CITALOPRAM

Warnings and Precautions ( 5.3 , 5.4 ) 8/2023

1 INDICATIONS AND USAGE Citalopram Capsules are indicated for the treatment of Major Depressive Disorder (MDD) in adults [see Clinical Studies ( 14 )] . Citalopram Capsules is a selective serotonin reuptake inhibitor (SSRI) indicated for treatment of Major Depressive Disorder (MDD) in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Do not initiate treatment with Citalopram Capsules. Use another citalopram product for initial dosage titration or dosages other than 30 mg once daily. ( 2.1 ) Administer once daily with or without food. ( 2.1 ) Recommended dosage of Citalopram Capsules is 30 mg once daily. ( 2.1 ) Citalopram dosages above 40 mg once daily are not recommended due to the risk of QT prolongation. ( 2.1 ) When discontinuing Citalopram Capsules, reduce dose gradually. Gradual dosage reduction will require use of another citalopram product. ( 2.4 , 5.6 ) 2.1 Recommended Dosage Do not initiate treatment with Citalopram Capsules because the only available dose strength is 30 mg. Use another citalopram product for initial dosage, titration, and dosages other than 30 mg once daily. Refer to Prescribing Information of the other citalopram products for the recommended dosage for those products. Administer Citalopram Capsules orally, once daily, with or without food. Citalopram should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg once daily at an interval of no less than one week. Citalopram 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 Capsules Prior to initiating treatment with Citalopram Capsules 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 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepresssant At least 14 days must elapse between discontinuation of an monoamine oxidase inhibitor (MAOI) and initiation of therapy with Citalopram Capsules. Conversely, at least 14 days must elapse after stopping Citalopram Capsules before starting an MAOI antidepressant [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . 2.4 Discontinuing Treatment with Citalopram Capsules Adverse reactions may occur upon discontinuation of Citalopram Capsules [see Warnings and Precautions ( 5.6 )] . Gradually reduce the dosage rather than stopping Citalopram Capsules abruptly whenever possible. Given that 30 mg is only available dosage strength of Citalopram Capsules, gradual dosage reduction will require the use of another citalopram product.

3 DOSAGE FORMS AND STRENGTHS 30 mg: White to off-white powder filled in size “3” white opaque cap/white opaque body hard gelatin capsules imprinted with “CL” on cap and “30” on body in black ink. Citalopram capsules dosage strength is based on the active moiety, citalopram. Capsules: 30 mg ( 3 )

4 CONTRAINDICATIONS Citalopram Capsules is contraindicated in patients: 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 )] . taking pimozide because of risk of QT prolongation [see Drug Interactions ( 7 )] . with known hypersensitivity to citalopram or any of the inactive ingredients in Citalopram Capsules. Reactions have included angioedema and anaphylaxis [see Adverse Reactions ( 6.2 )] . Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing an MAOI. ( 4 ) Concomitant use of pimozide. ( 4 ) Known hypersensitivity to citalopram or any of the inactive ingredients of Citalopram Capsules. ( 4 )

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 Adolescent 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 commonly observed adverse reactions (incidence at least twice the incidence of placebo) are: fever, arthalgia, myalgia, anorexia, agitation, yawning, sinusitis, ejaculation disorder (primarily ejaculatory delay), decreased libido, and impotence ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of citalopram capsules for the treatment for major depressive disorder (MDD) in adults is based upon adequate and well-controlled studies of another citalopram product. The results of these adequate and well-controlled studies of citalopram are presented below. The safety for citalopram included 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 in 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 Treatment in Short-Term, Placebo-Controlled, Depression Trials Body System/Adverse Reaction Citalopram* (N=1,063) % Placebo (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 cat …

7 DRUG INTERACTIONS Table 5 presents clinically important drug interactions with Citalopram Capsules. CYP2C19 inhibitors and CYP2C19 poor metabolizers: Avoid concomitant use. There is an increased risk of QT prolongation with concomitant use. ( 7 ) Table 5: Clinically Important Drug Interactions with Citalopram Capsules Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs, including Citalopram Capsules, and MAOIs increases the risk of serotonin syndrome. Intervention: Citalopram Capsules is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . Pimozide Clinical Impact: Concomitant use of citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of citalopram alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Citalopram Capsules is contraindicated in patients taking pimozide [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Drugs that Prolong the QTc Interval Clinical Impact: Concomitant use of citalopram with drugs that prolong QT can cause additional QT prolongation compared to the use of citalopram alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of Citalopram Capsules with drugs that prolong the QT interval (Citalopram Capsules is contraindicated in patients taking pimozide) [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . CYP2C19 Inhibitors Clinical Impact: Concomitant use of citalopram with CYP2C19 inhibitors increases the risk of QT prolongation and/or ventricular arrhythmias compared to the use of citalopram alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of Citalopram Capsules with CYP2C19 inhibitors [see Warnings and Precautions ( 5.2 )]. Other Serotonergic Drugs Clinical Impact: Concomitant use of Citalopram Capsules with other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during Citalopram Capsules initiation and changes in citalopram dosage. If serotonin syndrome occurs, consider discontinuation of Citalopram Capsules and/or concomitant serotonergic drugs [see Dosage and Administration ( 2.1 , 2.4 ), Warnings and Precautions ( 5.3 )] . Drugs That Interfere With Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: Concomitant use of citalopram and an antiplatelet or anticoagulant may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of Citalopram Capsules and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions ( 5.4 )].

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 ) Elderly patients: Not recommended. ( 8.5 ) Hepatic Impairment: Not recommended. ( 8.6 ) 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 register patients 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 Capsules, 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 Capsules 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 gener …

12.1 Mechanism of Action The mechanism of action of citalopram as an antidepressant 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 capsules contain citalopram, a selective serotonin reuptake inhibitor (SSRI). Citalopram hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5carbonitrile, 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 is a white to almost white crystalline powder. Citalopram hydrobromide is freely soluble in methanol, sparingly soluble in water, in alcohol and in chloroform. Citalopram capsules is for oral administration and contains 30 mg of citalopram, equivalent to 37.5 mg of citalopram hydrobromide, USP. The strengths reflect citalopram base equivalent content. Citalopram capsules also contain the inactive ingredients copovidone, corn starch, croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The hard gelatin capsule shell contains gelatin and titanium dioxide. The capsules are imprinted with black ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac. str

10 OVERDOSAGE The following have been reported with citalopram tablet overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension most commonly seen, but rarely can see hypotension alone or with co‐ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in citalopram capsules overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a citalopram capsules overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Citalopram Capsules are supplied as: 30 mg capsules: Hard shell gelatin capsules, with “ALM” printed axially on the blue opaque cap in black ink and “691” printed axially on the white opaque body in black ink: NDC 52427-691-30 Bottle of 30 capsules Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].