Ava-Citalopram (Avanstra, 10 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

AVA-CITALOPRAM (Citalopram hydrobromide) is indicated for the symptomatic relief of depressive illness.

The relapse rate was significantly lower in citalopram-treated patients than in placebo-treated patients in two placebo-controlled studies, that were conducted over a 24-week period in patients who responded to 6 or 8 weeks of acute treatment with Citalopram (see Clinical Trials under

ACTION AND CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use

AVA-CITALOPRAM for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Pediatrics (< 18 years of age): Safety and effectiveness in patients below the age of 18 have not been established.

Geriatrics (> 65 years of age): There is limited information on the use of AVA-CITALOPRAM

in patients over 65 years of age (see WARNINGS AND PRECAUTIONS, Special Populations,

Geriatrics).

CONTRAINDICATIONS

$ Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

^$ Monoamine Oxidase Inhibitors: In patients, receiving selective serotonin reuptake inhibitors (SSRIs) in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma.

These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome.

Therefore, AVA-CITALOPRAM should not be used in combination with a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing AVA-CITALOPRAM treatment before starting a

MAOI.

PIMOZIDE

Citalopram should not be used in combination with the anti-psychotic drug pimozide, as results from a controlled study with racemic citalopram indicate that concomitant use is associated with an increased risk of QTc prolongation compared to pimozide alone. This apparent

pharmacodynamic interaction occurred in the absence of a clinically significant pharmacokinetic interaction; the mechanism is unknown (see PRECAUTIONS, Drug Interactions)

WARNINGS AND PRECAUTIONS

POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES,

INCLUDING SELF-HARM

Pediatrics: Placebo-Controlled Clinical Trial Data

• Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioral and emotional changes, including an increased risk of suicidal ideation and behavior over that of placebo.

• The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

  Adults and Pediatrics: Additional data

Serious Warnings and Precautions

• Potential for Interaction with MAO Inhibitors (see CONTRAINDICATIONS)
• SUICIDE

The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high risk patients should be closely supervised throughout therapy with AVA-CITALOPRAM (citalopram hydrobromide) and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for AVA-CITALOPRAM should be written for the smallest quantity of drug consistent with good patient management.

• There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm and harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behavior is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioral changes.

Discontinuation Symptoms

Patients currently taking Citalopram should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

General

Bleeding Disorders

There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with

SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDS)) as well as in patients with a history of bleeding disorders.

Carcinogenesis and Mutagenesis

See TOXICOLOGY, Mutagenic potential/carcinogencity for discussion on animal data.

Cardiovascular

Citalopram 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 trials during the drug's premarketing assessment. However, the electrocardiograms of patients, who received Citalopram in clinical trials, indicate that Citalopram was not associated with the development of clinically significant ECG abnormalities.

In clinical trials, Citalopram caused small but statistically significant decreases in heart rate (see ECG under ADVERSE REACTIONS). Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

Discontinuation of treatment with Citalopram

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances [including paresthesias and electric shock sensations], agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance.( see ADVERSE REACTIONS). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See ADVERSE REACTIONS and DOSAGE and

ADMINISTRATION).

Diabetic Patients

Citalopram has not been systematically evaluated in diabetic patients since diabetes constituted an exclusion criterion. Although 13 patients did receive insulin during the studies, this number is too small to determine whether Citalopram affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram should be used with caution in diabetic patients on insulin or other antidiabetic drugs.

Electroconvulsive Therapy (ECT)

The safety and efficacy of the concurrent use of Citalopram and ECT have not been studied.

Hepatic/Biliary/Pancreatic

In subjects with hepatic impairment, Citalopram clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see PHARMACOKINETICS).

Consequently, the use of Citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).

Hyponatremia

Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported as a rare adverse event with use of Citalopram as with other SSRls. Elderly female patients in particular seem to be a group at risk.

Interference with cognitive and motor performance

In studies in normal volunteers, Citalopram in doses of 40 mg/day did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that Citalopram does not affect them adversely.

Psychiatric

ACTIVATION OF MANIA/HYPOMANIA

In placebo-controlled trials with Citalopram, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patients treated with Citalopram versus none of the

426 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 antidepressants. If a patient enters a manic phase, Citalopram should be discontinued.

Renal

No dosage adjustment is needed in patients with mild to moderate renal impairment. Since, no information is available on the pharmacokinetic or pharmacodynamic effects of Citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min), Citalopram should be used with caution in these patients.

Seizures

Citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of Citalopram. In clinical trials, seizures occurred in 0.25% of patients treated with Citalopram and in 0.23% patients treated with placebo. Like other antidepressants, Citalopram should be used with caution in patients with a history of seizure disorder. The drug should be discontinued in any patients who develop seizures.

Serotonin Syndrome

Rarely, the occurrence of serotonin syndrome has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition.

Serotonergic Drugs

There have been rare postmarketing reports describing patients with weakness, hyperreflexia and incoordination, following the concomitant use of SSRI and the antimigraine drug sumatriptan, a 5-HT₁ agonist. Such interaction should be considered if AVA-CITALOPRAM is to be used with a 5-HT₁ agonist. St-John’s Wort: In common with other SSRI’s, pharmacodynamic interactions between citalopram and the herbal remedy St-John’s Wort may occur and result in undesirable effects.

Suicide

The possibility of a suicide attempt is inherent in depression and may persist until remission occurs.

Therefore, high risk patients should be closely supervised throughout therapy with Citalopram and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for AVA-CITALOPRAM should be written for the smallest quantity of drug consistent with good patient management (see Potential Association with Behavioral and Emotional Changes, Including Self-Harm under WARNINGS).

Special Populations

Pregnant Women: The safety of Citalopram during pregnancy and lactation has not been established.

Therefore, Citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus.^{page 13}

Nursing Women: Citalopram is excreted in human milk. Citalopram should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child.

Post-marketing reports indicate that some neonates exposed to SSRIs such as Citalopram and other antidepressants 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 other newer anti-depressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS - Serotonin Syndrome). When treating a pregnant woman with Citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).

Pediatrics (< 18 years of age): Safety and effectiveness in patients below the age of 18 have not been established.

Geriatrics ($65 years of age): In premarketing clinical trials, 800 elderly patients ($65 years of age)

have been treated with Citalopram. Of these patients 298 were $75 years old. In a pharmacokinetic study (N=11, age 73 to 90 years), clearance was substantially decreased and half-life prolonged (see

PHARMACOKINETICS). In a 6-week placebo-controlled study, approximately equal numbers of patients received Citalopram at 20 or 30 mg per day, as the final dose. In about 5% of patients, the final

dose was 10 mg per day (see CLINCAL TRIALS under ACTION AND CLINICAL

PHARMACOLOGY). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION)

ADVERSE REACTIONS

Adverse Drug Reaction Overview

During the premarketing clinical development, 3652 patients received Citalopram (citalopram hydrobromide) for the treatment of depression. Of these patients, 66% were females and 34% were males. The mean age of the patients was 50 years, with 70% being <60 years old (30% <40 years old,

40% 40 to 59 years old) and 30% being $60 years old. Adverse events observed with Citalopram are in general mild and transient. They usually attenuate during the first one or two weeks of treatment.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

ADVERSE FINDINGS OBSERVED IN SHORT-TERM, PLACEBO-CONTROLLED TRIALS

Adverse Reactions Leading to Discontinuation of Treatment

From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the Citalopram-treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 7.7% (33/426).

