CELEXA (Brand for CITALOPRAM HBR)

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

Route-Specific Administration

Oral Administration
-May administer with or without food.
Oral Liquid Formulations
-Oral solution: Administer with a calibrated measuring device to ensure accuracy of dose.

Adverse gastrointestinal (GI) effects are among the most frequently reported adverse reactions during treatment with SSRIs. During clinical trial evaluation, xerostomia (20%), nausea (21%), diarrhea (8%), dyspepsia (5%), vomiting (4%), anorexia (4%), and abdominal pain (3%) occurred more frequently in citalopram-treated patients compared to those receiving placebo. Hypersalivation, flatulence, weight gain, and weight loss were reported in at least 1% of patients. With continued treatment over several weeks, adaptation to some GI adverse events (e.g., nausea) may occur, but other effects (e.g., dry mouth) may continue. Adverse GI events associated with discontinuation of treatment more frequently with citalopram than placebo included nausea (4%), xerostomia (1%), and vomiting (1%). Thirst (polydipsia) was reported rarely (1% or less) during clinical trial evaluation; in some cases, thirst may be associated with dry mouth. Other infrequent (0.1% to 1%) GI events reported include gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding (bruxism), gingivitis, and esophagitis. Very rarely (less than 0.1%), colitis, gastric ulcer, cholecystitis, cholelithiasis, peptic ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, and hiccups occurred. Significant weight loss may be an undesirable result of SSRI treatment for some patients, but on average, patients in controlled trials with citalopram had minimal (0.5 kg) weight loss vs. placebo. However, because decreased appetite and weight loss have been observed during use of SSRIs, periodic monitoring of weight and height are recommended in pediatric patients receiving citalopram. During postmarketing use, gastrointestinal hemorrhage and pancreatitis have been reported.

Tremor (8%), drowsiness (18%), and insomnia (15%) were reported more frequently in citalopram-treated patients than those receiving placebo during clinical trial evaluation. Both drowsiness and insomnia were considered dose-related and were also associated with treatment discontinuation more frequently in the citalopram group than in the placebo group (drowsiness 2% and insomnia 3%). Migraine headaches and paresthesias were also reported in at least 1% of citalopram-treated patients. Similar to other SSRIs, extrapyramidal effects or movement disorders have been reported rarely (less than 1%) during citalopram treatment and include hyperkinesis, hypertonia, involuntary muscle contractions, hypokinesia, abnormal gait, ataxia, and abnormal coordination; akathisia, dyskinesia, myoclonia, and nystagmus. Other nervous system disorders rarely reported during clinical trial evaluation include vertigo, neuralgia (neuropathic pain), hypoesthesia, hyperesthesia, ptosis, and stupor (lethargy). Dizziness was associated with treatment discontinuation in 2% of citalopram-treated patients. Dystonic reaction and choreoathetosis have been reported postmarketing. Seizures have been reported postmarketing.

During clinical trial evaluation, anxiety (4%) and agitation (3%) occurred more frequently in citalopram-treated patients than those receiving placebo, respectively. Suicidal ideation (suicide attempt), depression, aggravated depression, impaired concentration, amnesia, apathy, and confusion were reported in 1% or more of patients. Adverse psychiatric effects reported during premarketing evaluation in 0.1% to 1% of patients include aggressive reaction, paroniria (abnormal dreams or nightmares), drug dependence, depersonalization, delusion or hallucinations, euphoria, psychotic depression, paranoia, emotional lability, panic reaction, and psychosis. Rarely (less than 0.1%), catatonic reaction and melancholia were reported. Delirium has been reported with postmarketing use. Antidepressants can precipitate mania in susceptible individuals. In placebo-controlled trials, activation of mania/hypomania was reported in 0.2% of patients treated with citalopram. Manic symptoms and suicidal ideation appear to be more prevalent in pediatric patients with or at high risk for bipolar disorder on antidepressants; monitor such patients closely. In a study of 52 young adult and pediatric 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. 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.

