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Telmisartan; Amlodipine: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Tenecteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Terbinafine: (Moderate) Systemic terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as selective serotonin reuptake inhibitors (SSRIs). The clinical relevance of the interaction is not known. Topical forms of terbinafine do not interact.
Tetrabenazine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and tetrabenazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Because tetrabenazine causes a small increase in the corrected QT interval (QTc), the manufacturer recommends avoiding use of tetrabenazine with other drugs known to prolong QTc.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with fluvoxamine; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); fluvoxamine is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If fluvoxamine and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Theophylline, Aminophylline: (Major) Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2. Aminophylline is metabolized by this enzyme. If aminophylline is co-administered with fluvoxamine, the aminophylline daily dosage should be reduced and plasma aminophylline concentrations should be monitored. Patients should report any increase in methylxanthine-induced side effects, like tremor, nausea, or vomiting promptly. (Major) Fluvoxamine inhibits the activity of the hepatic isozyme CYP1A2. Theophylline is metabolized by this enzyme. If theophylline is co-administered with fluvoxamine, the theophylline daily dosage should be reduced and plasma theophylline concentrations should be monitored. Patients should report any increase in methylxanthine-induced side effects, like tremor, nausea, or vomiting promptly.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use with agents that may prolong the QT interval and increase the risk of TdP. Because of the potential for TdP, use of fluvoxamine with thioridazine is contraindicated. In addition, although fluvoxamine is not known to inhibit CYP2D6 significantly, fluvoxamine has been reported to elevate serum concentrations of both thioridazine and mesoridazine by roughly 3-fold, probably due to fluvoxamine inhibition of CYP2C19 and CYP2D6. Substantial increases in serum thioridazine concentrations may lead to QT prolongation, TdP, and sudden death.
Thrombin Inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ticagrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving ticagrelor. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Tirofiban: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Tizanidine: (Contraindicated) Concomitant use of tizanidine and fluvoxamine is contraindicated due to the risk of tizanidine toxicity, including clinically significant hypotension, bradycardia, and sedation. Tizanidine is a CYP1A2 substrate and fluvoxamine is a strong CYP1A2 inhibitor. After a single 4 mg tizanidine dose, Cmax, AUC, and half-life increased by 12-fold, 33--fold, and 3-fold, respectively, when administered with fluvoxamine during pharmacokinetic trials.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking fluvoxamine. Smoking tobacco has been observed to increase the metabolism of fluvoxamine by 25% and may reduce its efficacy.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with fluvoxamine. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with fluvoxamine. Fluvoxamine is a strong CYP2C19 and moderate CYP3A4 inhibitor; tofacitinib is a CYP3A4/CYP2C19 substrate. Coadministration with another strong CYP2C19 and moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold.
Tolmetin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Tolterodine: (Moderate) Both fluvoxamine and tolterodine have been associated with QT prolongation, and torsade de pointes (TdP) has been reported with fluvoxamine. In addition, there is a possibility that fluvoxamine may increase the exposure to tolterodine. In patients who are CYP2D6 poor metabolizers (CYP2D6 PMs), the CYP3A4 pathway becomes important in tolterodine elimination. Because it can be difficult to assess which patients will be CYP2D6 PMs of tolterodine, those patients receiving CYP3A4 inhibitors, such as fluvoxamine, should generally not receive greater than 2 mg/day of tolterodine.
Tolvaptan: (Major) Avoid coadministration of fluvoxamine when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluvoxamine. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Toremifene: (Major) Avoid coadministration of fluvoxamine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported during fluvoxamine post-marketing use.
Torsemide: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluvoxamine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures.
Tramadol; Acetaminophen: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluvoxamine with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures.
Trandolapril; Verapamil: (Moderate) Certain SSRIs, including fluvoxamine, are inhibitors of CYP3A4, and may theoretically increase verapamil serum concentrations.
Tranylcypromine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Trazodone: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, coadministration of trazodone and fluvoxamine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue fluvoxamine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
Triamterene: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with fluvoxamine and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and fluvoxamine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trifluoperazine: (Minor) Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of fluvoxamine and trifluoperazine. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Trifluoperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Trimipramine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as trimipramine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, trimipramine is metabolized by CYP2D6, CYP2C9, and CYP2C19. Fluvoxamine is a strong inhibitor of CYP2C19 and a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving fluvoxamine. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval and torsade de pointes (TdP) has also been reported during fluvoxamine post-marketing use.
Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of tryptophan and a selective serotonin reuptake inhibitor (SSRI) is not recommended. Since tryptophan is converted to serotonin, the use of tryptophan in patients receiving SSRIs could lead to serotonin excess and, potentially, serotonin syndrome. Discontinuation of tryptophan usually resolves symptoms.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with fluvoxamine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and fluvoxamine is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
Valerian, Valeriana officinalis: (Moderate) Substances that act on the CNS, including psychoactive drugs, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluvoxamine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/L have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of fluvoxamine should be considered in patients who develop symptomatic hyponatremia.
Vandetanib: (Major) Avoid coadministration of vandetanib with fluvoxamine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation of the QT interval and TdP has been reported during fluvoxamine postmarketing use.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with fluvoxamine due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. There may also be an increased risk for QT prolongation and torsade de pointes (TdP) during coadministration. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in the QTc interval.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as selective serotonin reuptake inhibitors. Use together may increase the pressor and antidiuretic effects of vasopressin.
Vemurafenib: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or elevated vemurafenib concentrations during concurrent use of fluvoxamine and vemurafenib. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended. In addition, concomitant use of vemurafenib and fluvoxamine may result in increased concentrations of fluvoxamine and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP1A2 and CYP2D6. Fluvoxamine is an inhibitor of CYP3A4 and a substrate of CYP1A2 and CYP2D6. Use caution and monitor patients for toxicity and efficacy.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluvoxamine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluvoxamine. Venetoclax is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor.
Venlafaxine: (Major) Concomitant use of fluvoxamine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Both venlafaxine and fluvoxamine are associated with reports of QT prolongation and TdP. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Verapamil: (Moderate) Certain SSRIs, including fluvoxamine, are inhibitors of CYP3A4, and may theoretically increase verapamil serum concentrations.
Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining selective serotonin reuptake inhibitors (SSRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored closely for toxicity. In addition, because vilazodone is a primary CYP3A4 substrate, the manufacturer recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as fluvoxamine. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with fluvoxamine is necessary. Vinblastine is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluvoxamine is necessary. Vinorelbine is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with fluvoxamine. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Additive QT prolongation may also occur. Voclosporin is a sensitive CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and TdP while QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
Voriconazole: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated voriconazole concentrations during concurrent use of fluvoxamine and voriconazole. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, voriconazole is partially metabolized by CYP2C19 and CYP3A4, and fluvoxamine is a potent inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Theoretically, drugs that are inhibitors of these enzymes, such as fluvoxamine, may result in decreased clearance and elevated voriconazole serum concentrations when coadministered.
Vorinostat: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and vorinostat. Vorinostat therapy is associated with a risk of QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be co-administered with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluvoxamine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluvoxamine is a moderate CYP3A4 and weak CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP3A4/CYP1A2 substrate. Fluvoxamine is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. An increased risk of bleeding, including gastrointestinal bleeding, has been reported with drugs that interfere with serotonin reuptake; thus, concurrent use of fluoxetine and warfarin may result in an additive risk of bleeding events. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with fluvoxamine. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of fluvoxamine, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Major) Concomitant use of ziprasidone and fluvoxamine should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as ziprasidone. Decreased metabolism of ziprasidone may lead to adverse reactions, such as extrapyramidal symptoms or QT prolongation.
Zolmitriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering zolmitriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of fluvoxamine, since the metabolism of zolpidem may be decreased by CYP3A4, CYP1A2, and CYP2C9 inhibition of fluvoxamine. There is evidence of an increase in pharmacodynamic effects and systemic exposure of zolpidem when the drug is co-administered with some potent inhibitors of CYP3A4, such as azole antifungals. In addition, disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including fluvoxamine. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. In one case report, an elderly female patient experienced visual hallucinations and amnesia of the events three days after an increase in fluvoxamine dose to 50 mg three times daily after stabilization on zolpidem 10 mg/night, and fluvoxamine 50 mg twice daily. The mechanism for the interaction is unknown but may be pharmacodynamic in nature and/or related to increased zolpidem exposure from fluvoxamine inhibition of CYP3A4.
