CITALOPRAM- citalopram hydrobromide_tablet, film coated

CLINICAL PHARMACOLOGY
The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro in vivo 1A, 2A 1 2, 1 2 1 The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2. 5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. In vitro Age - Citalopram pharmacokinetics in subjects >= 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects >= 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS DOSAGE AND ADMINISTRATION WARNINGS DOSAGE AND ADMINISTRATION max WARNINGS DOSAGE AND ADMINISTRATION In vitro in vivo in vivo WARNINGS DOSAGE AND ADMINISTRATION The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e. , patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc. ) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
Pharmacodynamics
The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro in vivo 1A, 2A 1 2, 1 2 1
Pharmacokinetics
The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2. 5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. In vitro Age - Citalopram pharmacokinetics in subjects >= 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects >= 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS DOSAGE AND ADMINISTRATION WARNINGS DOSAGE AND ADMINISTRATION max WARNINGS DOSAGE AND ADMINISTRATION In vitro in vivo in vivo WARNINGS DOSAGE AND ADMINISTRATION.
ANIMAL TOXICOLOGY
Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day (13 times the maximum recommended daily human dose of 60 mg on a mg/m 2 2 In a one-year toxicology study, 5 of 10 beagle dogs receiving oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of 60 mg on a mg/m 2 www. aurobindousa. com/product-medication-guides Aurobindo Pharma USA LLC Aurobindo Pharma Limited.
Cardiovascular Changes in Dogs
In a one-year toxicology study, 5 of 10 beagle dogs receiving oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of 60 mg on a mg/m 2 www.aurobindousa.com/product-medication-guides Aurobindo Pharma USA LLC Aurobindo Pharma Limited

Citalopram tablets, USP are indicated for the treatment of depression. CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY

DOSAGE AND ADMINISTRATION
Citalopram tablets should be administered once daily, in the morning or evening, with or without food. Citalopram tablets 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. 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 Neonates exposed to citalopram tablets and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram tablets in two studies have 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 tablets (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 tablets 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 CLINICAL PHARMACOLOGY Symptoms associated with discontinuation of citalopram tablets and other SSRIs and SNRIs have been reported (see PRECAUTIONS At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram tablets. Conversely, at least 14 days should be allowed after stopping citalopram tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS Do not start citalopram tablets 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 WARNINGS WARNINGS.
Initial Treatment
Citalopram tablets 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.

Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including citalopram, alone but particularly 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 (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). CONTRAINDICATIONS DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
The premarketing development program for citalopram included citalopram exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1370 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 were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. Among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i. , 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 Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled, Depression Trials Body System/Adverse Event Percentage of Patients Discontinuing Citalopram Placebo General Asthenia 1% <1% Gastrointestinal Disorders Nausea 4% 0% Dry Mouth 1% <1% Vomiting 1% 0% Central and Peripheral Nervous System Disorders Dizziness 2% <1% Psychiatric Disorders Insomnia 3% 1% Somnolence 2% 1% Agitation 1% <1% Table 3 TABLE 3 TABLE 3 Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials* Body System/Adverse Event (Percentage of Patients Citalopram Placebo * Events reported by at least 2% of patients treated with citalopram are reported, except for the following events which had an incidence on placebo >= citalopram: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain. 1 2 3 Autonomic Nervous System Disorders Dry Mouth 20% 14% Sweating Increased 11% 9% Central & Peripheral Nervous System Disorders Tremor 8% 6% Gastrointestinal Disorders Nausea 21% 14% Diarrhea 8% 5% Dyspepsia 5% 4% Vomiting 4% 3% Abdominal Pain 3% 2% General Fatigue 5% 3% Fever 2% <1% Musculoskeletal System Disorders Arthralgia 2% 1% Myalgia 2% 1% Psychiatric Disorders Somnolence 18% 10% Insomnia 15% 14% Anxiety 4% 3% Anorexia 4% 2% Agitation 3% 1% Dysmenorrhea 1 3% 2% Libido Decreased 2% <1% Yawning 2% <1% Respiratory System Disorders Upper Respiratory Tract Infection 5% 4% Rhinitis 5% 3% Sinusitis 3% <1% Urogenital Ejaculation Disorder 2,3 6% 1% Impotence 3 3% <1% The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10 mg, 20 mg, 40 mg, and 60 mg. Jonckheere’s trend test revealed a positive dose response (p<0. 05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning. Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Treatment Citalopram Placebo Abnormal Ejaculation 6. 1% 1% Libido Decreased 3. 8% <1% Impotence 2. 8% <1% In female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1. 3% (n=638 females) and 1. 1% (n=252 females), respectively. Citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes. Patients treated with citalopram in controlled trials experienced a weight loss of about 0. 5 kg compared to no change for placebo patients. Citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment. In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS Table 3 Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Rare: Frequent: Infrequent: Rare: Infrequent: Rare: Infrequent: Rare: Frequent: Infrequent: Rare: Infrequent Rare Frequent: Infrequent: Rare: - Frequent: Infrequent Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, angle closure glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.
Adverse Findings Observed in Short-Term,Placebo-Controlled Trials
Among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i. , 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 Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled, Depression Trials Body System/Adverse Event Percentage of Patients Discontinuing Citalopram Placebo General Asthenia 1% <1% Gastrointestinal Disorders Nausea 4% 0% Dry Mouth 1% <1% Vomiting 1% 0% Central and Peripheral Nervous System Disorders Dizziness 2% <1% Psychiatric Disorders Insomnia 3% 1% Somnolence 2% 1% Agitation 1% <1% Table 3 TABLE 3 TABLE 3 Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials* Body System/Adverse Event (Percentage of Patients Citalopram Placebo * Events reported by at least 2% of patients treated with citalopram are reported, except for the following events which had an incidence on placebo >= citalopram: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain. 1 2 3 Autonomic Nervous System Disorders Dry Mouth 20% 14% Sweating Increased 11% 9% Central & Peripheral Nervous System Disorders Tremor 8% 6% Gastrointestinal Disorders Nausea 21% 14% Diarrhea 8% 5% Dyspepsia 5% 4% Vomiting 4% 3% Abdominal Pain 3% 2% General Fatigue 5% 3% Fever 2% <1% Musculoskeletal System Disorders Arthralgia 2% 1% Myalgia 2% 1% Psychiatric Disorders Somnolence 18% 10% Insomnia 15% 14% Anxiety 4% 3% Anorexia 4% 2% Agitation 3% 1% Dysmenorrhea 1 3% 2% Libido Decreased 2% <1% Yawning 2% <1% Respiratory System Disorders Upper Respiratory Tract Infection 5% 4% Rhinitis 5% 3% Sinusitis 3% <1% Urogenital Ejaculation Disorder 2,3 6% 1% Impotence 3 3% <1% The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10 mg, 20 mg, 40 mg, and 60 mg. Jonckheere’s trend test revealed a positive dose response (p<0. 05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning. Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Treatment Citalopram Placebo Abnormal Ejaculation 6. 1% 1% Libido Decreased 3. 8% <1% Impotence 2. 8% <1% In female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1. 3% (n=638 females) and 1. 1% (n=252 females), respectively. Citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes. Patients treated with citalopram in controlled trials experienced a weight loss of about 0. 5 kg compared to no change for placebo patients. Citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment. In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes.
Other Events Observed During the Premarketing Evaluation of Citalopram Hydrobromide
Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS Table 3 Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Rare: Frequent: Infrequent: Rare: Infrequent: Rare: Infrequent: Rare: Frequent: Infrequent: Rare: Infrequent Rare Frequent: Infrequent: Rare: - Frequent: Infrequent Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Frequent: Infrequent: Rare:

The use of MAOIs intended to treat psychiatric disorders with citalopram tablets or within 14 days of stopping treatment with citalopram tablets are contraindicated because of an increased risk of serotonin syndrome. The use of citalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders are also contraindicated (see WARNINGS DOSAGE AND ADMINISTRATION WARNINGS DOSAGE AND ADMINISTRATION PRECAUTIONS

Pregnancy
Pregnancy Category C 2 2 2 2 2 2 Neonates exposed to citalopram and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the 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 features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS Serotonin Syndrome DOSAGE AND ADMINISTRATION.
Nursing Mothers
As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING WARNINGSen dash-Clinical Worsening and Suicide Risk
Geriatric Use
Of 4422 patients in clinical studies of citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 mg and 40 mg (see DOSAGE AND ADMINISTRATION PRECAUTIONS, Hyponatremia CLINICAL PHARMACOLOGY WARNINGS DOSAGE AND ADMINISTRATION
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
Treatment of Pregnant Women During the Third Trimester
Neonates exposed to citalopram tablets and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS

Drug Interactions
Serotonergic Drugs CONTRAINDICATIONS , WARNINGS , DOSAGE AND ADMINISTRATION . Triptans WARNINGS - Serotonin Syndrome - - CONTRAINDICATIONS WARNINGS DOSAGE AND ADMINISTRATION max WARNINGS DOSAGE AND ADMINISTRATION - max - - - - - - max WARNINGS , DOSAGE AND ADMINISTRATION , CLINICAL PHARMACOLOGY ). - - In vitro
Switching a Patient 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 tablets. Conversely, at least 14 days should be allowed after stopping citalopram tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS
Use of Citalopram Tablets with Other MAOIs,Such as Linezolid or Methylene Blue
Do not start citalopram tablets 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 WARNINGS WARNINGS