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). Hematologic and lymphatic effects that occurred in 0.1% to 1% of patients who received citalopram during premarketing evaluation included purpura, anemia (unspecified), epistaxis, leukocytosis, leukopenia, and lymphadenopathy. Effects that occurred rarely (less than 0.1%) included pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulopathy, and gingival bleeding. Coagulopathy, ecchymosis, GI bleeding, hemolytic anemia, thrombosis, and thrombocytopenia have been reported postmarketing, although causality to the drug has not been determined. An increased risk of bleeding complications is possible in patients receiving antiplatelet or anticoagulant medications concurrently with citalopram.

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 a dehydrated state, 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 citalopram, as well as implementation of the appropriate medical interventions.

Sinus tachycardia, hypotension, and orthostatic hypotension were reported in 1% or more of citalopram-treated patients during pre-marketing evaluation. Other cardiovascular events including hypertension, bradycardia, peripheral edema, angina pectoris, extrasystoles, heart failure, flushing, syncope, myocardial infarction, cerebrovascular accident (stroke), myocardial ischemia were reported infrequently (0.1% to 1%). Rarely (less than 0.1%), transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, and bundle-branch block occurred. Chest pain (unspecified), ventricular fibrillation, and ventricular tachycardia have been reported during postmarketing use. Citalopram causes a dose-dependent QT prolongation; torsade de pointes (TdP) has been reported during postmarketing use. During a placebo-controlled electrocardiogram study evaluating outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline, 1.9% of citalopram-treated patients had a change from baseline in QTcF more than 60 msec compared to 1.2% of placebo-treated patients. None of the patients in the placebo group had a post-dose QTcF more than 500 msec compared to 0.5% of citalopram-treated patients. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of citalopram-treated patients who were bradycardia outliers was 0.9% versus 0.4% of placebo-treated patients. Citalopram was also evaluated for QT prolongation in a randomized, placebo and moxifloxacin controlled, crossover study in 119 healthy subjects. The maximum mean difference in individually corrected QTc (QTcNi) from the placebo arm was 8.5 (10.8) msec in the citalopram 20 mg group and 18.5 (21) msec in the citalopram 60 mg group. The predicted QTcNi change from placebo under the Cmax for a dose of 40 mg was 12.6 (14.3) msec.

During clinical trial evaluation, fatigue (5%) and fever (2%) were reported more frequently in citalopram-treated patients than in those receiving placebo. Fatigue was considered dose-related. Asthenia was associated with treatment discontinuation in 1% of citalopram-treated patients. Other general adverse effects reported in 0.1% to 1% of patients include hot flushes, rigors, and alcohol intolerance.

During clinical trial evaluation, dysmenorrhea (3%) occurred more frequently in patients receiving citalopram than placebo. Amenorrhea was reported in females at an incidence of 1% or more. Reproductive effects that occurred in 0.1% to 1% of patients, dependent on gender, included galactorrhea, mastalgia (breast pain), breast enlargement, and vaginal bleeding (hemorrhage). Similar to other SSRIs, hyperprolactinemia has occurred during treatment with citalopram, and may be associated with some adverse reproductive effects of the drug. Rarely (less than 0.1%), gynecomastia has been reported with citalopram use. Priapism, a medical emergency in males, has been reported rarely with all SSRIs, including citalopram, during postmarketing use. If priapism develops during treatment with an SSRI, the drug should be discontinued and appropriate medical interventions should be initiated.

During clinical trial evaluation of citalopram, hyperhidrosis occurred more frequently (11%) in patients receiving citalopram than placebo and was considered a dose-related response. Dermatologic and allergic effects that occurred in 1% or more of patients during premarketing evaluation of citalopram included rash (unspecified) and pruritus. Urticaria, acne vulgaris, skin discoloration, eczema, alopecia, atopic dermatitis, xerosis, photosensitivity, and psoriasis occurred in more than 0.1% but less than 1% of patients. Rarely (less than 0.1%), facial edema, hypertrichosis, decreased sweating, melanosis, cellulitis, and pruritus ani were reported. Serious allergic and dermatologic reactions, including anaphylaxis, anaphylactoid reactions, angioedema, erythema multiforme, and toxic epidermal necrolysis (TEN) have been reported postmarketing. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of citalopram according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Citalopram should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.