The events associated with discontinuation of Citalopram in 1 % or more of patients at a rate of at least twice that of placebo, were as follows:

Nausea (4.1% versus 0.0%), insomnia (2.4% versus 1.2%), somnolence (2.4% versus 1.2%), dizziness

(2.3% versus 0.7%), vomiting (1.3% versus 0.0%), agitation (1.2% versus 0.0%), asthenia (1.1 % versus 0.5%), and dry mouth (1.1 % versus 0.2%).

Incidence of Adverse Events in Placebo-controlled Studies

Table 1 enumerates the incidence of treatment emergent adverse events that occurred in 1027 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. Reported adverse events were classified using the standard World Health Organization (WHO)-based dictionary terminology.

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.

TABLE 1 TREATMENT-EMERGENT ADVERSE EVENTS* INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS

Reproductive, Male³

Ejaculation disorder¹ Impotence³

6.2 3.2

1.1 0.6

* 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

¹ Statistically significantly higher incidence in the citalopram group (p<0.05)

² Denominator used was for females only (N=623 for Citalopram; N=245 for Placebo) ³ Denominator used was for males only (N=404 for Citalopram; N=181 for Placebo)

The following events had an incidence on placebo $ Citalopram: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.

Most Frequent Adverse Events

Adverse events that occurred in Citalopram-treated patients in the course of the short-term, placebo-controlled trials with an incidence greater than, or equal to, 10% were: nausea, dry mouth, somnolence, and increased sweating (Table 1).

Dose Dependency of Adverse Events

The potential relationship between the dose of Citalopram and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received Citalopram at doses of 10, 20, 40 or 60 mg per day. The incidence of diarrhea, dry mouth, fatigue, insomnia, increased sweating, nausea and somnolence was dose-related.

Male and Female Sexual Dysfunction with SSRIs

While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) may induce sexual side

effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature, and therefore, it is thought that sexual side effects with SSRIs may be underestimated.

In placebo-controlled, short-term clinical trials, the reported incidence of decreased libido, ejaculation disorders (primarily ejaculation delay and ejaculation failure), and impotence in male depressed patients receiving Citalopram (N=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving Citalopram (N=623), the reported incidence of decreased libido and anorgasmia was

1.3% and 1.1%, respectively. The reported incidence of each of these adverse events was #1% among male and female depressed patients receiving placebo.

Weight Changes

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

ECG

Retrospective analyses of electrocardiograms in Citalopram-treated (N=779 <60 years and N=313 $60 years) and placebo-treated (N=74 <60 years and N=43 $60 years) patients indicated that Citalopram decreases heart rate. In patients <60 years old, the mean decrease was approximately 5 bpm, while in patients $60 years old, mean decreases ranged between 5 to 10 bpm. Following the initial drop, heart rate remained decreased but stable over prolonged periods of time (up to one year in over 100 younger and over 50 elderly patients). The effect was reversible within approximately a week after stopping treatment.

In the 6-week, fixed dose, dose-response study, the mean decreases in heart rate ranged between 2-6 bpm in the 20-60 mg/day dose range, but the effect did not seem to be dose-related and was independent of gender. In placebo-treated patients heart rates remained unaffected. The differences in heart rates between Citalopram- and placebo-treated patients were statistically significant.

ECG parameters, including QT interval, remained unaffected.

ADVERSE REACTIONS FOLLOWING DISCONTINUATION OF TREATMENT (OR DOSE

REDUCTION)

There have been reports of adverse reactions upon the discontinuation of Citalopram (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance, (see PRECAUTIONS and DOSAGE AND

ADMINISTRATION).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors. (see PRECAUTIONS and DOSAGE AND ADMINISTRATION)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

ADDITIONAL ADVERSE EVENTS OBSERVED DURING THE PREMARKETING EVALUATION

OF CITALOPRAM

The events listed below include all adverse events that were reported in the overall development program of Citalopram (N=3652). All reported events are included except those already listed in Table

1 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with Citalopram, they were not necessarily caused by it. The events are enumerated using the following criteria:frequent: adverse events that occurred on one or more occasions in at least 1/100 patients; infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients; rare: adverse events that occurred in fewer than 1/1000 patients.

Body as a Whole - General Disorders

Frequent: Influenza-like symptoms, non-pathological trauma, pain. Infrequent: Alcohol intolerance, allergic reaction, allergy, chest pain, edema, hot flushes, leg pain, malaise, rigors, syncope. Rare:

Peripheral edema, sudden death, traumatic injury.

Cardiovascular Disorders

Frequent: Postural hypotension, tachycardia. Infrequent: Angina pectoris, arrhythmia, bradycardia, cardiac failure, cerebrovascular disorders, edema dependent, extrasystoles, flushing, hypertension, hypotension, myocardial infarction, myocardial ischemia, peripheral ischemia. Rare: Aggravated hypertension, bundle branch block, cardiac arrest, coronary artery disorder, ECG abnormal, heart disorder, phlebitis, supraventricular extrasystoles.

Central and Peripheral Nervous System Disorders

Frequent: Migraine, paraesthesia. Infrequent: Abnormal gait, ataxia, convulsions, dysphonia, dystonia, extrapyramidal disorder, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, involuntary muscle contractions, leg cramps, neuralgia, speech disorder, vertigo. Rare: Abnormal coordination, convulsions grand mal, hyperesthesia, ptosis, sensory disturbance, stupor.

Collagen Disorders

Rare: Rheumatoid arthritis.

Endocrine Disorders

Rare: Goiter, gynecomastia, hypothyroidism.

Gastrointestinal System Disorders

Frequent: Flatulence. Infrequent: Colitis, dental abscess, dysphagia, eructation, gastritis, gastroenteritis, gastrointestinal disorder (not specified), hemorrhoids, increased saliva, teeth-grinding,

toothache. Rare: Appendicitis, esophagitis, gastric ulcer, gastroesophageal reflux, gingivitis, stomatitis, tooth disorder, ulcerative stomatitis.

Hematopoietic and Lymphatic Disorders

Infrequent: Anemia, epistaxis, leukocytosis, purpura. Rare: Coagulation disorder, gingival bleeding, granulocytopenia, hematoma, leukopenia, lymphadenopathy, lymphocytosis, pulmonary embolism.

Liver and Biliary System Disorders

Infrequent: Cholecystitis, cholelithiasis, increased gamma-GT, increased SGPT. Rare: Bilirubinemia, increased SGOT, jaundice.

Metabolic and Nutritional Disorders

Frequent: Appetite decreased, weight decrease, weight increase. Infrequent: Leg edema, xerophthalmia. Rare: Dehydration, edema, hypoglycemia, hypokalemia, increased alkaline phosphatase, obesity, thirst.

Musculo-Skeletal System Disorders

Infrequent: Arthralgia, arthritis, arthrosis, dystonia, muscle weakness, myalgia. Rare: Bone disorder, bursitis, osteoporosis, tendon disorder.

