Citalopram: Package Insert and Label Information

CITALOPRAM- citalopram hydrobromide tablet, film coated
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

Citalopram tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Administer citalopram tablets once daily, with or without food, at an initial dosage of 20 mg once daily, with an increase to a maximum dosage of 40 mg once daily at an interval of no less than one week.

Dosages above 40 mg once daily are not recommended due to the risk of QT prolongation [see Warnings and Precautions (5.2)].

2.2 Screen for Bipolar Disorder Prior to Starting Citalopram Tablets

Prior to initiating treatment with citalopram tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.5)].

2.3 Recommended Dosage for Specific Populations

The maximum recommended dosage of citalopram tablets for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers is 20 mg once daily [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

2.4 Dosage Modifications with Concomitant Use of CYP2C19 Inhibitors

The maximum recommended dosage of citalopram tablets when used concomitantly with a CYP2C19 inhibitor is 20 mg once daily [see Warnings and Precautions (5.2), Drug Interactions (7)].

2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of therapy with citalopram tablets. Conversely, at least 14 days must elapse after stopping citalopram tablets before starting an MAOI antidepressant [see Contraindications (4) and Warnings and Precautions (5.3)].

2.6 Discontinuing Treatment with Citalopram Tablets

Adverse reactions may occur upon discontinuation of citalopram tablets [see Warnings and Precautions (5.6)]. Gradually reduce the dosage rather than stopping citalopram tablets abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS

Citalopram Tablets, USP are available containing citalopram hydrobromide, USP equivalent to 10 mg, 20 mg or 40 mg citalopram.

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The 10 mg tablets are orange, film-coated, round, unscored tablets debossed with MX31 on one side of the tablet and plain on the other side.

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The 20 mg tablets are pink, film-coated, round, scored tablets debossed with MX32 on one side of the tablet and a score line on the other side.

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The 40 mg tablets are white, film-coated, round, scored tablets debossed with MX33 on one side of the tablet and a score line on the other side.

4 CONTRAINDICATIONS

Citalopram tablets are contraindicated in patients:

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taking, or within 14 days of stopping, MAOIs (including MAOIs such as linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)].

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taking pimozide because of risk of QT prolongation [see Drug Interactions (7)].

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with known hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets. Reactions have included angioedema and anaphylaxis [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

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 tablets are 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
18-24 years old	5 additional patients
	Decreases Compared to Placebo
25-64 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 tablets, 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 tablets 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 tablets doses, it is recommended that citalopram tablets not be given at doses above 40 mg once daily [see Dosage and Administration (2.1), Clinical Pharmacology (12.2)].

Citalopram tablets 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 tablets 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 tablets 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 tablets 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 tablets in patients who are found to have persistent QTc measurements > 500 ms. If patients taking citalopram tablets 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 tablets, 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, 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 of serotonin syndrome were noted in 0.1% of MDD patients treated with citalopram tablets 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 tablets with MAOIs is contraindicated. In addition, do not initiate citalopram tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking citalopram tablets, discontinue citalopram tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)].

Monitor all patients taking citalopram tablets for the emergence of serotonin syndrome. Discontinue treatment with citalopram tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of citalopram tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including citalopram tablets, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of citalopram tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions (7)].

5.5 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with citalopram tablets or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were excluded; however, symptoms of mania or hypomania were reported in 0.1% of undiagnosed patients treated with citalopram tablets. Prior to initiating treatment with citalopram tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.2)].

5.6 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.6)].

5.7 Seizures

Citalopram tablets have not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. In clinical trials of citalopram tablets, seizures occurred in 0.3% of patients treated with citalopram tablets (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Citalopram tablets should be prescribed with caution in patients with a seizure disorder.