Upper respiratory tract infection (5%), rhinitis (5%), sinusitis (3%), and yawning (2%) occurred in patients receiving citalopram more frequently than in patients receiving placebo during clinical trial evaluation of citalopram; yawning was considered a dose-related response. Cough was reported in at least 1% of patients. Other respiratory events that occurred in 0.1% to 1% of patients included bronchitis, dyspnea, influenza-like symptoms, and pneumonia. Rarely (less than 0.1%), asthma, laryngitis, bronchospasm, pneumonitis, and increased sputum were reported. In reports from postmarketing use, anosmia and hyposmia have occurred.

Abnormal accomodation (blurred vision) and taste perversion (dysgeusia) were reported at an incidence of 1% or more during treatment with citalopram during clinical trials. Other adverse effects related to special senses that occurred in 0.1% to 1% of patients receiving citalopram included tinnitus, conjunctivitis, xerophthalmia, and ocular pain. Rarely (less than 0.1%), mydriasis, photophobia, diplopia, abnormal lacrimation, cataracts, keratitis, and taste loss were reported. Angle closure glaucoma (ocular hypertension) has been reported during postmarketing.

Citalopram is extensively metabolized in the liver. Rare (1% or less) adverse hepatobiliary effects reported during premarketing evaluation of citalopram included elevated hepatic enzymes, hyperbilirubinemia, and hepatitis. Hepatic necrosis has been reported during postmarketing use.

During premarketing evaluation, polyuria was the most frequently reported urinary effect (1% or more). Increased urinary frequency, urinary incontinence, urinary retention, and dysuria were reported in 0.1% to 1% of patients. Rarely (less than 0.1%), hematuria, oliguria, pyelonephritis, nephrolithiasis, and renal flank pain occurred. Acute renal failure (unspecified) and rhabdomyolysis have been reported during postmarketing use.

Similar to other SSRIs, citalopram has been associated with altered glycemic control, although this effect appears to be infrequent. Metabolic and nutritional orders reported during clinical trials include abnormal glucose tolerance or hyperglycemia (0.1 to 1%). Rarely (less than 0.1%), dehydration, hypoglycemia and hypokalemia have been reported with citalopram use. Rare endocrine disorders include hypothyroidism and goiter.

Arthralgia (2%) and myalgia (2%) occurred in citalopram-treated patients more frequently than in patients receiving placebo. Arthritis, myasthenia, leg muscle cramps, and bone pain occurred in 0.1% to 1% of patients. Rarely (less than 0.1%), bursitis and osteoporosis were reported. Selective serotonin reuptake inhibitors (SSRIs) should be used cautiously 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 may be associated with reduced bone density.

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. 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, citalopram and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

A withdrawal syndrome has been reported during post-marketing use of citalopram. The most commonly reported SSRI discontinuation symptoms include fatigue, abdominal pain or nausea, dizziness/light-headedness, tremor, chills, diaphoresis, and incoordination. Other reported symptoms include dysphoric mood, impaired memory, insomnia, irritability, shock sensations, headache, paresthesia, agitated state, and aggression. Withdrawal symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and remit within 1 to 2 weeks. The difference in the incidence of withdrawal symptoms among SSRIs is most likely due to differences in the half-lives of the active moieties. Nevertheless, gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of withdrawal symptoms. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

A neonatal abstinence syndrome has been reported in infants exposed to serotonergic agents such as citalopram in utero 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. Additionally, 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 maternal use of SSRIs in the third trimester and the development of persistent pulmonary hypertension of the newborn (PPHN). 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 citalopram. 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. In controlled clinical trials of citalopram, patients had an average weight loss of approximately 0.5 kg compared to no change in those receiving placebo. 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.