The effectiveness of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin-reuptake blockade, although the exact mechanism is unknown. The precise antidepressant action of SSRIs is not fully understood, but it is believed that the most important effect is the enhancement of the actions of serotonin (5-HT) due to highly specific serotonin reuptake blockade at the neuronal membrane. Initial administration of SSRIs results an increased availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is a primary mechanism of therapeutic effect. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do the tricyclic antidepressant drugs due to dramatically decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors.
Fluvoxamine is administered orally. It is approximately 80% protein bound. Because the drug has a large volume of distribution, extensive tissue distribution is likely. It is primarily metabolized in the liver by oxidative demethylation. The nine metabolites that have been identified account for approximately 85% of urinary excretion products. Only 2% of a dose is excreted renally as unchanged drug. The mean elimination half-lives of the immediate-release and extended-release formulations at steady-state in healthy volunteers are approximately 15.6 hours and 16.3 hours, respectively.
Affected cytochrome P450 (CYP450) enzymes and drug transporters: CYP1A2, CYP2C19, CYP3A4, CYP2C9, CYP2D6
Fluvoxamine is thought to be a substrate of isoenzymes CYP2D6 and CYP1A2. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, a moderate inhibitor of CYP3A4, and a weak inhibitor of CYP2C9. In vitro, fluvoxamine is a weak inhibitor of CYP2D6, but the in vivo effect has not been determined. Because fluvoxamine inhibits multiple isoenzymes, concurrent use with a drug that is metabolized by oxidation and has a narrow therapeutic window warrants close monitoring. The product labeling provides individual dosage recommendations for some drug interactions.
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of immediate-release fluvoxamine is 53%. Maximum plasma concentrations at steady-state occur within 3 to 8 hours of oral dosing with the immediate-release formulation. In one single-dose crossover study, the mean Cmax was 38% lower for extended-release fluvoxamine versus immediate-release fluvoxamine and the relative bioavailability was 84% for the extended-release formulation. Oral bioavailability is not significantly affected by food; therefore, the drug may be administered without regard to meals. Steady-state is achieved after approximately a week of oral dosing with the immediate-release or extended-release formulation.
-Special Populations
Hepatic Impairment
In one comparison study of healthy adult subjects to adult patients with hepatic dysfunction, there was a 30% decrease in fluvoxamine clearance in those with hepatic dysfunction. A lower initial dose and slower titration may be needed in patients with hepatic impairment.
Renal Impairment
No accumulation of fluvoxamine has been shown in renally impaired patients with creatinine clearances of 5 to 45 mL/minute. Due to a large volume of distribution, hemodialysis is unlikely to have a significant effect on clearance of the drug.
Pediatrics
Evaluations of immediate-release fluvoxamine in pediatrics have shown that steady-state plasma concentrations are 2- to 3-fold higher in children (6 to 11 years of age) than in adolescents (12 to 17 years of age). The AUC and Cmax in children are 1.5- to 2.7-fold higher than in adolescents. Similar to adults, both children and adolescents exhibit nonlinear multiple-dose pharmacokinetics. Because female children show a significantly higher AUC and Cmax compared to male children, lower doses may produce therapeutic benefit in females. No gender differences have been identified in adolescents. Fluvoxamine exposure appears similar between adults and adolescents. The pharmacokinetics of extended-release fluvoxamine have not been evaluated in pediatric patients.
Geriatric
In elderly patients, mean maximum plasma concentrations are roughly 40% higher than in young adults and clearance reduced by about 50%. In one study, the half-life of fluvoxamine was 17.4 to 25.9 hours in the elderly compared to 13.6 to 15.6 hours in young adults at steady state.
Gender Differences
No gender differences have been identified in adults. However, female children (age 6 to 11 years) have a significantly higher AUC and Cmax than male children. Therefore, lower doses in female children may produce therapeutic response.
Other
Smokers
Smokers have a 25% increase in the metabolism of fluvoxamine compared to nonsmokers; however, no dosage adjustments are recommended in this patient population.