citalopram hydrobromide

Bryant Ranch Prepack
Bryant Ranch Prepack

FULL PRESCRIBING INFORMATION: CONTENTS*

• CITALOPRAM HYDROBROMIDE DESCRIPTION
• CLINICAL PHARMACOLOGY
• CITALOPRAM HYDROBROMIDE INDICATIONS AND USAGE
• CITALOPRAM HYDROBROMIDE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General
  • Information for Patients
  • Laboratory Tests
  • Drug Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Labor and Delivery
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• CITALOPRAM HYDROBROMIDE ADVERSE REACTIONS
• DRUG ABUSE AND DEPENDENCE
• OVERDOSAGE
• CITALOPRAM HYDROBROMIDE DOSAGE AND ADMINISTRATION
• ANIMAL TOXICOLOGY
•                                                                  Medication Guide
• Citalopram 40mg Tablet

FULL PRESCRIBING INFORMATION

CITALOPRAM HYDROBROMIDE DESCRIPTION

Citalopram HBr is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile, HBr with the following structural formula:

The molecular formula is C H BrFN O and its molecular weight is 405.35. _{20 22 2}

Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is sparingly soluble in water and soluble in ethanol.

Citalopram 10 mg tablets, USP are film-coated, round, plain tablets containing citalopram HBr in strengths equivalent to 10 mg citalopram base. Citalopram 20 mg and 40 mg tablets, USP are film coated, oval, scored tablets containing citalopram HBr in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: Copolyvidone, Corn Starch, Croscarmellose Sodium, Lactose Monohydrate, Magnesium Stearate, Colloidal Silicon Dioxide, Microcrystalline Cellulose, Titanium Dioxide, Hypromellose 6, and Polyethylene Glycol-4000. In addition, citalopram tablet contains iron oxide red and yellow iron oxide; tablet contains iron oxide red and black iron oxide; tablet contains polysorbate 80. 10 mg 20 mg 40 mg

CLINICAL PHARMACOLOGY

CITALOPRAM HYDROBROMIDE INDICATIONS AND USAGE

Citalopram HBr, USP is indicated for the treatment of depression.

The efficacy of Citalopram tablets, USP in the treatment of depression was established in 4-6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-lll and DSM-lll-R category of major depressive disorder (see ). CLINICAL PHARMACOLOGY

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

The antidepressant action of Citalopram tablets, USP in hospitalized depressed patients has not been adequately studied.

The efficacy of Citalopram tablets, USP in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials (see ). Nevertheless, the physician who elects to use Citalopram tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CLINICAL PHARMACOLOGY

CITALOPRAM HYDROBROMIDE CONTRAINDICATIONS

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see ). WARNINGS

Concomitant use in patients taking pimozide is contraindicated (see ). PRECAUTIONS

Citalopram Hydrobromide tablets are contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in Citalopram Hydrobromide tablets.

WARNINGS

PRECAUTIONS

General

Discontinuation of Treatment with Citalopram Hydrobromide tablets

During marketing of Citalopram Hydrobromide tablets and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with Citalopram HBr tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see ). DOSAGE AND ADMINISTRATION

Abnormal Bleeding

SSRIs and SNRIs, including Citalopram HBr, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the 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. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Citalopram HBr and NSAIDs, aspirin, or other drugs that affect coagulation.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Citalopram HBr. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Citalopram HBr was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of Citalopram HBr should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

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.

Activation of Mania/Hypomania

In placebo-controlled trials of Citalopram HBr tablets, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with Citalopram HBr tablets and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed anti-depressants. As with all antidepressants, Citalopram should be used cautiously in patients with a history of mania.

Seizures

Although anticonvulsant effects of citalopram have been observed in animal studies, Citalopram HBr tablets has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In clinical trials of Citalopram HBr tablets, seizures occurred in 0.3% of patients treated with Citalopram HBr tablets (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).  Like other antidepressants, Citalopram HBr tablets should be introduced with care in patients with a history of seizure disorder.

Interference with Cognitive and Motor Performance

In studies in normal volunteers, Citalopram HBr tablets in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psycho-active drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Citalopram HBr tablets therapy does not affect their ability to engage in such activities.