Neoplasm

Rare: Breast neoplasm malignant female.

Psychiatric Disorders

Frequent: Abnormal dreaming, aggravated depression, amnesia, apathy, confusion, depression, impaired concentration, increased appetite, sleep disorder, suicide attempt. Infrequent: Abnormal thinking, aggressive reaction, delusion, depersonalization, drug abuse, drug dependence, emotional

lability, euphoria, hallucination, increased libido, manic reaction, neurosis, paranoid reaction, paroniria, psychosis, psychotic depression. Rare: Catatonic reaction, hysteria, personality disorder.

Reproductive Disorders, Female

Frequent: Abnormal orgasm Infrequent: Amenorrhea, breast pain, lactation nonpuerperal, menorrhagia, menstrual disorder, premenstrual syndrome, salpingitis, unintended pregnancy, vaginal dryness, vaginitis. Rare: Breast enlargement, vaginal hemorrhage.

Reproductive Disorders, Male

Infrequent: Penis disorder, prostatic disorder, testis disorder.

Resistance Mechanism Disorders

Infrequent: Abscess, fungal infection, herpes simplex infection, otitis media, viral infection. Rare:

Bacterial infection, moniliasis, sepsis.

Respiratory System Disorders

Infrequent: Bronchitis, coughing, dyspnea, pneumonia. Rare: Asthma, bronchospasm, increased sputum, laryngitis, pneumonitis, respiratory disorder.

Skin and Appendage Disorders

Frequent: Pruritus, rash. Infrequent: Acne, alopecia, dermatitis, dry skin, eczema, photosensitivity reaction, psoriasis, rash erythematous, rash maculo-papular, skin discoloration, urticaria. Rare:

Cellulitis, decreased sweating, hypertrichosis, melanosis, pruritus ani.

Special Senses, Vision, Hearing and Vestibular Disorders

Frequent: Abnormal accommodation. Infrequent: Conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus. Rare: Eye abnormality, keratitis, photophobia.

Urinary System Disorders

Frequent: Polyuria. Infrequent: Abnormal urine, cystitis, hematuria, micturition frequency, urinary incontinence, urinary retention, urinary tract infection. Rare: Dysuria, facial edema, oliguria, renal calculus, renal pain.

Post-Market Adverse Drug Reactions

Adverse events which have been reported to be temporally (but not necessarily causally) associated with Citalopram treatment in at least 3 patients since its market introduction include:

Abnormal hepatic function, acute renal failure, aggravated condition, aggravated migraine, akathisia, anaphylaxis, angioedema, asthma, choreoathetosis, convulsion NOS, decreased drug level, decreased prothrombin time, delirium, dyskinesia, ecchymosis, eosinophilia, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, gynecological problems, hemolytic anemia, hepatitis, hypersensitivity NOS, hyperprolactinemia, hypomania, hyponatremia, increased drug level, increased prothrombin time, menometrorrhagia, myoclonic jerks, neuroleptic malignant syndrome, neuropathy, nystagmus, pancreatitis, pancytopenia, purpura NOS, rhabdomyolysis, serotonin syndrome, SIADH, spontaneous abortion/fetal death, suicide ideation, thrombocytopenia, vasodilatation, ventricular arrhythmia, Torsades de pointes, withdrawal syndrome.

DRUG INTERACTIONS

Overview

Using in vitro models of human liver microsomes, the biotransformation of citalopram to its demethyl metabolites was shown to depend on both CYP2C19 and CYP3A4, with a small contribution from

CYP2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP2D6 and CYP2C19 and a weak or negligible inhibitor of CYP3A4 and CYPlA2.

One in vitro study using human liver microsomes has shown that ketoconazole and omeprazole reduced the rate of formation of the demethylcitalopram metabolite of citalopram to 45-60% and 75-

85% of control, respectively. As data are not available from multi-dose pharmacokinetic studies, the

possibility that the clearance of citalopram will be decreased when Citalopram is administered with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should be considered.

Various scientific publications have acknowledged that the main components in grapefruit juice may act as a CYP3A4 inhibitor. Citalopram is also metabolized by other isoenzymes not affected by grapefruit juice, namely CYP2C19 and CYP2D6. Although there is a theoretical possibility of pharmacokinetic drug interactions resulting from co-administration of citalopram with grapefruit juice, the onset of an interaction is considered unlikely.

Alcohol: Although Citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and Citalopram should be avoided.

The studies described in this section were carried out in young, healthy, mostly male volunteers, In addition, some of the studies, namely interactions with metoprolol, warfarin, digoxin, imipramine, and levomepromazine, utilized only single doses of these drugs, although Citalopram was given repeatedly to attain steady state. Thus, data are not available in patients who would be receiving these drugs on an ongoing basis at therapeutic doses.

Drug-Drug Interactions

Monoamine Oxidase Inhibitors (MAOI)

For interactions between citalopram and MAOI, see CONTRAINDICATIONS.

Metoprolol

Coadministration of Citalopram (40 mg/day for 22 days) and the β-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a twofold increase in the plasma levels of metoprolol.

However, the effect of metaprolol on blood pressure and heart rate was not affected.

Warfarin

Administration of Citalopram (40 mg/day for 21 days), did not affect either the pharmacokinetics or the pharmacodynamics (prothrombin time) of a single, 25 mg dose of warfarin.

Digoxin

Administration of Citalopram (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin

(single dose of 1 mg), although the serum levels of Citalopram were slightly lower in the presence of digoxin.

Imipramine

Coadministration of Citalopram (40 mg/day for 10 days) and the tricyclic antidepressant, imipramine

(single dose of 100 mg), did not affect the pharmacokinetics of either drug. However, in the presence of Citalopram, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that Citalopram does not interfere with the demethylation of imipramine to desipramine but does inhibit the metabolism of desipramine to its 2-hydroxy metabolite. Consequently, concomitant treatment with Citalopram and imipramine/desipramine should be undertaken with caution.

Levomepromazine

Coadministration of Citalopram (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), did not affect the pharmacokinetics of either drug.

Lithium

Coadministration of Citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days), did not affect the pharmacokinetics of either drug. However, since lithium may increase serotonergic neurotransmission, concomitant treatment with these two drugs should be undertaken with caution.

Cimetidine

Citalopram 40 mg/day was administered for 29 days. During the last 8 days of treatment, cimetidine

(400 mg bid) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes, the C_max and AUC of Citalopram was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of Citalopram when it is used concomitantly with high doses of cimetidine.

Carbamazepine

Carbamazepine, titrated to 400 mg/day, was given for 21 days alone and then in combination with

Citalopram (40 mg/day) for an additional 14 days. Citalopram did not affect the plasma levels of either carbamazepine, a CYP3A4 substrate, or its metabolite, carbamazepine-epoxide. However, since carbamazepine is a microsomal enzyme inducer, the possibility that carbamazepine may increase the clearance of Citalopram should be considered if the two drugs are given concomitantly.

Pimozide

In a double-blind crossover study in healthy young adults, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values at Tmax of approximately 12 msec compared to pimozide when given with placebo. The mechanism of this apparent pharmacodynamic interaction is not known.