Citalopram is contraindicated in patients with a citalopram hypersensitivity or hypersensitivity to any of the formulation components. Escitalopram is the active isomer of racemic citalopram; therefore, the two drugs should not be taken together as this would constitute duplicative therapy. Cross-sensitivity with citalopram should be anticipated in patients with an escitalopram hypersensitivity.

Avoid abrupt discontinuation of any SSRI if possible. Gradual tapering is recommended during discontinuation of citalopram 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.

The risks or benefits of using citalopram during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date.

Citalopram is not FDA-approved for use in pediatric patients. Antidepressants increased the risk of suicidal thoughts and behavior in children and adolescents in short-term studies. If used in pediatric patients, prescribe citalopram 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. 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.

Citalopram has demonstrated anticonvulsant effects in animal studies. However, since citalopram has not been systematically evaluated in patients with seizures or a history of seizure disorder, it should be used cautiously in such patients. In clinical trials, seizures occurred in 0.3% of patients treated with citalopram and 0.5% of patients treated with placebo.

Renal excretion of unchanged citalopram is a minor route of elimination. Dosage adjustments are not necessary in patients with mild to moderate renal impairment. Citalopram should be used with caution in patients with severe renal impairment (i.e., CrCl less than 20 mL/minute) or renal failure until these populations have been evaluated during chronic treatment with citalopram. There is no information on the use of citalopram in patients with chronic renal failure who receive hemodialysis.

Citalopram causes dose-dependent QT prolongation which, in some cases, has been associated with torsade de pointes (TdP), ventricular tachycardia, and sudden death. Hence, citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure, or in patients receiving medications associated with QT prolongation. However, if citalopram therapy is considered essential under any of these circumstances, ECG monitoring is recommended. Patients at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia and/or hypomagnesemia should be corrected prior to treatment initiation. Use citalopram with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, 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. A lower maximum daily dose is recommended in patients with hepatic impairment, those who are poor metabolizers of CYP2C19, or those who are receiving a concurrent CYP2C19 inhibitor since higher systemic exposures would be expected, increasing the risk for QT prolongation. Patients who develop symptoms of arrhythmia (e.g., dizziness, palpitation, syncope) should undergo prompt evaluation and cardiac monitoring. Citalopram should be discontinued in patients who experience persistent QTc measurements above 500 milliseconds.

Citalopram should be used with caution in patients with hepatic disease because the drug is extensively metabolized in the liver. The maximum recommended dose for adult patients with hepatic impairment or who are CYP2C19 poor metabolizers is 20 mg/day, due to the risk of QT prolongation from decreased clearance and increased plasma concentrations of the drug. Quantitative guidelines for dose limits are not available for pediatric patients with hepatic impairment or who are CYP2C19 poor metabolizers. The use of citalopram capsules is not recommended in patients with mild, moderate, or severe hepatic impairment or CYP2C19 poor metabolizers because dosage adjustments are not possible with the available strength of the capsules.

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 citalopram, as well as implementation of the appropriate medical interventions.

Decreased appetite and weight loss have been observed during administration of SSRIs. Therefore, caution is advisable when administering citalopram to patients with anorexia nervosa or other conditions where weight loss is undesirable.

Citalopram did not produce impairment of intellectual function or psychomotor performance in studies in normal volunteers. However, because impairment of judgment, thinking, or motor skills can occur, patients should use caution when engaging in activities requiring coordination and concentration until they are aware of the effects of citalopram on their cognition.

Monitor patients taking an SSRI such as citalopram 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 should be instructed to promptly report any bleeding events to the practitioner.

Caution is recommended when prescribing citalopram 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.

Citalopram is contraindicated for concomitant use in patients receiving MAOI therapy, due to the risk for serotonin syndrome. Citalopram should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders. Conversely, at least 14 days should be allowed after stopping citalopram before starting an MAOI intended to treat psychiatric disorders. In addition, do not start citalopram in a patient who is being treated with linezolid or intravenous methylene blue. Serotonin syndrome has been reported with SSRIs and SNRIs, including citalopram, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort). If such symptoms occur, discontinue citalopram and initiate supportive treatment. If concomitant use of citalopram with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

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 citalopram. 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. 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.

