Citalopram Hydrobromide

Warnings and Precautions ( 5.3 , 5.4 ) 8/2023

INDICATIONS AND USAGE Citalopram tablets, USP are indicated for the treatment of depression. The efficacy of citalopram 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 tablets, USP in hospitalized depressed patients has not been adequately studied. The efficacy of citalopram 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

DOSAGE AND ADMINISTRATION Citalopram tablets, USP should be administered once daily, in the morning or evening, with or without food. Initial Treatment Citalopram tablets, USP 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 should be used with caution in patients with severe renal impairment. Treatment of Pregnant Women During the Third Trimester Neonates exposed to citalopram 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 tablets 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 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 (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 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 Trials under CLINICAL PHARMACOLOGY ). 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 Tablets, USP Symptoms associated with discontinuation of citalopram 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. Conversely, at least 14 days should be allowed after stopping citalopram before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ). Use of Citalopram with Other MAOIs, Such as Linezolid or Methylene Blue Do not start citalopram 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 therapy may re …

3 DOSAGE FORMS AND STRENGTHS Citalopram tablets, USP are available as: • 10 mg: Tan coloured, round shaped, biconvex film coated tablets with ‘10’ debossed on one side and plain on the other side. • 20 mg: Tan coloured, oval shaped, biconvex film coated tablets with ‘2│0’ debossed (‘2’ on left side and ‘0’ on right side of the break line) on one side and ‘1010’ on the other side. • 40 mg: Tan coloured, oval shaped, biconvex film coated tablets with ‘4│0’ debossed (‘4’ on left side and ‘0’ on right side of the break line) on one side and ‘1011’ on the other side Tablets: 10 mg; 20 mg, scored; and 40 mg, scored ( 3 )

CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with citalopram or within 14 days of stopping treatment with citalopram is contraindicated because of an increased risk of serotonin syndrome. The use of citalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE and ADMINISTRATION ). Starting citalopram 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 hydrobromide is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hypersensitivity reactions [see Contraindications ( 4 )] Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions ( 5.1 )] QT-prolongation and torsade de pointes [see Warnings and Precautions ( 5.2 )] Serotonin syndrome [see Warnings and Precautions ( 5.3 )] Increased risk of bleeding [see Warnings and Precautions ( 5.4 )] Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] Discontinuation syndrome [see Warnings and Precautions ( 5.6 )] Seizures [see Warnings and Precautions ( 5.7 )] Angle-closure glaucoma [see Warnings and Precautions ( 5.8 )] Hyponatremia [see Warnings and Precautions ( 5.9 )] Sexual Dysfunction [see Warnings and Precautions ( 5.10 )] Most common adverse reaction (incidence ≥ 5% and twice placebo) is ejaculation disorder (primarily ejaculation delay) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Exelan Pharmaceuticals Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety for Citalopram included citalopram exposures in patients and/or healthy subjects from 3 different groups of studies: 429 healthy subjects in clinical pharmacology/pharmacokinetic studies; 4,422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1,370 patient-exposure years. There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies. The conditions and duration of treatment with Citalopram varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and short-term and long-term exposure. Adverse Reactions Associated with Discontinuation of Treatment Among 1,063 patients with MDD who received Citalopram at doses ranging from 10 mg to 80 mg once daily in placebo- controlled trials of up to 6 weeks duration, 16% discontinued treatment due to an adverse reaction, as compared to 8% of 446 patients receiving placebo. The adverse reactions associated with discontinuation (i.e., associated with discontinuation in at least 1% of Citalopram-treated patients at a rate at least twice that of placebo) are shown in Table 2. Table 2: Adverse Reactions Associated with Discontinuation of Citalopram Treatment in Short-Term, Placebo-Controlled MDD Trials * A patient can report more than one reason for discontinuation and be counted more than once in this table. Body System/Adverse Reaction Citalopram Placebo (N=1,063) % (N=446) % General Asthenia 1 60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-dose QTcF >500 msec compared to 0.5% of the patients in the Citalopram group. The incidence of tachycardic outliers was 0.5% in the Citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the Citalopram group and 0.4% in the placebo group. Other Adverse Reactions Observed During the Premarketing Evaluation of Citalopram The following list of adverse reactions does not include reactions that are: 1) included in Table 3 or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, and those occurring in only one patient. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in less t …

