FLUVOXAMINE MALEATE ER

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
-Immediate-release tablets: To minimize side effects, administer at bedtime. Administer doses > 50 mg/day in two divided doses; if doses are not equal, give the larger dose at bedtime.
-Extended-release capsules: Patient should swallow whole. Do not crush or chew. To minimize side effects, administer at bedtime. NOTE: The extended-release capsule formulation is not FDA-approved for use in pediatric patients.

Weight loss was reported more frequently in patients receiving fluvoxamine compared to those receiving placebo during pediatric clinical trials. Overall, the adverse effect profile reported in pediatric trials was similar to that observed in adult trials. In adult trials, 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%) were reported more frequently in patients receiving fluvoxamine than placebo. Nausea usually subsides after a few weeks of therapy and may potentially be minimized by administration of the drug with food. Weight gain was reported in at least 1% of patients. 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 occurred postmarketing.

Hyperkinesis was reported more frequently in fluvoxamine-treated patients compared to placebo-treated patients during pediatric clinical trials. Overall, the adverse event profile of fluvoxamine was similar between pediatric and adult patients. In adult clinical trials, 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%) were reported more frequently in patients receiving fluvoxamine than placebo. Hyperkinesis, myoclonia, and hypokinesia were reported in at least 1% of patients. Akathisia, ataxia, CNS depression, abnormal dreams, seizures, dyskinesia, dystonic reaction, extrapyramidal syndrome, twitching, unsteady gait, hemiplegia, hypersomnia, hypotonia, muscle paralysis, stupor, vertigo, incoordination, and sleep disorder were reported in 0.1% to 1% of adult patients. Rare events (less than 0.1%) included akinesia, coma, fibrillations, mutism, hyporeflexia, dysarthria, tardive dyskinesia, torticollis, and trismus. Teeth grinding (bruxism), dysarthria, pseudoparkinsonism, gait disturbance, loss of consciousness, and shock have been reported postmarketing. Although sedation occurred in approximately 25% of adults during clinical trials, activation cluster adverse events (i.e., hyperactivity, motor and behavioral activation, or disinhibition) were reported in 45% of pediatric patients receiving fluvoxamine for anxiety disorders in 1 study; therefore, close monitoring is recommended for early identification of activation symptoms.

In pediatric clinical trials, mania and emotional lability occurred more frequently in fluvoxamine-treated patients than those receiving placebo. Overall, the adverse effect profile in pediatric patients was similar to that observed in adults. In adult trials, nervousness (10% to 12%), anxiety (5% to 8%), agitation (2% to 3%), depression (2%), apathy (3%), abnormal thinking (3%), and neurosis (2%) were reported more frequently in patients receiving fluvoxamine than placebo. 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. Obsessions were reported rarely (less than 0.1%). Aggression, feeling drunk (impaired cognition), feeling jittery, homicidal ideation, impulsive behavior, irritability, self-injurious behavior, anger, and activation syndrome have been reported during postmarketing use. In one study of children and adolescents with an anxiety disorder, activation cluster adverse events (i.e., hyperactivity, activation, or disinhibition) occurred in 45% of participants receiving fluvoxamine versus 4% of those receiving placebo; therefore, close monitoring is recommended for early identification of activation symptoms. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. 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. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. Suicidal tendencies, suicide attempts, and overdose were reported in 0.1% to 1% of patients during clinical trial evaluation of fluvoxamine. Manic symptoms and suicidal ideation appear to be more prevalent in children with or at high-risk for bipolar disorder on antidepressants; monitor such patients closely. In a study of 52 patients (mean age: 15 years, range: 7 to 22 years) with bipolar disorder or subthreshold manic symptoms and exposure to antidepressants, 50% developed antidepressant-induced mania and 25.5% had new-onset suicidal ideation.

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, hematomas, petechiae, hemorrhage). Both ecchymosis and epistaxis were reported more frequently in the fluvoxamine arm compared to the placebo arm during pediatric clinical trials. Overall, the adverse effect profile reported in pediatric trials was similar to that seen in adults. In adult trials, ecchymosis (4%) and epistaxis (2%) also occurred more frequently in the fluvoxamine are compared to the placebo arm. Events occurring in 0.1% to 1% of adult patients included anemia, GI bleeding (i.e., hemorrhage), rectal hemorrhage, vaginal bleeding/hemorrhage, leukocytosis, lymphadenopathy, and thrombocytopenia. Rarely (less than 0.1%), leukopenia and purpura were reported. Purpura, aplastic anemia, agranulocytosis, and porphyria have been reported during post-marketing use. 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. Patients 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.