Use in Patients with Concomitant Illness

Clinical experience with Citalopram HBr tablets in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Citalopram HBr tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Citalopram HBr tablets has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. However, the electrocardiograms of 1116 patients who received Citalopram HBr tablets in clinical trials were evaluated and the data indicate that Citalopram HBr tablets is not associated with the development of clinically significant ECG abnormalities.

In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of Citalopram HBr tablets in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see ). DOSAGE AND ADMINISTRATION

Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Citalopram HBr tablets however, it should be used with caution in such patients (see ). DOSAGE AND ADMINISTRATION

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe Citalopram HBr tablets.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Citalopram HBr tablets and triptans, tramadol or other serotonergic agents.

Although in controlled studies Citalopram HBr tablet has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Citalopram HBr tablet therapy does not affect their ability to engage in such activities.

Patients should be told that, although Citalopram HBr tablets has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of Citalopram HBr tablets and alcohol in depressed patients is not advised.

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

Patients should be cautioned about the concomitant use of Citalopram Hydrobromide tablets and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breast feeding an infant.

While patients may notice improvement with Citalopram HBr tablets therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Citalopram and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Citalopram.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Clinical Worsening and Suicide Risk:

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Based on the mechanism of action of SNRIs and SSRIs including Citalopram HBr tablets, and the potential for serotonin syndrome, caution is advised when Citalopram HBr tablet is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see ). The concomitant use of Citalopram HBr tablet with other SSRIs, SNRIs or tryptophan is not recommended (see ). Serotonergic Drugs: WARNINGS-Serotonin Syndrome PRECAUTIONS - Drug Interactions

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Citalopram HBr tablet with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see ). Triptans: WARNINGS - Serotonin Syndrome

CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking Citalopram HBr tablets is not recommended.

Monoamine Oxidase Inhibitors (MAOI’s) - See and . CONTRAINDICATIONS WARNINGS

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Citalopram is initiated or discontinued.

Cimetidine - In subjects who had received 21 days of 40 mg/day Citalopram Hydrobromide tablets, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and C of 43% and 39%, respectively. The clinical significance of these findings is unknown. _max

Digoxin - In subjects who had received 21 days of 40 mg/day Citalopram Hydrobromide tablets, combined administration of Citalopram Hydrobromide and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium - Coadministration of Citalopram HBr tablets (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when Citalopram HBr tablets and lithium are coadministered.

Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or C of pimozide. The mechanism of this pharmacodynamic interaction is not known. _max

Theophylline - Combined administration of Citalopram HBr tablets (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of Citalopram was not evaluated.

Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with Sumatriptan and an SSRI (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.

Warfarin - Administration of 40 mg/day Citalopram HBr tablets for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine - Combined administration of Citalopram HBr tablets (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Triazolam - Combined administration of Citalopram HBr tablets (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole - Combined administration of Citalopram HBr tablets (40 mg) and ketoconazole (200 mg) decreased the C and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. _max

CYP3A4 and 2C19 Inhibitors - studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. In vitro

Metoprolol - Administration of 40 mg/day Citalopram HBr tablets for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Citalopram HBr tablets and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine and Other Tricyclic Antidepressants (TCAs) - studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of Citalopram HBr tablets (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with Citalopram. In vitro

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and Citalopram HBr tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Citalopram HBr tablet 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 ) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown. ^{2 2}

Mutagenesis

Citalopram was mutagenic in the bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the chromosomal aberration assay in human lymphocytes or in two mouse micronucleus assays. in vitro in vitro in vitro in vitro/in vivo in vitro in vivo

Impairment of Fertility

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 ) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD. ²

Pregnancy

Pregnancy Category C

In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.

In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m ) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit. ^{2 2 2}

When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m basis. The no effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m basis. A no effect dose was not determined in that study. ^{2 2 2}

There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonates exposed to Citalopram Hydrobromide and other SSRIs or 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

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating a pregnant woman with Citalopram Hydrobromide during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see ). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. DOSAGE AND ADMINISTRATION

Labor and Delivery

The effect of Citalopram HBr tablets on labor and delivery in humans is unknown.

