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.

CELEXA is indicated for the treatment of major depressive disorder (MDD) in adults . CELEXA is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) in adults.

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

Administer once daily with or without food . Initial dosage is 20 mg once daily; after one week may increase to maximum dosage of 40 mg once daily. Patients greater than 60 years of age, patients with hepatic impairment, and CYP2C19 poor metabolizers: maximum recommended dosage is 20 mg once daily. When discontinuing CELEXA, reduce dosage gradually

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

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 . 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 , Clinical Pharmacology ]

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 . 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 . 2. 6 Discontinuing Treatment with C ELEXA Adverse reactions may occur upon discontinuation of CELEXA . Gradually reduce the dosage rather than stopping CELEXA abruptly whenever possible.

QT-Prolongation and Torsade de Pointes : Dose-dependent QTc prolongation, Torsade de pointes, ventricular tachycardia, and sudden death have occurred. Avoid use of CELEXA 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 CELEXA 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 CELEXA and serotonergic agents and initiate supportive measures. In cr eased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin and other anticoagulants may increase this risk. Activation of Mania/Hypomania : Screen patients for bipolar disorder. Seizures: Use with caution in patients with seizure disorder. Angle-Closure Glaucoma: Avoid use of CELEXA in patients with untreated anatomically narrow angles. Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone secretion. Sexual Dysfunction : CELEXA may cause symptoms of sexual dysfunction

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 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 *CELEXA is not approved for use in pediatric 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 CELEXA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors

QT-Prolongation and Torsade de Pointes CELEXA 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 . Because of the risk of QTc prolongation at higher CELEXA doses, it is recommended that CELEXA not be given at doses above 40 mg once daily . CELEXA 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. CELEXA should also be avoided in patients who are taking other drugs that prolong the QTc interval . 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 . Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for treatment with CELEXA 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 CELEXA use is not recommended unless the benefits clearly outweigh the risks for a particular patient . These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval. Discontinue CELEXA in patients who are found to have persistent QTc measurements >500 ms. If patients taking CELEXA 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

Serotonin Syndrome SSRIs, including CELEXA, 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 . 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 CELEXA 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 CELEXA with MAOIs is contraindicated. In addition, do not initiate CELEXA 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 CELEXA, discontinue CELEXA before initiating treatment with the MAOI . Monitor all patients taking CELEXA for the emergence of serotonin syndrome. Discontinue treatment with CELEXA and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of CELEXA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms

Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including CELEXA, 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. Based on data from the 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 . 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 CELEXA and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ see Drug Interactions]

Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with CELEXA 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 CELEXA. Prior to initiating treatment with CELEXA, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [se e Dosage and Administration] . 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 [se e Dosage and Administration]

Seizures CELEXA has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. In clinical trials of CELEXA, seizures occurred in 0.3% of patients treated with CELEXA (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). CELEXA should be prescribed with caution in patients with a seizure disorder

Angle-closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including CELEXA, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including CELEXA, in patients with untreated anatomically narrow angles. 5. 9 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including CELEXA. Cases of serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue CELEXA and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [ see Use in Specific Populations ]

0 Sexual Dysfunction Use of SSRIs, including CELEXA, may cause symptoms of sexual dysfunction [ see Adverse Reactions ] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of CELEXA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

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 . 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 . Intervention: CELEXA is contraindicated in patients taking pimozide . 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 . Intervention: Avoid concomitant use of CELEXA with drugs that prolong the QT interval (CELEXA is contraindicated in patients taking pimozide) . 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 . Intervention: The maximum recommended dosage of CELEXA is 20 mg daily when used concomitantly with a CYP2C19 inhibitor . 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] . 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] . CYP2C19 Inhibitors: CELEXA 20 mg daily is the maximum recommended dosage for patients taking concomitant CYP2C19 inhibitors ( 5.2 , 7.1).