Celexa

Warnings and Precautions ( 5.3 , 5.4 ) 08/2023

1 INDICATIONS AND USAGE CELEXA is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )] . CELEXA is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) in adults ( 1 ).

2 DOSAGE AND ADMINISTRATION Administer once daily with or without food ( 2 ) . Initial dosage is 20 mg once daily; after one week may increase to maximum dosage of 40 mg once daily ( 2.1 ). Patients greater than 60 years of age, patients with hepatic impairment, and CYP2C19 poor metabolizers: maximum recommended dosage is 20 mg once daily ( 2.2 ). When discontinuing CELEXA, reduce dosage gradually ( 2.4 , 5.6 ). 2.1 Recommended Dosage Administer CELEXA 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 CELEXA Prior to initiating treatment with CELEXA 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 Speci fic Populations The maximum recommended dosage of CELEXA for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers is 20 mg once daily [ s ee Warnings and Precautions ( 5.2 ) , Clinical Pharmacology ( 12.3 ) ] . 2.4 Dosage Modification s with Concomitant Use of CYP2C19 Inhibitors The maximum recommended dosage of CELEXA 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 t o or f rom 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 CELEXA. Conversely, at least 14 days must elapse after stopping CELEXA before starting an MAOI antidepressant [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] . 2. 6 Discontinuing Treatment with C ELEXA Adverse reactions may occur upon discontinuation of CELEXA [see Warnings and Precautions ( 5.6 )] . Gradually reduce the dosage rather than stopping CELEXA abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS CELEXA tablets are available as: 10 mg: beige, oval with “FP” imprinted on one side, “10 mg” imprinted on the other side 20 mg: pink, oval, scored with “F” imprinted on left side of score line and "P" imprinted on right side of score line, “20 mg” imprinted on non-scored side 40 mg: white, oval, scored with “F” imprinted on left side of score line and "P" imprinted on right side of score line, “40 mg” imprinted on non-scored side Tablets: 10 mg; 20 mg, scored; and 40 mg, scored ( 3 )

4 CONTRAINDICATIONS CELEXA 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 CELEXA. 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 a MAOI ( 4 ). Concomitant use of pimozide ( 4 ) . Known hypersensitivity to citalopram or any of the inactive ingredients of CELEXA ( 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 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 AbbVie at 1-800-678-1605 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 CELEXA 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 CELEXA 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 CELEXA 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 CELEXA-treated patients at a rate at least twice that of placebo) are shown in Table 2 . Table 2: Adverse Reactions Associated with Discontinuation of CELEXA Treatment in Short-Term, Placebo-Controlled MDD Trials Body System/Adverse Reaction CELEXA 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 CELEXA group. The incidence of tachycardic outliers was 0.5% in the CELEXA group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the CELEXA group and 0.4% in the placebo group. Other Adverse Reactions Observed During the Premarketing Evaluation of CELEXA 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 than 1/100 patients to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients. Cardiovascular - Frequent: tachycardia, postural hypoten …

7 DRUG INTERACTIONS Table 5 presents clinically important drug interactions with CELEXA. Table 5: Clinically Important Drug Interactions with CELEXA Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of SSRIs, including CELEXA, and MAOIs increases the risk of serotonin syndrome. Intervention CELEXA is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.5 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . Pimozide Clinical Impact: Concomitant use of CELEXA 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 CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: CELEXA 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 CELEXA with drugs that prolong QT can cause additional QT prolongation compared to the use of CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: Avoid concomitant use of CELEXA with drugs that prolong the QT interval (CELEXA is contraindicated in patients taking pimozide) [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]. CYP2C19 Inhibitors Clinical Impact: Concomitant use of CELEXA with CYP2C19 inhibitors increases the risk of QT prolongation and/or ventricular arrhythmias compared to the use of CELEXA alone [see Clinical Pharmacology ( 12.2 )]. Intervention: The maximum recommended dosage of CELEXA is 20 mg daily when used concomitantly with a CYP2C19 inhibitor [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 )]. Other Serotonergic Drugs Clinical Impact: Concomitant use of CELEXA and 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 CELEXA initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of CELEXA and/or concomitant serotonergic drugs [ see Warning and Precautions ( 5.3 )] . Drugs That Interfere With Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: Concomitant use of CELEXA 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 CELEXA and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ see Warning and Precautions ( 5.4 )] . CYP2C19 Inhibitors: CELEXA 20 mg daily is the maximum recommended dosage for patients taking concomitant CYP2C19 inhibitors ( 5.2 , 7.1).

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 CELEXA, 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 CELEXA 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 CELEXA 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. Animal Data Citalopram …

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 CELEXA contains citalopram, a selective serotonin reuptake inhibitor (SSRI). Citalopram hydrobromide is a racemic bicyclic phthalane structure and is 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. CELEXA tablets are for oral administration and are available as film-coated oval tablets. The strengths reflect 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 20 mg and 40 mg tablets are scored. I nactive ingredients: copolyvidone, corn starch, crosscarmellose sodium, glycerin, lactose monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron oxides are used as coloring agents in the beige (10 mg) and pink (20 mg) tablets. the following structural formula:Celexa contains citalopram, a selective serotonin reuptake inhibitor (SSRI). Citalopram hydrobromide is a racemic bicyclic phthalane structure and is designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile hydrobromide.

10 OVERDOSAGE The following have been reported with CELEXA 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 CELEXA overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a CELEXA 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 CELEXA (citalopram) tablets are supplied as follows: Strength Color/Shape Engraved Descriptors Package Configuration NDC Number 10 mg Beige, oval “FP” on one side and “10 mg” on other side. Bottle of 100 NDC # 0456-4010-01 20 mg Pink, oval Scored with “F” on left side of score line and "P" on right side of score line; “20 mg” on non-scored side Bottle of 100 NDC # 0456-4020-01 10 x 10 unit dose NDC # 0456-4020-63 40 mg White, oval Scored with “F” on left side of score line and "P" on right side of score line; “40 mg” on non-scored side Bottle of 100 NDC # 0456-4040-01 10 x 10 unit dose NDC # 0456-4040-63 Storage and Handling CELEXA 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 ].