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 breast feeding 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 HBr tablets therapy should take into account the risks of citalopram exposure for the infant and the benefits of Citalopram HBr tablets treatment for the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see and ). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Citalopram in a child or adolescent must balance the potential risks with the clinical need. BOX WARNING WARNINGS—Clinical Worsening and Suicide Risk

Geriatric Use

Of 4422 patients in clinical studies of Citalopram HBr tablets, 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 HBr tablets in clinical trials received daily doses between 20 and 40 mg (see ). DOSAGE AND ADMINISTRATION

SSRIs and SNRIs, including Celexa, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see , ) PRECAUTIONS Hyponatremia

In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively (see ). 20 mg/day is the recommended dose for most elderly patients (see ). CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION

CITALOPRAM HYDROBROMIDE ADVERSE REACTIONS

The premarketing development program for Citalopram HBr tablets 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 HBr tablets 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.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials

Adverse Events Associated with Discontinuation of Treatment

Among 1063 depressed patients who received Citalopram HBr tablets 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.e., associated with discontinuation in at least 1% of Citalopram HBr tablets-treated patients at a rate of at least twice that of placebo) are shown in . It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table. TABLE 2

Adverse Events Occurring at an Incidence of 2% or More among Citalopram HBr tablets-Treated Patients

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment emergent adverse events that occurred 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. Events included are those occurring in 2% or more of patients treated with Citalopram and for which the incidence in patients treated with Citalopram was greater than the incidence in placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The only commonly observed adverse event that occurred in Citalopram HBr tablets patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see ). TABLE 3

Dose Dependency of Adverse Events

The potential relationship between the dose of Citalopram HBr tablets administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or Citalopram HBr tablets 10, 20, 40 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.

Male and Female Sexual Dysfunction with SSRIs

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.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to under-estimate their actual incidence.

The table below displays the incidence of sexual side effects reported by at least 2% of patients taking Citalopram in a pool of placebo-controlled clinical trials in patients with depression.

In female depressed patients receiving Citalopram HBr tablets, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.

There are no adequately designed studies examining sexual dysfunction with Citalopram treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

Citalopram HBr tablets 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 HBr tablets treatment. In addition, a comparison of supine and standing vital sign measures for Citalopram HBr tablets and placebo treatments indicated that Citalopram HBr tablets treatment is not associated with orthostatic changes.

Weight Changes

Patients treated with Citalopram HBr tablets in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

Laboratory Changes

Citalopram HBr tablets 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 HBr tablets treatment.

ECG Changes

Electrocardiograms from Citalopram HBr tablets (N=802) and placebo (N=241) groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. The only statistically significant drug-placebo difference observed was a decrease in heart rate for Citalopram HBr tablets of 1.7 bpm compared to no change in heart rate for placebo. There were no observed differences in QT or other ECG intervals.

Other Events Observed During the Premarketing Evaluation of Citalopram

Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the section, reported by patients treated with Citalopram HBr tablets at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with Citalopram HBr tablets, they were not necessarily caused by it. ADVERSE REACTIONS

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

- : tachycardia, postural hypotension, hypotension. : hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. : transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block. Cardiovascular Frequent Infrequent Rare

- : paresthesia, migraine. : hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. : abnormal coordination, hyperesthesia, ptosis, stupor. Central and Peripheral Nervous System Disorder Frequent Infrequent Rare

- : hypothyroidism, goiter, gynecomastia. Endocrine Disorder Rare

- : saliva increased, flatulence. : gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. : colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups. Gastrointestinal Disorders Frequent Infrequent Rare

- : hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. : hayfever. General Infrequent Rare

- : purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. : pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding. Hemic and Lymphatic Disorders Infrequent Rare

- : decreased weight, increased weight. : increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. : bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration. Metabolic and Nutritional Disorders Frequent Infrequent Rare

- : arthritis, muscle weakness, skeletal pain. : bursitis, osteoporosis. Musculoskeletal System Disorders Infrequent Rare

- : impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. : increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. : catatonic reaction, melancholia. Psychiatric Disorders Frequent Infrequent Rare

- : amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage. Reproductive Disorders/Female* Frequent

* % based on female subjects only: 2955

- : coughing. Infrequent: bronchitis, dyspnea, pneumonia. : asthma, laryngitis, bronchospasm, pneumonitis, sputum increased. Respiratory System Disorders Frequent Rare