Palpitations (3%), peripheral vasodilation (2%), chest pain (unspecified) (3%), and hypertension (2%) were reported more frequently in patients receiving fluvoxamine than placebo during adult clinical trials. Syncope and hypotension were reported in at least 1% of adult patients. Overall, the adverse effect profile in pediatric patients was similar to that seen in adults. Infrequent cardiac or peripheral vascular events in adult trials included angina, bradycardia, cardiomyopathy, cardiovascular disease, 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, ventricular arrhythmia, ventricular tachycardia sinus tachycardia, and cardio-pulmonary arrest (cardiac arrest) have occurred during postmarketing use. QT prolongation and torsade de pointes (TdP) have been reported with fluvoxamine use in clinical practice/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; the drug should be avoided in patients with a history of congenital long QT syndrome.

Dysmenorrhea was reported more frequently with fluvoxamine than placebo during pediatric clinical trials. Overall, the adverse effect profile reported in pediatric clinical trials was similar to that observed in adult trials. In adult trials, increased urinary frequency (3%), urinary retention (1%), menorrhagia (3%), urinary tract infection (2%), and polyuria (2%) were reported more frequently in fluvoxamine-treated patients than placebo-treated patients. Hematuria, anuria, cystitis, delayed menstruation, dysuria, galactorrhea, metrorrhagia, nocturia, premenstrual syndrome, impaired urination, and vaginitis were reported in 0.1% to 1% of patients. Nephrolithiasis and oliguria were reported rarely (less than 0.1%). Acute renal failure (unspecified), renal impairment (unspecified), and amenorrhea have occurred during post-marketing use. As with other SSRIs, several cases of priapism have been reported during fluvoxamine therapy which have been reversible upon discontinuation of the drug.

Asthenia (14% to 26%), chills (2%), pain (10%), myalgia (5%), and accidental injury (5%) were reported more frequently with fluvoxamine than with placebo during adult clinical trials. In addition, malaise and edema were reported in at least 1% of adult patients. Overall, the adverse effect profile reported in pediatric trials was similar to that observed in adults. Infrequently (0.1% to 1%), arthralgia, arthritis, bursitis, generalized muscle spasm, and myasthenia were reported in adult trials. Rarely (less than 0.1%), myopathy occurred. Fatigue, lethargy, fall, and rhabdomyolysis have been reported postmarketing.

Rash (unspecified) was reported more frequently with fluvoxamine than placebo during pediatric clinical trials. In general, the overall adverse event profile of fluvoxamine was similar to that seen in adults. Dermatologic effects noted in adult clinical trials included hyperhidrosis (6% to 7%), acne vulgaris (2%), and vasodilation such as flushing (3%). Urticaria, photosensitivity reaction, alopecia, xerosis, exfoliative dermatitis, furunculosis, seborrhea, skin discoloration, and atopic dermatitis were reported in 0.1% to 1% of adult patients. Bullous rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactoid reactions, and angioedema have occurred during post-marketing use.

The overall adverse effect profile reported in pediatric clinical trials was similar to that observed in adult trials, although increased cough, epistaxis, and sinusitis occurred more frequently in fluvoxamine-treated pediatrics than placebo-treated pediatrics. In adults, the following respiratory effects or infections were reported more frequently in patients receiving fluvoxamine than placebo: influenza (3%), viral infection (2%), upper respiratory infection (9%), dyspnea (2%), yawning (2% to 5%), pharyngitis (6%), laryngitis (3%), bronchitis (2%). Epistaxis occurred in 2% or less of adult patients. Infrequent events (0.1% to 1%) included asthma (bronchospasm), hoarseness, epistaxis, and hyperventilation. Hemoptysis, laryngismus (laryngospasm), apnea, upper airway congestion, hiccups, obstructive pulmonary disease, and pneumonia were reported rarely (less than 0.1%). Interstitial lung disease and fever have been reported postmarketing.

In adult trials, amblyopia (2% to 3%) and dysgeusia (2% to 3%) were reported more frequently in patients receiving fluvoxamine than placebo. 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%). Overall, the adverse effect profile reported in pediatric trials was similar to that observed in adult trials. Rare effects reported with SSRIs include ocular hypertension (angle-closure glaucoma). Anosmia and hyposmia have also been reported with postmarketing use.