Description: Citalopram is a selective serotonin reuptake inhibitor (SSRI). Unlike some SSRIs, citalopram is not FDA approved for any use in children or adolescents, although it has been used off-label in children as young as 6 years of age. Several clinical guidelines, including the American Academy of Child and Adolescent Psychiatry (AACAP) practice parameter, describe a role for SSRIs in treating childhood depression, although there is limited evidence of efficacy for citalopram. Based on the positive results of one randomized controlled trial, these guidelines recommend citalopram as an alternative to fluoxetine in patients with intolerance, potential drug interactions, lack of or poor response, and/or family resistance to fluoxetine. In addition, some data suggest that citalopram is effective in treating childhood anxiety, and AACAP considers SSRIs the medications of choice in treating childhood anxiety disorders when pharmacologic therapy is indicated. Product labels for all antidepressants contain a warning related to an increased risk of suicidality in children and adolescents, particularly during initial treatment. Citalopram is associated with a dose-related risk of QT prolongation, and precautions apply to those with cardiac conditions, hepatic disease, and during use of certain CYP inhibitors.

For the treatment of major depression*:
Oral dosage:
Children and Adolescents 7 to 17 years: 10 mg PO once daily, initially. Some experts recommend initial doses of 20 mg/day PO in those 12 years and older, and a few pediatric studies have used this higher starting dose in patients as young as 7 years. Guidelines recommend starting with a low dose and increasing the dose by 10 mg/day at 4-week intervals if inadequate response and depending on tolerability. Some studies have reported titration as often as every week. A dose of 20 mg/day PO is considered effective; reported mean dose range is 20 to 25 mg/day. Max: 40 mg/day or 20 mg/day in CYP2C19 poor metabolizers. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with minimal or no response after 8 weeks of treatment will likely need alternative treatment. Continuation of medication for 6 to 12 months after symptom remission is recommended; those who require further maintenance therapy should be periodically reassessed to determine the need for ongoing treatment.

For the treatment of social phobia (social anxiety disorder)*:
Oral dosage:
Children and Adolescents 8 to 17 years: 10 mg PO once daily initially, followed by titration to response and tolerability. Data are extremely limited. In one small, open-label pilot study combining pharmacologic with psychotherapeutic interventions, 12 patients received an initial citalopram dose of 10 mg/day PO followed by upward titration to a maximum of 40 mg/day based upon response and tolerability. Nine children completed the study (12 weeks). Based on clinician global ratings of change, 41.7% of subjects were very much improved and 41.7% were much improved. No subjects worsened. At study end, the mean dosage was 35 mg/day. Patients should be periodically reassessed to determine the need for ongoing maintenance treatment. Max: 40 mg/day in the general population and 20 mg/day in poor metabolizers of CYP2C19 due to the potential for QT prolongation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of obsessive-compulsive disorder (OCD)*:
Oral dosage:
Children and Adolescents 6 to 17 years: 10 mg PO once daily initially, followed by titration based on response and tolerability. Data are extremely limited. Results from small open-label studies suggest a possible role of citalopram in the treatment of childhood OCD. In one study, citalopram was initiated at 10 mg/day PO followed by titration based upon response and tolerability to a maximum dose of 20 mg/day PO in children (6 years of age and older) and 30 mg/day PO in adolescents. Ninety-three percent of participants were considered responders according to the primary efficacy measure (CY-BOCS). In a separate study, doses of 10 to 40 mg/day PO were effective in 75% of participating children and adolescents (9 years of age and older). Patients should be periodically reassessed to determine the need for ongoing maintenance treatment. Max: 40 mg/day in the general population and 20 mg/day in poor metabolizers of CYP2C19 due to the potential for QT prolongation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of posttraumatic stress disorder (PTSD)*:
Oral dosage:
Adolescents: Data are limited. One open study has suggested that 20 mg/day PO is effective. Max: 40 mg/day in the general population and 20 mg/day in poor metabolizers of CYP2C19 due to the potential for QT prolongation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

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 12 years: Safety and efficacy have not been established; however, doses up to 40 mg/day PO have been used off-label for depression and anxiety disorders. Do not exceed 20 mg/day PO in poor metabolizers of CYP2C19.
-Adolescents
Safety and efficacy have not been established; however, doses up to 40 mg/day PO have been used off-label for depression and anxiety disorders. Do not exceed 20 mg/day PO in poor metabolizers of CYP2C19.