Serotonergic Drugs

There have been rare postmarketing reports describing patients with weakness, hyperreflexia and incoordination, following the concomitant use of a SSRI and the antimigraine drug sumatriptan, a 5-

HT_l agonist. Such interaction should be considered if Citalopram is to be used in combination with a 5-

HT₁ agonist.

Other Drugs

No pharmacodynamic interactions have been noted in clinical trials where Citalopram has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, non-NSAIDs), antihistamines, antihypertensives or other cardiovascular drugs. Pharmacokinetic interactions between citalopram and these drugs were not specifically studied.

Drug-Herb Interactions

St-John's Wort: In common with other SSRI's, pharmacodynamic interactions between citalopram and the herbal remedy St-John's Wort may occur and may result in undesirable effects.

DOSAGE AND ADMINISTRATION

AVA-CITALOPRAM (citalopram hydrobromide) is not indicated for use in children under 18 years of age (see Potential Association with Behavioral and Emotional Changes, Including Self-Harm under WARNINGS).

Dosing Considerations

AVA-CITALOPRAM (citalopram hydrobromide) should be administered once daily, in the morning or evening, with or without food.

Recommended Dose and Dosage Adjustment

Adults: AVA-CITALOPRAM should be administered as a single oral dose of 20 mg/day. In patients who do not respond adequately, an increase of dosage to 40 mg/day should be considered. Certain patients may require 60 mg/day. However, in a dose-response study, the 60 mg/day dose did not demonstrate an advantage regarding effectiveness over the 40 mg/day dose.

Dose increases should usually occur in increments of 20 mg, at intervals of no less than one week.

Treatment of pregnant women during the third trimester: Post-marketing reports indicate that some neonates exposed to SSRIs such as Citalopram and other newer antidepressants late in the third

trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with Citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Citalopram in the third trimester.

Elderly Patients: A single oral dose of 20 mg/day is the recommended dose for most elderly patients.

Some patients may respond to a 10 mg/day dose (see Clinical Trials under ACTION AND CLINICAL

PHARMACOLOGY). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated.

As with other SSRIs, caution should be exercised in treating elderly female patients who may be more susceptible to adverse events such as hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion). (See PRECAUTIONS).

Hepatic Impairment: Patients with reduced hepatic function should receive dosages of no more than

30 mg/day.

Renal Impairment: No dosage adjustment is necessary for patients with mild to moderate renal impairment. Since there is no information available on the pharmacokinetic or pharmacodynamic effects of Citalopram in patients with severe renal impairment, AVA-CITALOPRAM should be used with caution in these patients.

Maintenance Treatment: Evaluation of Citalopram in two placebo-controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8 weeks of initial treatment (total of 32 weeks) (See Clinical Trials under ACTION AND CLINICAL

PHARMACOLOGY). In the flexible dose study, the great majority of patients were receiving 20 or 40 mg/day doses both at 12 and 24 weeks. During maintenance therapy, the dosage should be kept at the lowest effective level and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients to or from Monoamine Oxidase Inhibitor (MAOI): At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with Citalopram. Similarly, at least

14 days should be allowed after stopping Citalopram before starting a MAOI (see

CONTRAINDICATIONS).

Discontinuation of Citalopram treatment: Symptoms associated with the discontinuation or dosage reduction of Citalopram have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (See PRECAUTIONS and

ADVERSE REACTIONS).

A gradual reduction in the dose over several weeks rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See PRECAUTIONS and ADVERSE REACTIONS).

Children: See Potential Association with Behavioral and Emotional Changes, Including Self-Harm under WARNINGS.

Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

OVERDOSAGE

Citalopram (citalopram hydrobromide) has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of Citalopram either alone or in combination with other drugs and/or alcohol.

Cases of overdoses of Citalopram ranging from 180 mg to 2000 mg have been reported during the pre-

marketing clinical development. All patients recovered. One patient, ingesting over 1500 mg

Citalopram, had reversible ECG abnormalities, the most important of which was prolongation of QTc.

Citalopram is given to patients at potential risk of suicide and reports of attempted suicide have been received after its market introduction. Post-marketing reports of drug overdoses involving citalopram have included fatalities with citalopram alone as well as non-fatal overdoses of up to 5200 mg. In many cases, details regarding the precise dose of citalopram or combination with other drugs and/or alcohol are often lacking Although most patients recovered without sequelae, fatalities have been reported at doses of Citalopram up to 3920 mg.

Fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide

(Manerix) and Citalopram. The plasma concentrations of moclobemide were between 16 and 90 mg/L,

(therapeutic range: 1 to 3 mg/L) and those of Citalopram between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L). This indicates that a relatively low dose of Citalopram, given with an overdose of moclobemide represents a serious risk for the patient.

Symptoms most often accompanying Citalopram overdose included dizziness, sweating, nausea, vomiting, tremor, and somnolence. In more rare cases, observed symptoms included confusion, loss of consciousness, convulsions, coma, sinus tachycardia, cyanosis, hyperventilation and rhabdomyolysis.

For management of a suspected drug overdose, contact youer regional Poison Control Centre.

Management of overdose:

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for

Citalopram.

Due to the large volume of distribution of Citalopram, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

In managing overdosage, the possibility of multiple drug involvement must be considered.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

AVA-CITALOPRAM (citalopram hydrobromide) is a highly selective and potent serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor with minimal effects on the neuronal reuptake of norepinephrine (NE) and dopamine (DA). The ability of citalopram to potentiate serotonergic activity in the central nervous system via inhibition of the neuronal reuptake of serotonin is thought to be responsible for its antidepressant action. Tolerance to the inhibition of serotonin reuptake is not induced by long-term (14 days) treatment of rats with citalopram.

Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT_1A, 5-HT₂, dopamine D₁, and D₂, α₁-,α₂-, β-adrenergic, histamine H₁, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors.

Pharmacokinetics

Absorption: Following the administration of a single oral dose of citalopram (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram was about 80% (range 52 to 93%) relative to an intravenous dose.

Absorption was not affected by food.

Distribution: After intravenous infusion in healthy male volunteers, the apparent volume of distribution (V_d) β was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution;

(V_d) β oral was about 17 L/kg (range 14-21L/kg). The binding of citalopram and its demethylated metabolites to human plasma proteins is about 80%.

Steady-state: The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Steady-state plasma levels are achieved in patients in

1-2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114)

with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long-term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established.

Metabolism: Citalopram is metabolized in the liver to demethylcitalopram (DCT),

didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma.

In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6.

Excretion: The elimination half-life of citalopram (t_1/2β) is approximately 37 hours (range: 30-42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance

(CI_s) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6-21%) of the daily dose is excreted in urine as unchanged citalopram.

Special Populations and Conditions

Pediatrics (< 18 years of age): Safety and effectiveness in patients below the age of 18 have not been established.

Geriatrics: Elderly patients (4 males and 7 females aged 73-90 years), received a 20 mg/day dose of citalopram for 3-4 weeks. In the elderly, steady state plasma levels were elevated (106 ng/mL), half-life prolonged (1.5 - 3.75 days) and clearance decreased (0.08 - 0.3 L/min). Elevation of citalopram

plasma levels occurred at an earlier age in females than in males. In this population, lower doses and a lower maximum dose of citalopram are recommended (see PRECAUTIONS and DOSAGE AND

ADMINISTRATION).