- : rash, pruritus. : photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. : hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani. Skin and Appendages Disorders Frequent Infrequent Rare

- : accommodation abnormal, taste perversion. : tinnitus, conjunctivitis, eye pain. : mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss. Special Senses Frequent Infrequent Rare

- : polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. : facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain. Urinary System Disorders Frequent Rare

Other Events Observed During the Postmarketing Evaluation of Citalopram HBr

It is estimated that over 30 million patients have been treated with Citalopram HBr tablets since market introduction. Although no causal relationship to Citalopram HBr tablets treatment has been found, the following adverse events have been reported to be temporally associated with Citalopram HBr tablets 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, glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, Torsades de pointes, and withdrawal syndrome.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Citalopram HBr is not a controlled substance.

Physical and Psychological Dependence

Animal studies suggest that the abuse liability of Citalopram HBr tablets is low. Citalopram HBr tablets have not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with Citalopram HBr tablets did not reveal any drug seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Citalopram HBr tablets patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug seeking behavior).

OVERDOSAGE

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, Celexa (Innovator Brand Citalopram HBr Tablets) overdoses including overdoses of up to 6000 mg have been reported. As with other SSRI’s, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported. ^®

Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of Torsades de pointes). Acute renal failure has been very rarely reported accompanying overdose.

Management of Overdose

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Citalopram HBr tablets.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

CITALOPRAM HYDROBROMIDE DOSAGE AND ADMINISTRATION

Initial Treatment

Citalopram should be administered at an initial dose of 20 mg once daily, generally with an increase to a dose of 40 mg/day. Dose increases should usually occur in increments of 20 mg at intervals of no less than one week. Although certain patients may require a dose of 60 mg/day, 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; doses above 40 mg are therefore not ordinarily recommended.

Citalopram tablets should be administered once daily, in the morning or evening, with or without food.

Special Populations

20 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment, with titration to 40 mg/day only for nonresponding patients.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram tablets should be used with caution in patients with severe renal impairment.

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 ). When treating pregnant women with Citalopram tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Citalopram tablets in the third trimester. PRECAUTIONS

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 has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of Citalopram tablets (20-60 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 under ). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.   Clinical Trials CLINICAL PHARMACOLOGY

Discontinuation of Treatment with Citalopram tablets

Symptoms associated with discontinuation of Citalopram tablets and other SSRIs and SNRIs have been reported (see ). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. PRECAUTIONS

Switching Patients To or From a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of Citalopram therapy. Similarly, at least 14 days should be allowed after stopping Citalopram before starting a MAOI (see ). and Contraindications Warnings

ANIMAL TOXICOLOGY

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 basis). Similar findings were not present in rats receiving 24 mg/kg/day for two years, in mice treated for 18 months at doses up to 240 mg/kg/day or in dogs treated for one year at doses up to 20 mg/kg/day (4, 20 and 10 times, respectively, the maximum recommended daily human dose on a mg/m basis). ^{2 2}

Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.

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 basis) died suddenly between weeks 17 and 31 following initiation of treatment. Although appropriate data from that study are not available to directly compare plasma levels of citalopram (CT) and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to levels that have been achieved in humans, pharmacokinetic data indicate that the relative dog to human exposure was greater for the metabolites than for citalopram. Sudden deaths were not observed in rats at doses up to 120 mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those observed in dogs at doses of 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs. This effect occurred in dogs at doses producing peak DDCT plasma levels of 810 to 3250 nM (39-155 times the mean steady state DDCT plasma level measured at the maximum recommended human daily dose of 60 mg). In dogs, peak DDCT plasma concentrations are approximately equal to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma concentrations are less than 10% of steady state CT plasma concentrations. Assays of DDCT plasma concentrations in 2,020 citalopram treated individuals demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level of DDCT in human overdose was 138 nM. While DDCT is ordinarily present in humans at lower levels than in dogs, it is unknown whether there are individuals who may achieve higher DDCT levels. The possibility that DCT, a principal metabolite in humans, may prolong the QT interval in dogs has not been directly examined because DCT is rapidly converted to DDCT in that species. ²

                                                                 Medication Guide

                              Antidepressant Medicines, Depression and other Serious Mental                                               Illnesses, and Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness

Citalopram 40mg Tablet