Fluvoxamine, like other SSRIs, may cause altered glycemic control, although this effect appears to be uncommon. Hyperglycemia, diabetes mellitus, and hypoglycemia have been reported in rare instances during fluvoxamine administration. Other metabolic effects reported infrequently (0.1% to 1%) include dehydration and hypercholesterolemia. Hyperlipidemia, hypokalemia, and increased lactate dehydrogenase have been reported rarely (less than 0.1%).

Hypothyroidism (0.1% to 1%) and goiter (less than 0.1%) were rarely reported in adult patients during clinical trials of fluvoxamine.

Serotonin syndrome has been reported during use of SSRIs alone, during concurrent use of other medications known to increase CNS serotonin levels, or during SSRI overdose. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. If serotonin syndrome becomes evident during treatment, the SSRI and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, should be used with caution in patients with osteopenia or risk factors for osteopenia. Some data suggest an association between the use of SSRIs and reduced bone density and bone fractures.

Withdrawal symptoms have been reported with abrupt or rapid discontinuation of short-acting SSRIs such as fluvoxamine. The most commonly reported withdrawal symptoms of SSRIs 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 discontinuation of the SSRI and subside 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 in utero to serotonergic agents such as fluvoxamine, with features consistent with either a direct toxic effect of serotonergic agents (e.g., serotonin syndrome), or possibly a drug discontinuation syndrome. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) have been 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. Other potential adverse events have also been reported, including a potential association between third trimester SSRI use and persistent pulmonary hypertension of the newborn (PPHN). However, some retrospective studies have not shown an increased risk of PPHN with SSRI exposure. The FDA has stated that an increased risk of PPHN from SSRI exposure cannot be determined due to conflicting data.

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.

In general, fluvoxamine should not be used in patients who have had a severe hypersensitivity reaction attributed to fluvoxamine.

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.

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 and adolescents 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. 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. 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.

Mania or hypomania can be precipitated in predisposed individuals during treatment with an antidepressant, including fluvoxamine. Children with a family history of bipolar disorder, those who have a diagnosis of bipolar disorder, and those with subthreshold manic symptoms may be at increased risk for developing mania during treatment. In addition, patients with pre-existing bipolar disorder type I, compared to those with subsyndromal or type II bipolar disorder, and those with psychiatric comorbidities may be at increased risk for antidepressant-induced mania. Younger patients may be more likely to experience antidepressant-induced mania. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar disorder on antidepressants. In a study of 52 patients (mean age of 15 years, ranging from 7 to 22 years) with bipolar disorder or subthreshold manic symptoms, 25.5% had new-onset suicidal ideation within the first 3 months of antidepressant use. Progressive evaluation of youth at risk for bipolar disorder who were exposed to antidepressants (n = 21; age range of 9 to 20 years) suggested psychiatric adverse events such as irritability, aggression, impulsivity, and hyperactivity were more common in younger patients. A major depressive episode may be the initial presentation of bipolar disorder. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. The response of patients with a previously established history of bipolar disorder should be closely monitored if therapy with an antidepressant is indicated.

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.

The risks or benefits of using fluvoxamine during electroconvulsive therapy (ECT) have not been established in clinical studies.

During premarketing studies, 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) 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. Patients 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, 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.

Patients taking fluvoxamine should be monitored 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). Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking fluvoxamine should be instructed to promptly report any bleeding events to the practitioner.

Because fluvoxamine may impair judgment, thinking, or motor skills, patients should use caution when engaging in activities requiring coordination and concentration (such as riding bicycles, driving, or operating machinery) until they are aware of the effects of fluvoxamine on their cognition.

Caution is recommended when prescribing fluvoxamine to patients with closed-angle glaucoma. 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.

Decreased appetite and weight loss have been observed during administration of SSRIs. Therefore, caution is advisable when administering fluvoxamine to patients with anorexia nervosa or other conditions where weight loss is undesirable. Monitor growth and weight in any pediatric patient receiving fluvoxamine.

Neonates with in utero exposure to SSRIs late in the third trimester have developed 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 either a direct toxic effect of SSRIs, a drug discontinuation syndrome, or serotonin syndrome. In addition, although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN; effects were not significant for other variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1,000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation.

The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving fluvoxamine. 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 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.