Hepatic Insufficiency: The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41-60 years) to those seen in 12 healthy male volunteers (aged 21 - 43 years). In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours versus 37 hours), steady state citalopram concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency: In patients with mild to moderate reduction of the renal function (4 female and 3 male patients aged 30-55 years), citalopram was being eliminated more slowly than in 12 healthy male volunteers (aged 21-43 years); half-lives being 49 hours versus 37 hours. However, mild to moderate renal impairment had no major influence on the kinetics of citalopram. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance

<20 mL/min). (See PRECAUTIONS.)

STORAGE AND STABILITY

AVA-CITALOPRAM tablets should be stored in a dry place at room temperature between 15^o and

30^oC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

AVA-CITALOPRAM (citalopram hydrobromide) is available as film-coated, white tablets.

10 mg tablets: White, round, biconvex film-coated tablets, engraved C11 on one side and plain on the other side. Bottles of 100 tablets.

Composition: AVA-CITALOPRAM tablets contain citalopram hydrobromide corresponding to

10 mg and the following non-medicinal ingredients: copovidone, croscarmellose sodium, glycerine, hydroxypropylmethylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyoxyethylene stearate and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Citalopram hydrobromide

Chemical name: (RS)- 1 -[3-(Dimethylamino)propyl]- 1 -(p-fluoropheny1)-

5-phthalancarbonitrile, hydrobromide

Molecular formula and molecular mass: C₂₀H₂₂BrFN₂O, 405.35

Structural formula:

Physicochemical properties:

Description: White to off-white, crystalline material having no more than a slight odour.

Melting Range: 184^o-188^oC

Solubility: Soluble in methanol, ethanol and acetonitrile

Sparingly soluble in water and in actone

Slightly soluble in isopropyl alcohol, toluene and methylethyl ketone

Freely soluble in dimethylformamide, dimethyl sulfoxide, chloroform and methylenedichloride

CLINICAL TRIALS

The efficacy of Citalopram in the treatment of depression was established in five placebo-controlled studies in patients who met the DSM-III or DSM-III-R criteria for major depression. Response to treatment was evaluated by the Hamilton Depression Rating Scale (HAMD) and/or the Montgomery

Asberg Depression Rating Scale (MADRS), as well as the Clinical Global Impression (CGI) Severity

Scale. On the HAMD and MADRS, total scores, selected single items, and percentage of responders

(defined as patients whose HAMD/MADRS total score decreased by at least 50% versus baseline)

were assessed.

In a 6-week fixed-dose, dose-response study, patients received Citalopram, at doses of 10, 20, 40, or 60 mg/day or placebo (n=129 to 131 per group). The 40 and 60 mg/day doses were titrated, with patients reaching these designated doses within 4 and 8 days, respectively. The study showed that the 40 and 60 mg/day doses were significantly more effective than placebo, although the 60 mg/day dose was not more effective than the 40 mg/day dose. The lower doses did not show statistically significant superiority over placebo, except on the MADRS; on this scale the percent of `responders' was significantly higher in all the Citalopram-treated groups than in the placebo-treated group.

The second study was a 4-week flexible-dose study in which 85% of the depressed patients met the criteria for melancholia. At entry, 89 and 91 patients were randomized to the Citalopram and placebo groups, respectively. This was the only study in which more male than female patients participated

(64% versus 36%). The initial dose of Citalopram, 20 mg/day, could be titrated to the maximal tolerated dose or a maximum dose of 80 mg/day. Patients treated with Citalopram showed significantly greater improvement than patients treated with placebo. At week 4, the average daily dose was 63 mg, with 52% of patients receiving the 80 mg/day dose.

In a 6-week fixed-dose study, patients received Citalopram, 20 or 40 mg/day, or placebo (n=64 to 70 per group). Patients treated with Citalopram, 40 mg/day, showed significantly greater improvement than placebo-treated patients. The difference between the lower dose of Citalopram and placebo was not significant.

In another 6-week fixed-dose study, patients received Citalopram, 20 or 40 mg/day or placebo (n=88 to

97 per group). Although Citalopram-treated patients improved to a somewhat greater degree than the placebo-treated patients, the differences between drug and control groups did not reach statistical significance due to a high placebo response, i.e., substantial improvement in the placebo group.

A 6-week, flexible-dose study was conducted in elderly, depressed patients (the mean age of male and female patients was 75 and 77 years, respectively) to determine the antidepressant effect and safety of

Citalopram in this subpopulation. The number of patients who received Citalopram and placebo was 98 and 51, respectively. The study allowed patients to enter with lower baseline HAMD scores than are usually acceptable ($18 in clinical trials). However, only a small percentage of patients had HAMD scores of less than 18 at entry. The dose of Citalopram was titrated from a starting dose of 10 mg/day to a maximum dose of 30 mg/day. Patients treated with Citalopram showed significantly greater improvement than patients treated with placebo. The final dose of Citalopram was 10, 20 and 30 mg/day in 5%, 51% and 44% of patients, respectively.

The effectiveness of Citalopram in preventing relapse was assessed in two long-term studies.

Depressed patients who responded to Citalopram during an initial 6 or 8 weeks of acute treatment

(fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study)

were randomized to continue on Citalopram or receive placebo. The number of patients who received

Citalopram and placebo was 257 and 116, respectively. In both studies, patients who continued on

Citalopram experienced significantly lower relapse rates over the subsequent 6 months compared to

those receiving placebo. In the fixed-dose study, the relapse rates were similar at the 20 and 40 mg/day doses, namely 10% and 12%, respectively. Of the placebo-treated patients, 31% experienced relapse.

In the flexible-dose study, the relapse rates were 14% and 24% in the Citalopram and placebo-treated patients, respectively. While the majority of patients (76%) were maintained on 20 or 40 mg/day of

Citalopram during most of the study, some patients received 60 mg/day, while a few patients were maintained on less than 20 mg/day.

COMPARATIVE BIOAVAILBILITY DATA

A randomized, single-dose, cross-over comparative bioavailability study was conducted between

Citalopram 40 mg tablets (Avanstra Inc., Canada) and Celexa^® 40 mg tablets (Lundbeck, Canada Inc.,

Canada) in 28 healthy male subjects, aged 18-55, under fasting conditions. The Comparative

Bioavailability Data are summarized in Table 2.

TABLE 2: SUMMARY TABLE OF COMPARATIVE BIOAVAILABILITY DATA

^* Citalopram 40 mg Tablets (Avanstra Inc., Canada)

^† Celexa® 40 mg Tablets (Lundbeck Canada Inc., Canada), purchased in Canada ^§ Expressed as the arithmetic mean (CV%) only

Note: Due to the nature of citalopram (long half-life) and the design of the study, AUC_I and T_1/2 could not be accurately estimated; therefore, they are not reported in the above table.

DETAILED PHARMACOLOGY

Citalopram is a racemic mixture with the S (+) enantiomer mediating the pharmacological effects. The

R (-) enantiomer contributes little to the activity of citalopram.