Clinical Efficacy Trials
The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e. , patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc. ) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
Comparison of Clinical Trial Results
Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
WARNINGS
Clinical Worsening and Suicide Risk There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 TABLE 1 Age Range Drug-Placebo Difference in Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case >=65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. PRECAUTIONS DOSAGE AND ADMINISTRATIONem dashDiscontinuation of Treatment with Citalopram Tablets Such monitoring should include daily observation by families and caregivers. Citalopram 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. max A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that citalopram is not approved for use in treating bipolar depression. The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including citalopram, alone but particularly 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 (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). CONTRAINDICATIONS DOSAGE AND ADMINISTRATION.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m 2 2 Citalopram was mutagenic in the in vitro in vitro in vitro in vitro/in vivo in vitro in vivo When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses >= 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m 2.
Labor and Delivery
The effect of citalopram on labor and delivery in humans is unknown.
Other Events Observed During the Postmarketing Evaluation of Citalopram Hydrobromide
It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, angle closure glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.
OVERDOSAGE
In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 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. 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.
Human Experience
In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 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.
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.
Maintenance Treatment
It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram tablets in two studies have 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 tablets (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 tablets 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 CLINICAL PHARMACOLOGY
Retinal Changes in Rats
Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day (13 times the maximum recommended daily human dose of 60 mg on a mg/m 2 2
MEDICATION GUIDE
Citalopram Tablets, USP What is the most important information I should know about citalopram tablets ? 1. Suicidal thoughts or actions: Citalopram tablets and other antidepressant medicines may increase suicidal thoughts or actions first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when citalopram tablets are started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Citalopram tablets may be associated with these serious side effects: 2. Changes in the electrical activity of your heart (QT prolongation and Torsade de Pointes). Chest pain fast or slow heartbeat shortness of breath dizziness or fainting 3. Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity 4. Severe allergic reactions: rash, itchy welts (hives) or blisters, alone or with fever or joint pain 5. Abnormal bleeding: registered registered 6. Seizures or convulsions 7. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts, reckless behavior unusually grand ideas excessive happiness or irritability, talking more or faster than usual 8. Changes in appetite or weight. 9. Low salt (sodium) levels in the blood. headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 10. Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Do not stop citalopram tablets without first talking to your healthcare provider. anxiety, irritability, high or low mood, feeling restless or changes in sleep habits headache, sweating, nausea, dizziness electric shock-like sensations, shaking, confusion What are citalopram tablets ? Major Depressive Disorder (MDD) Talk to your healthcare provider if you do not think that your condition is getting better with citalopram tablets treatment. Who should not take citalopram tablets? are allergic to citalopram or escitalopram or any of the ingredients in citalopram tablets. See the end of this Medication Guide for a complete list of ingredients in citalopram tablets. take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 2 weeks of stopping citalopram tablets unless directed to do so by your physician. Do not start citalopram tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take citalopram tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) have a heart problem including congenital long QT syndrome. Do not take citalopram tablets with Orap registered What should I tell my healthcare provider before taking citalopram tablets? Ask if you are not sure. Are taking certain drugs such as: Medicines for heart problems Medicines that lower your potassium or magnesium levels in your body Cimetidine Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, amphetamines, or antipsychotics Tramadol Over-the-counter supplements such as tryptophan or St. John’s Wort have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. It is not known if citalopram tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy are breast-feeding or plan to breastfeed. Some citalopram may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking citalopram tablets. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Citalopram tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects. If you take citalopram tablets, you should not take any other medicines that contain citalopram or escitalopram including: Lexapro. How should I take citalopram tablets ? Take citalopram tablets exactly as prescribed. Your healthcare provider may need to change the dose of citalopram tablets until it is the right dose for you. Citalopram tablets may be taken with or without food. If you miss a dose of citalopram tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of citalopram tablets at the same time. If you take too much citalopram, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking citalopram tablets? What are the possible side effects of citalopram tablets? See “What is the most important information I should know about citalopram tablets?” : Nausea Sleepiness Weakness Dizziness Feeling anxious Trouble sleeping Sexual problems Sweating Shaking Not feeling hungry Dry mouth Constipation Diarrhea Respiratory Infections Yawning Other side effects in children and adolescents include: increased thirst abnormal increase in muscle movement or agitation nose bleed urinating more often heavy menstrual periods possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with citalopram tablets. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of citalopram tablets. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store citalopram tablets ? Store citalopram tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Keep citalopram tablets bottle closed tightly. Keep citalopram tablets and all medicines out of the reach of children. General information about citalopram tablets What are the ingredients in citalopram tablets ? registered registered registered Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides Aurobindo Pharma USA, Inc. Aurobindo Pharma Limited

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CITALOPRAM- citalopram hydrobromide_tablet, film coated Product manual source documgent