citalopram 20 MG Oral Tablet

INDICATIONS & USAGE Citalopram oral solution, USP is indicated for the treatment of depression. The efficacy of citalopram oral solution, USP in the treatment of depression was established in 4 to 6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-III and DSM-III-R category of major depressive disorder (see CLINICAL PHARMACOLOGY ). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The antidepressant action of citalopram oral solution, USP in hospitalized depressed patients has not been adequately studied. The efficacy of citalopram oral solution, USP in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials (see CLINICAL PHARMACOLOGY ). Nevertheless, the physician who elects to use citalopram oral solution, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

DOSAGE AND ADMINISTRATION Citalopram Oral Solution should be administered once daily, in the morning or evening, with or without food. Initial Treatment Citalopram Oral Solution should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose. Special Populations 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor ( see WARNINGS ). No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram Oral Solution should be used with caution in patients with severe renal impairment. Treatment of Pregnant Women During the Third Trimester Neonates exposed to Citalopram Oral Solution and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding ( see PRECAUTIONS ). When treating pregnant women with Citalopram Oral Solution during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Maintenance Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of Citalopram Oral Solution in two studies has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of Citalopram Oral Solution (20 to 60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of Citalopram Oral Solution 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups ( see CLINICAL PHARMACOLOGY ; Clinical Efficacy Trials ). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered. Discontinuation of Treatment with Citalopram Oral Solution Symptoms associated with discontinuation of Citalopram Oral Solution and other SSRIs and SNRIs have been reported ( see PRECAUTIONS ). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 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. Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Citalopram Oral Solution. Conversely, at least 14 days should be allowed after stopping Citalopram Oral Solution before starting an MAOI intended to treat psychiatric disorders ( see CONTRAINDICATIONS ). Use of Citalopram Oral Solution with Other MAOIs, Such as Linezolid or Methylene Blue Do not start Citalopram Oral Solution in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered ( see CONTRAINDICATIONS ). In some cases, a patient already receiving Citalopram Oral Solution therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Citalopram Oral Solution should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Citalopram Oral Solution may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue ( see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Citalopram Oral Solution is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use ( see WARNINGS ).

WARNINGS AND PRECAUTIONS QT-Prolongation and Torsade de Pointes : Dose-dependent QTc prolongation, Torsade de pointes, ventricular tachycardia, and sudden death have occurred. Avoid use of citalopram in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure and patients taking other drugs that prolong the QTc interval. Monitor electrolytes in patients at high risk for hypokalemia or hypomagnesemia. Discontinue citalopram in patients with persistent QTc measurements > 500 ms ( 5.2 , 7 ) . Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue citalopram and serotonergic agents and initiate supportive measures ( 5.3 ) . Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin and other anticoagulants may increase this risk ( 5.4 ) . Activation of Mania/Hypomania : Screen patients for bipolar disorder ( 5.5 ) . Seizures : Use with caution in patients with seizure disorder ( 5.7 ). Angle-Closure Glaucoma : Avoid use of citalopram in patients with untreated anatomically narrow angles ( 5.8 ) . Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone secretion ( 5.9 ) . Sexual Dysfunction : Citalopram may cause symptoms of sexual dysfunction. ( 5.10 ) . 5.1 Suicidal Thoughts and Behavior in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients *Citalopram is not approved for use in pediatric patients. Age Range* Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing citalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 QT-Prolongation and Torsade de Pointes Citalopram causes dose-dependent QTc prolongation an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram [see Adverse Reactions 6.2) ] . Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram not be given at doses above 40 mg once daily [see Dosage and Administration (2.1) , Clinical Pharmacology (12.2) ] . Citalopram should be avoided in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure unless the benefits outweigh the risks for a particular patient. Citalopram should also be avoided in patients who are taking other drugs that prolong the QTc interval [see Drug Interactions (7) ] . Such drugs include Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). The citalopram dose should be limited in certain populations. The maximum dose should be limited to 20 mg once daily in patients who are CYP2C19 poor metabolizers or those patients receiving concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected. The maximum dose should also be limited to 20 mg once daily in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures [see Dosage and Administration (2.3 , 2.4) , Drug Interactions (7) , Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) ] . Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for treatment with citalopram who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ECG monitoring is recommended in patients for whom citalopram use is not recommended unless the benefits clearly outweigh the risks for a particular patient (see above). These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval. Discontinue citalopram in patients who are found to have persistent QTc measurements >500 ms. If patients taking citalopram experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring. 5.3 Serotonin Syndrome SSRIs, including citalopram, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7) ]. Serotonin syndrome can also occur when these drugs are used alone. Symptoms ofserotonin syndrome were noted in 0.1% of MDD patients treated with citalopram in premarketing clinical trials. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of citalopram with MAOIs is contraindicated. In addition, do not initiate c

CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with citalopram oral solution or within 14 days of stopping treatment with citalopram oral solution is contraindicated because of an increased risk of serotonin syndrome. The use of citalopram oral solution within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE and ADMINISTRATION ). Starting citalopram oral solution in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION ). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS ). Citalopram oral solution is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in citalopram oral solution.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of citalopram is unclear, but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). 12.2 Pharmacodynamics In vitro and in vivo studies in animals suggest that citalopram is a selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Citalopram has no or very low affinity for 5-HT 1A , 5-HT 2A , dopamine D 1 and D 2 , α 1 -, α 2 -, and β-adrenergic, histamine H 1 , gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Cardiac Electrophysiology Individually corrected QT c (QT c Ni) interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 119 healthy subjects. The maximum mean (upper bound of the 95% one-sided confidence interval) difference from placebo were 8.5 (10.8) and 18.5 (21.0) msec for 20 mg and 60 mg (1.5 times the maximum recommended dosage) citalopram, respectively. Based on the established exposure-response relationship, the predicted QTcNi change from placebo (upper bound of the 95% one-sided confidence interval) under the C max for the dose of 40 mg is 12.6 (14.3) msec [see Warnings and Precautions ( 5.2 )] . 12.3 Pharmacokinetics The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. Absorption Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. Distribution The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. Elimination Metabolism Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, 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. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram. Excretion Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. Specific Populations Geriatric Patients Citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects ≥ 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.5 )] . Male and Female Patients In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. Patients with Hepatic Impairment Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.6 )] . Patients with Renal Impairment In patients with mild to moderate renal impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severe renal impairment (creatinine clearance < 20 mL/min). CYP2C19 poor metabolizers In CYP2C19 poor metabolizers, citalopram steady state C max and AUC was increased by 68% and 107%, respectively [see Dosage and Administration ( 2.3 ),Warnings and Precautions ( 5.2 )] . CYP2D6 poor metabolizers Citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6. Drug Interaction Studies In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these enzymes. However, in vivo data to address this question are limited. CYP3A4 and CYP2C19 Inhibitors Since CYP3A4 and CYP2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and inhibitors of CYP2C19 (e.g., omeprazole, cimetidine) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. 20 mg/day is the maximum recommended citalopram dose in patients taking concomitant cimetidine or another CYP2C19 inhibitor, because of the risk of QT prolongation [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Cimetidine In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and C max of 43% and 39%, respectively [see Dosage and Administration ( 4 ),Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . CYP2D6 Inhibitors Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers. Digoxin In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Pimozide In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or C max of pimozide. The mechanism of this pharmacodynamic interaction is not known [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Theophylline Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single do