IN VITRO EXPERIMENTS

(a) Neuronal reuptake of serotonin, norepinephrine and dopamine

The primary pharmacological effect of citalopram is inhibition of the 5-HT reuptake mechanism.

Citalopram was shown to inhibit 5-HT uptake in rabbit blood platelets, with an IC₅₀ of 14 nM.

Similarly, the drug inhibits 5-HT uptake in rat brain synaptosomal preparations.

Uptake of 3H Amines into Rat Brain Synaptosomes

IC₅₀ nM

The data indicate that citalopram is a potent and specific 5-HT uptake inhibitor with no activity on the neuronal reuptake of norepinephrine (NE) or dopamine (DA). The metabolites of citalopram are also specific inhibitors of 5-HT reuptake, albeit less active than the parent drug.

The ratio between the concentrations inhibiting the in vitro uptake of NE and 5-HT determine the selectivity of a SSRI. According to this criterion citalopram is a highly selective SSRI.

(b) Effect on neurotransmitter receptors

Citalopram has no or very low affinity for a series of receptors including 5-HT _1A, 5-HT₂, dopamine D₁ and D₂ receptors, α₁-, α₂,-, β-adrenoreceptors, histamine H₁, muscarinic cholinergic, benzodiazepine, and opioid receptors.

A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity.

BEHAVIORAL EFFECTS

In a `behavioral despair paradigm', mice, trained to swim in a glass jar, eventually exhibit immobility.

This behavior was dose-dependently reversed by citalopram.

The 5-HT precursors, tryptophan and 5-HTP, induce in mice and rats the 5-HT syndrome, characterized by tremor, hyperactivity, abnormal gait, lordosis, and abduction of the hind limbs.

Citalopram potentiated these behavioral manifestations. The demethyl, didemethyl, and N-oxide metabolites were less potent than the parent drug.

The characteristic head twitches, induced by a combined treatment with a MAOI and 5-HTP, were potentiated by citalopram. However, head twitches induced by quipazine, a direct 5-HT mimetic, were not affected by citalopram, indicating that the drug has no anti-5-HT activity.

Although citalopram has no antinociceptive activity per se, it potentiated the antinociceptive effect of morphine.

In a food reinforcement paradigm, delivered under a multiple schedule, citalopram did not affect the responding in pigeons but potentiated the 5-HTP-induced decrease in responding. In rats, citalopram did not facilitate self-stimulation, did not substitute for d-amphetamine, d-LSD, or 8-OHDPAT in a drug discrimination paradigm and did not increase ethanol consumption in an ethanol/water preference test. In the latter experiment, citalopram actually decreased ethanol consumption. These experiments indicate that citalopram would not be abused and would not cause dependence.

Citalopram had a slight protective effect against maximal electroshock-induced convulsions, isoniazide-induced convulsions and audiogenic seizure. However, in toxicity studies convulsions have been observed at very high plasma levels of citalopram (see TOXICOLOGY).

CARDIOVASCULAR EFFECTS

In conscious dogs, single oral doses of 5 mg/kg of citalopram caused pronounced fluctuation of the blood pressure and heart rate. A 10 mg/kg dose caused tachycardia and elevated blood pressure. The

ECG was unchanged.

In anaesthetized cats, single oral doses of 35 mg/kg decreased the following parameters: mean arterial blood pressure, left ventricular end diastolic pressure, contractility, cardiac performance, stroke volume, and cardiac output. Peripheral resistance was increased. ECG abnormalities included alterations in conduction, changes in rhythm and T-wave inversion in 2 of 6 cats.

Additional cardiovascular effects of citalopram and a metabolite are described under TOXICOLOGY.

Pharmacokinetics

Absorption: The kinetics of citalopram in mouse, rat, and dog are characterized by rapid absorption, with Tmax ranging from 0.5 to 4 hours. In contrast to man, reduced systemic bioavailability due to extensive first-pass metabolism has been demonstrated in animals.

Distribution: Pharmacokinetic analysis of single dose i.v. data suggests two-compartment distribution characteristics. High levels of drug and demethylated metabolites were found in the lungs, liver, and kidneys, and lower levels in the heart and brain. Citalopram and the demethylated metabolites were shown to pass the placental barrier and were excreted in small amounts in milk.

The plasma protein binding of citalopram has been estimated to be 70-80%. The binding protein(s) has not been identified.

Both in mice and dogs, tissue concentrations of parent drug as well as those of the demethylated metabolites increased with increasing doses, although not necessarily in a dose-related manner. Levels of the didemethylated metabolites were higher in dogs than in mice in relation to the parent drug, resulting in smaller citalopram/didemethylcitalopram ratios in the dog, particularly in the heart and kidneys.

Metabolism: There are no major qualitative differences in the metabolism of citalopram between animals and man. Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, citalopram-N-oxide, and the deaminated propionic acid.

Demethylcitalopram and didemethylcitalopram levels are more prominent in mouse, rat, and dog than in man.

Elimination: Elimination of citalopram after a single dose is rapid, the half-life ranging from 1.5-2 hours in the mouse to 3.5-8 hours in the dog. In the dog, the half-life is prolonged with increasing doses due to saturation of the first-pass metabolism.

Following the administration of 14C-labelled citalopram to rats, at a dose of 20 mg/kg, approximately equal amounts of the dose were excreted in the urine and feces, with total recovery being about 80%.

Toxicokinetics

Plasma levels were determined in several long-term toxicity studies. The table below summarizes the results seen in some of these studies.

^a: citalopram; b: demethylcitalopram; c: didemthylcitalopram; d: average value at week 52; ^e: 2 hours postdose - Week 52 (1 and 3 mg/kg dose groups), Week 57 (8 mg/kg dose group)

The data indicate that the plasma levels of citalopram, as well as those of the demethylated metabolites, are considerably higher in animals than in man. The approximate 0.9 mg/kg dose in man corresponds to the highest recommended dose (60 mg/day). The plasma levels of the parent drug, seen in rats and dogs at the highest doses, are approximately 10 times higher in animals than in man, while the levels of

the didemethyl metabolites are almost 100 fold higher. In the rat, a NOEL (no observable effect level)

could not be established in this study; at the low dose minimal vacuolization of hepatocytes with fatty infiltration, and foam cell accumulation in lungs were noted. The changes were reversible. In dogs, the

NOEL, was 3 mg/kg.

TOXICOLOGY

ACUTE TOXICITY

The LD₅₀ values of citalopram ranged between 900-1700 mg/kg after oral administration and 38-74 mg/kg after intravenous administration. However, some mortality was also seen in the 400-600 mg/kg dose range, indicating a very flat dose-response curve regarding mortality. Signs of toxicity were sedation and tremor, while convulsions occurred at doses close to or above the LD₅₀ values. ^{page 53}

LD₅₀ VALUES IN THE MOUSE AND RAT

(mg/kg body weight)

A number of single dose toxicity studies have been carried out in dogs to investigate the potential cardiovascular toxicity of citalopram. In these studies, cardiotoxicity was not observed, but tonic- clonic convulsions were seen after oral administration of 20-40 mg/kg, as well as after slow intravenous infusion of 20-24 mg/kg. The critical plasma concentration for convulsions was about

1950 ng/mL.