Drug Interactions Serotonergic Drugs: See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION. Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Error! Hyperlink reference not valid. ). CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs. Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended. Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)- Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued. Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and C max of 43% and 39%, respectively. Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see WARNINGS and DOSAGE AND ADMINISTRATION ) 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. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram and lithium are coadministered. 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. Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated. Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised. Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine - Combined administration …

8 USE IN SPECIFIC POPULATIONS Pregnancy: SSRI use, particularly late in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate ( 8.1 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.4 ) and Clinical Considerations] . Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including citalopram, during pregnancy . There also are risks associated with untreated depression in pregnancy (see Clinical Considerations) . In animal reproduction studies, citalopram caused adverse embryo/fetal effects at doses that caused maternal toxicity (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of citalopram tablet in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.4 )] . Fetal/Neonatal Adverse Reactions Neonates exposed to citalopram and other SSRIs late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.3 )] . Data Human Data Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1- 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Anima …

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).

11 DESCRIPTION Citalopram tablet contains citalopram hydrobromide, an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3- dihydroisobenzofuran-5-carbonitrile, hydrobromide with the following structural formula: The molecular formula is C 20 H 22 BrFN 2 O and its molecular weight is 405.35. Citalopram hydrobromide occurs as a fine, white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol. Citalopram is available only in tablet dosage form. Citalopram tablets, USP 10 mg are film-coated, round tablets containing citalopram hydrobromide in strengths equivalent to 10 mg citalopram base. Citalopram hydrobromide, USP 20 mg and 40 mg tablets are film-coated, round, scored tablets containing citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg citalopram base. Their strengths reflect their citalopram base equivalent content. The 10 mg, 20 mg and 40 mg strength tablets contain 12.49 mg, 24.98 mg and 49.96 mg of citalopram hydrobromide, respectively. The tablets also contain the following. Inactive ingredients : copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, opadry beige (HPMC 2910/hypromellose 6cp, titanium dioxide, macrogol/Peg400, iron oxide yellow and iron oxide red), opadry pink (HPMC 2910/hypromellose 6cP, titanium dioxide, macrogol/Peg400 and iron oxide red) and opadry white (titanium dioxide, HPMC 2910/hypromellose 3cp, HPMC 2910/ hypromellose 6cp, Macrogol/Peg400 and Polysorbate 80) are used as coloring agents in the beige (10 mg) and pink (20 mg) and white (40 mg) tablets. Image

OVERDOSAGE Human Experience In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2,000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6,000 mg, have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported. Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Management of Overdose Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for citalopram. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Citalopram Tablets, USP 10 mg: They are supplied in Bottle of 30 NDC # 76282-628-30, Bottle of 90 NDC # 76282-628-90, Bottle of 500 NDC # 76282-628-05 and Bottle of 1,000 NDC # 76282-628-10 Beige, film coated round, bi-convex tablets debossed with IG on one side and “206” on the other. 20 mg: They are supplied in Bottle of 30 NDC # 76282-629-30, Bottle of 90 NDC # 76282-629-90, Bottle of 500 NDC # 76282-629-05 and Bottle of 1,000 NDC # 76282-629-10 Pink, film coated, round, bi-convex tablets debossed with I on the left side of bisect and G on right side of bisect on one side and “207” on the other. 40 mg: They are supplied in Bottle of 30 NDC # 76282-208-30, Bottle of 90 NDC # 76282-208-90, Bottle of 500 NDC # 76282-208-05 and Bottle of 1,000 NDC # 76282-208-10 White, film coated, round, bi-convex tablets debossed with I on the left side of bisect and G on right side of bisect on one side and “208” on the other. Storage and Handling Citalopram tablets should be stored at 20-25°C (68 to 77°F); excursions permitted between 15 and 30°C (59-86°F) [see USP Controlled Room Temperature].