Patients with Hepatic Impairment Dosing
Citalopram 20 mg/day PO is the recommended maximum dose in adults with hepatic impairment, due to the risk of QT prolongation. There are no guidelines available for pediatric patients.

Patients with Renal Impairment Dosing
CrCl 20 mL/minute or more: No dosage adjustment is necessary.
CrCl less than 20 mL/minute: Specific guidelines for dosage adjustments are not available due to lack of available data.

Intermittent hemodialysis
Citalopram is unlikely to be significantly removed by hemodialysis given its large volume of distribution. Use caution when administering citalopram to patients with CrCl less than 20 mL/minute.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The precise antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), including citalopram, is not fully understood but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase 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 an important mechanism of effect. The therapeutic action of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin reuptake blockade, although the exact mechanism is unknown. SSRIs have less sedative, anticholinergic, and cardiovascular effects than tricyclic antidepressants due to dramatically decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors. However, unlike other SSRIs, citalopram is associated with a known, dose-dependent risk of QT prolongation.

Pharmacokinetics: Citalopram is administered orally. Citalopram exhibits linear and dose-proportional pharmacokinetics over the therapeutic dosage range. The volume of distribution of citalopram is 12 L/kg. Protein binding of citalopram and its metabolites is about 80%. The parent drug is extensively metabolized in the liver. N-demethylation occurs primarily by the CYP3A4 and CYP2C19 isoenzymes. The concentrations of the metabolites in plasma are about one-half to one-tenth that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. The half-life of citalopram in a healthy adult is 35 hours. Only 20% of the systemic clearance of citalopram is due to renal clearance.

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2 and CYP2D6
The primary isoenzymes involved in the metabolism of citalopram are CYP3A4 and CYP2C19. Because citalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease citalopram clearance. Citalopram exposure is significantly increased in patients receiving CYP2C19 inhibitors or who are poor metabolizers of CYP2C19, and, due to dose-dependent QT prolongation, a lower maximum citalopram daily dosage is recommended in these patients. In vitro, citalopram is a mild inhibitor of CYP1A2 and CYP2D6. Based on in vitro studies, citalopram does not appear to inhibit other isoenzymes (e.g., 3A4, 2C9, or 2E1) to any clinically significant degree.


-Route-Specific Pharmacokinetics
Oral Route
The absolute oral bioavailability of citalopram is 80% relative to intravenous administration. The tablet and oral solution formulations are bioequivalent. Absorption is not affected by food. Peak plasma concentrations occur in approximately 4 hours. Steady-state is achieved within about 1 week of daily oral dosing.


-Special Populations
Hepatic Impairment
Citalopram clearance was reduced by 37% and the half-life was doubled in adult patients with reduced hepatic function compared to healthy controls. A lower maximum daily dose is recommended in patients with hepatic impairment due to the risk of QT prolongation.

Renal Impairment
In adult patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to healthy controls. No dosage adjustment is recommended in adult patients with mild to moderate renal impairment. No information is available about the pharmacokinetics of citalopram in patients with severe renal impairment (CrCl less than 20 mL/minute). Citalopram is unlikely to be significantly removed by hemodialysis given its large volume of distribution.

Other
CYP2C19 Poor Metabolizers
In poor metabolizers of CYP2C19, citalopram steady-state Cmax and AUC are increased by 68% and 70%, respectively. Due to dose-dependent QT prolongation, a lower maximum daily dosage is recommended in patients who are poor metabolizers of CYP2C19.