LONG-TERM TOXICITY

Toxicological studies, including daily dosing for periods up to 26 weeks in mice and 52 weeks in rats and dogs, have been carried out. Plasma drug monitoring in the long-term safety studies documented that animals have been exposed to average citalopram levels of up to about 1200 ng/mL (dogs and rats)

and 2900 ng/mL (mice), as well as substantial levels of demethylcitalopram [up to about 1800 ng/mL,

(rats), 600 ng/mL, (dogs), 1150 ng/mL (mice)] and didemethylcitalopram [up to about 650 ng/mL

(rats), 600 ng/mL, (dogs), 300 ng/mL (mice)].

Apart from behavioral and functional characteristics of exaggerated 5-HT stimulation (e.g., hyperactivity, tremor, tail rigidity, mydriasis, reduced food consumption, and reduced body weight gain), two treatment-related findings have been demonstrated in rodents, namely fatty infiltration of the liver and lipidosis (vacuolization of lymphocytes). Both of the findings were reversible. In addition, retinal degeneration and testicular atrophy were also observed in rats.

In dogs, two treatment-related effects were found. Firstly, convulsions and death when plasma citalopram levels exceeded 1950 ng/mL (p.o. or i.v.). Secondly, fatal ventricular arrhythmias at combined high levels of the didemethyl metabolite (about 300 ng/mL) and citalopram (about 1950 ng/mL) were seen following i.v. infusion.

Hepatic Fatty Infiltration in Rodents

Fatty infiltration in the liver was first observed in a 3-month gavage study in rats given 8 - 32 mg/kg/day of citalopram. This administration resulted in dose-related hepatic fatty infiltration in all male rats but not in female rats at any of the doses. The fatty infiltration in male rats was also observed in a 4-week study, however, only at considerably higher doses (>160 mg/kg). In female rats only minimal fatty infiltration was seen at a 200 mg/kg/day dose.

Lipidosis (phospholipids) in Rodents

Phospholipidosis, which has been seen in rodents, is an abnormal accumulation of phospholipids in phagocytic cells and cells which catabolize biomembranes, such as pulmonary alveolar macrophages and circulating leucocytes (especially lymphocytes).

Phospholipidosis developed in rats receiving citalopram at daily doses of 120 mg/kg and slight vacuolization of peripheral lymphocytes was observed in mice at daily doses of 100 mg/kg, in the 52-week and 26-week studies, respectively. Both conditions were reversible within 3-4 weeks.

Retinal Degeneration/Atrophy in Rats

In the rat carcinogenicity study, a slight, dose-related increase in lens opacity was seen, affecting males only. In addition, increased incidence/severity of retinal degeneration/atrophy was seen in the high-dose group (80 mg/kg/day). The incidence was higher in females, however, more female than male rats survived the study. It was concluded by an independent pathologist that the retinal changes were most likely related to drug-induced pupillary dilatation (mydriasis) which increased the risk of retinal damage in the already light-sensitive albino rat.

Testicular Atrophy in Rats

In the 52-week rat toxicity study, testicular atrophy was seen at the 60 and 120 mg/kg/day doses of citalopram.

Convulsions and Death in Dogs

Toxicity studies in dogs revealed that citalopram administration led to fatal ventricular arrhythmias.

Consequently, studies were undertaken to elucidate the mechanism of this effect and to determine its relevance to humans.

The studies have shown that (1) i.v. infusion of citalopram, at a dose of 20 mg/kg, led to convulsions.

The blood levels of citalopram were 1950 ng/mL at this dose. In the presence of diazepam, also infused intravenously, higher doses of citalopram could be infused, namely up to 70 mg/kg (6800 ng/mL). (2)

Intravenous infusion of the didemethyl metabolite of citalopram caused QT prolongation in a dose range of 5 to 22 mg/kg. The blood levels of the metabolite were 300 ng/mL at the 5 mg/kg dose. The

QT prolongation was dose-dependent. (3) When citalopram, 20 mg/kg, and didemethylcitalopram, 5 mg/kg, were infused concomitantly (in the presence of diazepam in order to prevent convulsions), 5 out of 9 dogs died due to ventricular fibrillation. At these doses, the plasma levels of citalopram and didemethylcitalopram were 1950 ng/mL and 300 ng/mL, respectively.

As shown in the table below, there is a substantial difference in the plasma levels of citalopram and its metabolite in dogs and in humans at the recommended therapeutic doses.

REPRODUCTION STUDIES

Citalopram did not affect the reproductive performance of rats at dosages up to 16 mg/kg/day (males)

and 32 mg/kg/day (females).

In the teratology studies in rats, effects were observed in the conceptuses at dosages that were toxic to the dams. Minimal developmental toxicity was evident at 32 mg/kg/day: manifested as low incidences of resorptions, slightly reduced fetal and pup weights, and small reversible delays in ossification and postnatal development.

In rabbits, dosages of 4.8 mg/kg/day and above were toxic to the dams, and 16 mg/kg/day and above caused deaths. There were no effects on embryo-fetal development at the highest dose that could be assessed (16 mg/kg/day).

MUTAGENIC POTENTIAL

Citalopram did not have mutagenic activity in most of the in vitro tests (Ames Salmonella assay;

chromosome aberration assay in cultured human lymphocytes; gene mutation assay in cultured mouse lymphoma L5178Y) and in vivo tests (micronucleus test; unscheduled DNA synthesis). However, citalopram was mutagenic in some in vitro studies (Ames Salmonella assay and Chinese hamster lung cell assay).

CARCINOGENICITY

Citalopram did not show any carcinogenic potential in mice at daily doses of 40-240 mg/kg (1.5 years)

and in rats at 8-80 mg/kg (2 years). There was an increased incidence of small intestine carcinoma in rats treated with 8 and 24 mg/kg/day of citalopram but not in rats treated with an 80 mg/kg/day dose.

REFERENCES

PRECLINICAL/IN VITRO

1. 1.

   Hyttel J, Arnt J, Sánchez C. The pharmacology of citalopram. Rev Contemp Pharmacother

   1995; 6: 271-285.

2. 2. Rochat B, Amey M, Baumann P. Identification of cytochrome P450 isozymes involved in N– demethylation of citalopram in human microsomes. Experientia 1996; 52: A85. (Abstract)
3. 3.

   Skjelbo E, Brosen K Inhibitors of imipramine metabolism by human liver microsomes. Br J

   Clin Pharmac 1992; 34: 256-261.

CLINICAL/REVIEWS

1. 4.

   Ahlfors UG, Elovaara S, Harma P, et al. Clinical multicentre study of citalopram compared double-blindly with mianserin in depressed patients in Finland. Nord Psykiatr Tidsskr 1988;

   42(3): 201 - 210.

2. 5. Andersen J, Bech P, Benjaminsen S, et al. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 1986; 90: 131-138.
3. 6.

   Baldwin D, Johnson FN. Tolerability and safety of citalopram. Rev Contemp Pharmacother

   1995; 6: 315-325.