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.

Description: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) commonly used to treat obsessive-compulsive disorder (OCD) and various anxiety disorders. Fluvoxamine was the first SSRI approved for use in children. Although sedation occurred in approximately 25% of adults during clinical trials, activation cluster adverse events were reported in 45% of youth receiving fluvoxamine in the Research Units on Pediatric Psychopharmacology (RUPP) Anxiety Study. Therefore, close monitoring is recommended for early identification of increased motor activity and behavioral activation symptoms in children and adolescents receiving fluvoxamine.Clinical guidelines and treatment algorithms establish a role for SSRIs to treat childhood depression; however, the efficacy of fluvoxamine for depression in pediatric patients has not been established. SSRIs are also considered first-line therapy for childhood anxiety disorders requiring pharmacologic treatment, although few indications are FDA approved, and long-term safety and efficacy data are limited. Product labels for all antidepressants contain a warning related to an increased risk of suicidality in children and adolescents during the initial stages of therapy with an antidepressant. Therefore, the necessity of pharmacologic therapy should be carefully considered in the pediatric population, taking into account the risks of treatment versus clinical need. Fluvoxamine is FDA-approved for the treatment of OCD in children 8 years and older. Limited data suggest efficacy in children as young as 6 years for childhood anxiety disorders including generalized anxiety disorder, social phobia, and separation anxiety disorder.

For the treatment of obsessive-compulsive disorder (OCD):
Oral dosage (immediate-release tablets):
Children 8 to 11 years: 25 mg PO at bedtime initially. Increase by 25 mg every 4 to 7 days based on efficacy and tolerability, not to exceed 200 mg/day PO. Daily doses over 50 mg/day PO should be divided.
Children and Adolescents 12 to 17 years: 25 mg PO at bedtime initially. Increase by 25 mg every 4 to 7 days based on efficacy and tolerability, not to exceed 300 mg/day PO. Daily doses over 50 mg/day PO should be divided.
Oral dosage (extended-release capsules):
Children 8 to 11 years: 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. Usual 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).
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.

For the treatment of anxiety disorders* including social phobia (social anxiety disorder)*, generalized anxiety disorder (GAD)*, and/or separation anxiety disorder*:
Oral dosage:
Children 6 to 11 years: 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 +/- 1.3 mg/kg/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. 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. 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.
Children and Adolescents 12 to 17 years: 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 +/- 1.3 mg/kg/day PO. Max (12 years and older): 300 mg/day PO. The fluvoxamine group had a greater mean decrease in anxiety symptoms than those receiving placebo. 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. 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.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established.
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. Use of extended-release capsules not recommended.
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.
12 years: 300 mg/day PO.
-Adolescents
300 mg/day PO.

Patients with Hepatic Impairment Dosing
Because fluvoxamine is significantly metabolized in the liver, a lower initial dose and modification of the rate of subsequent dosage titration are advisable; however, quantitative guidelines are not available.

Patients with Renal Impairment Dosing
CrCl > 45 ml/min: No dosage adjustment needed.
CrCl 5-45 ml/min: No accumulation occurs and it appears that no dosage adjustments are needed based upon renal function.
CrCl < 5 ml/min: Specific guidelines are not available; it appears that no dosage adjustments are needed.

Intermittent hemodialysis
Specific guidelines 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

Monograph content under development

Mechanism of Action: 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.

Pharmacokinetics: Fluvoxamine is administered orally. Fluvoxamine is approximately 80% protein bound. Because the drug has a large volume of distribution, extensive tissue distribution is likely. Fluvoxamine 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 isoenzymes: CYP2D6, CYP1A2, CYP2C19, CYP3A4, and CYP2C9
Fluvoxamine is a substrate of isoenzymes CYP2D6 and CYP1A2. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, a moderate inhibitor of CYP3A4, and possibly a weak inhibitor of CYP2C9. In vitro, fluvoxamine is a weak inhibitor of CYP2D6, but the exact in vivo effect has not been determined.


-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of immediate-release fluvoxamine is 53%. Maximum plasma concentrations at steady-state occur within 3-8 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
Pediatrics
Children and Adolescents
Evaluations of immediate-release fluvoxamine in pediatrics have shown that steady-state plasma concentrations are 2-3 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.

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 5-45 ml/minute. Due to a large volume of distribution, hemodialysis is unlikely to have a significant effect on clearance of the drug.

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.