4. 7. Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clin Pharmacokinet 1996; 3 l(6): 444-469.
5. 8.

   Baumann P, Souche A, Montaldi S, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996;

   16(4): 307- 314.

6. 9. Bertilsson L, Dahl M-L. Polymorphic drug oxidation: Relevance to the treatment of psychiatric disorders. CNS Drugs 1996; 5(3): 200-223,
7. 10. Bouchard JM, Delaunay J, Delisle JP, et al. Citalopram versus maprotiline: a controlled clinical multicentre trial in depressed patients. Acta psychiatr scand 1987; 76: 583-592.
8. 11. Christensen P, Thomsen HY, Pedersen OL, et al. Orthostatic side effects of clomipramine and citalopram during treatment for depression. Psychopharmacology 1985; 86: 383-385.
9. 12. de Wilde J, Mertens C, Overo KF, et al. Citalopram versus mianserin. A controlled, double-blind trial in depressed patients. Acta psychiatr scand 1985; 72: 89-96.
10. 13. Fuglum E, Rosenberg C, Damsbo N, et al. Screening and treating depressed patients. A comparison of two controlled citalopram trials across treatment settings: hospitalized patients vs. patients treated by their family doctors. Acta Psychiatr Scand 1996; 94(1): 18-25.
11. 14.

    Gottfries CG. Scandinavian experience with citalopram in the elderly. Int Clin

    Psychopharmacol 1996; 11(Supp1 1): 41-44.

12. 15.

    Gravem A, Amthor KF, Astrup C, et al. A double-blind comparison of citalopram (Lu 10-171)

    and amitriptyline in depressed patients. Acta psychiatr scand 1987; 75: 478-486.

13. 16.

    Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Drug interactions with newer antidepressants:

    Role of human cytochromes P450. J Clin Psychiatry 1998; 59(Suppl 15): 19-27.

14. 17.

    Haffmans PMJ, Timmerman L, Hoogduin CAL, et al. Efficacy and tolerability of citalopram in comparison with fluvoxamine in depressed outpatients: a double-blind multicentre study. Int

    Clin Psychopharmacol 1996; 11(3): 157-164.

15. 18.

    Jeppesen U, Gram LF, Vistisen K, et al. Dose-dependent inhibition of CYPlA2, CYP2C19 and

    CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol l996; 51

    (1): 73-78.

16. 19.

    Mertens C. Citalopram versus mianserin: a controlled double-blind trial in depressed patients.

    In: Montgomery SA, ed. Citalopram - The New Antidepressant from Lundbeck Research.

    Proceedings of a Symposium, Aug 11, 1988 (XXII Nord Psykiater-Kongres, Aug. 10-13,

    1988). Excerpta Medica, Amsterdam, 1989; 50-55.

17. 20. Møller SE, de Beurs P, Timmerman L, et al. Plasma tryptophan and tyrosine ratios to competing amino acids in relation to antidepressant response to citalopram and maprotiline. A preliminary study. Psychopharmacology 1986; 88: 96-100.
18. 21.

    Montgomery SA, Rasmussen JGC, Lyby K, et al. Dose response relationship of citalopram 20 mg, citalopram 40 mg and placebo in the treatment of moderate and severe depression. Int Clin

    Psychopharmacol 1992; 6 (Suppl 5): 65-70.

19. 22. Montgomery SA, Rasmussen JGC. Citalopram 20 mg, citalopram 40 mg and placebo in the prevention of relapse of major depression. Int Clin Psychopharmacol 1992; 6 (Suppl 5): 71-73.
20. 23.

    Montgomery SA, Rasmussen JGC, Tanghøj P. A 24-week study of 20 mg citalopram, 40 mg citalopram, and placebo in the prevention of relapse of major depression. Int Clin

    Psychopharmacol 1993; 8: 181-188.

21. 24.

    Montgomery SA, Pedersen V, Tanghøj, et al. The optimal dosing regimen for citalopram - a meta-analysis of nine placebo-controlled studies. Int Clin Psychopharmacol 1994; 9(Suppl l):

    35-40.

22. 25.

    Muldoon C. The safety and tolerability of citalopram. Int Clin Psychopharmacol 1996; 11

    (Suppl 1): 35-40.

23. 26. Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al. Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet 1993; 342: 1419.
24. 27. Nyth AL, Gottfries CG, Lyby K, et al. A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta psychiatr scand 1992; 86: 138-145.
25. 28.

    Ostrom M, Eriksson A, Thorson J, et al. Fatal overdose with citalopram. Lancet 1996; 348:

    339- 340.

26. 29. Patris M, Bouchard J-M, Bougerol T, et al. Citalopram versus fluoxetine: A double-blind, controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. Int Clin Psychopharmacol 1996; 1l(2): 129-136.
27. 30.

    Priskorn M, Sidhu JS, Larsen F, et al. Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol l997; 44:

    199-202.

28. 31.

    Robert Ph, Montgomery SA. Citalopram in doses of 20-60 mg is effective in depression relapse prevention: a placebo-controlled 6 month study. Int Clin Psychopharmacol 1995; 10(Suppl 1):

    29-35.

29. 32.

    Rosenberg C, Damsbo N, Fuglum E, et al. Citalopram and imipramine in the treatment of depressive patients in general practice. A Nordic multicentre clinical study. Int.Clin.

    Psychopharmacol 1994; 9(Suppl 1): 41-48.

30. 33. Seifritz E, Hatzinger M, Müller MJ, et al. Hair loss associated with fluoxetine but not with citalopram. Can J Psychiatry 1995; 40(6): 362. (Letter to the Editor)
31. 34.

    Shaw DM, Crimmins R. A multicenter trial of citalopram and amitriptyline in major depressive illness. In: Montgomery SA, ed. Citalopram, The New Antidepressant from Lundbeck

    Research. Proceedings of a Symposium, August 11, 1988 (XXII Nord Psykiater-Kongres,

    August 10-13,1988). Excerpta Medica, Amsterdam 1989; 43-49.

32. 35.

    Timmerman L, de Beurs P, Tan BK, et al. A double-blind comparative clinical trial of citalopram vs maprotiline in hospitalized depressed patients. In Clin Psychopharmacol 1987; 2:

    239-253.

33. 36.

    Timmerman L, Haffmans PMJ, Hoogduin CAL, et al. Citalopram in major depression: a comparative study with fluvoxamine, preliminary results. In: Beige1 A, Lopez Ibor JJ, Costa e

    Silva JA eds. Past, Present and Future of Psychiatry, IX World Congress of Psychiatry, Volume

    II, Rio De Janiero, Brazil, June 6-12, 1993. World Scientific, London, 1994; 982-986.

34. 37.

    Von Moltke L.L. et al. Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects. Biol Psychiatry 1999; 46 (6): 839-

    849.

35. 38.

    A Single-Dose, Two-Period, Comparative Bioavailability Study of Two Formulations of

    Citalopram Tablets 40 mg Under Fasting Conditions. Data on file at Avanstra Inc.

36. 39.

    Celexa Product Monograph, Control No. 109203. Lundbeck Canada Inc., Montreal, Canada.

    Date of Preparation January 28, 1999. Date of Revision: November 17, 2006.