Ran-Citalopram Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

RAN-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 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, "₁-, "₂-, $-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)$ was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution;

(V_d)$ oral was about 17 L/kg (range 14-21 L/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.

Elimination

The elimination half-life of citalopram (t_1/2$) 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

Elderly Patients

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).

Reduced Hepatic Function

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).

Reduced Renal Function

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)

Clinical Trials

The efficacy of citalopram hydrobromide 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 hydrobromide, 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 hydrobromide-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 hydrobromide 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 hydrobromide, 20 mg/day, could be titrated to the maximal tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram hydrobromide 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 hydrobromide, 20 or 40 mg/day, or placebo (n=64 to 70 per group). Patients treated with citalopram hydrobromide, 40 mg/day, showed significantly greater improvement than placebo-treated patients. The difference between the lower dose of citalopram hydrobromide and placebo was not significant.

In another 6-week fixed-dose study, patients received citalopram hydrobromide, 20 or 40 mg/day or placebo (n=88 to 97 per group). Although citalopram hydrobromide-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 hydrobromide in this subpopulation. The number of patients who received citalopram hydrobromide 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 hydrobromide was titrated from a starting dose of 10 mg/day to a maximum dose of 30 mg/day. Patients treated with citalopram hydrobromide showed significantly greater improvement than patients treated with placebo. The final dose of citalopram hydrobromide was 10, 20 and

30 mg/day in 5%, 51% and 44% of patients, respectively.

The effectiveness of citalopram hydrobromide in preventing relapse was assessed in two long-term studies. Depressed patients who responded to citalopram hydrobromide 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 hydrobromide or receive placebo. The number of patients who received citalopram hydrobromide and placebo was 257 and 116, respectively. In both studies, patients who continued on citalopram hydrobromide 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 hydrobromide and placebo-treated patients, respectively. While the majority of patients (76%) were maintained on 20 or 40 mg/day of citalopram hydrobromide during most of the study, some patients received 60 mg/day, while a few patients were maintained on less than 20 mg/day.

Comparative Bioavailability

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of citalopram hydrobromide measured and compared following oral administration of a 40 mg dose of RAN-CITALOPRAM ( 1 x 40 mg) tablet or

Celexa^® (1 x 40 mg) tablet. The results from measured data are summarised as follows:

†Celexa^® manufactured by Lundbeck Canada Inc. was purchased in Canada.

*expressed as arithmetic mean (CV%) only.

Based on these results, the Ranbaxy Pharmaceuticals Canada Inc. (RAN-CITALOPRAM)

and Lundbeck Canada Inc. (Celexa^®) 40 mg citalopram hydrobromide tablets are bioequivalent under fasting conditions.

INDICATIONS AND CLINICAL USE

RAN-CITALOPRAM (citalopram hydrobromide) is indicated for the symptomatic relief of depressive illness.

The relapse rate was significantly lower in citalopram hydrobromide- 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 hydrobromide (see Clinical Trials under ACTION AND CLINICAL

PHARMACOLOGY). Nevertheless, the physician who elects to use citalopram hydrobromide for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

RAN-CITALOPRAM (citalopram hydrobromide) is contraindicated in patients with known hypersensitivity to citalopram hydrobromide or the excipients of the drug product.

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, RAN-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 RAN-CITALOPRAM treatment before starting a MAOI.

WARNINGS

POTENTIAL ASSOCIATION WITH THE OCCURENCE BEHAVIOURAL 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 suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour 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

• There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or 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 behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Discontinuation Symptoms

Patients currently taking RAN-CITALOPRAM (citalopram hydrobromide) 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.

PRECAUTIONS

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

RAN-CITALOPRAM (citalopram hydrobromide) and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for RAN-CITALOPRAM should be written for the smallest quantity of drug consistent with good patient management. (see WARNINGS: POTENTIAL ASSOCIATION

WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM)

Activation of Mania/Hypomania

In placebo-controlled trials with citalopram hydrobromide, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patients treated with citalopram hydrobromide 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, RAN-CITALOPRAM should be discontinued.

Seizures

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

Discontinuation of Treatment with Citalopram Hydrobromide

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).

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 a SSRI and the antimigraine drug sumatriptan, a 5-HT₁ agonist. Such interaction should be considered if citalopram hydrobromide is to be used in combination 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 may result in undesirable effects.

Hyponatremia

Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported as a rare adverse event with use of citalopram hydrobromide as with other

SSRIs. Elderly female patients in particular seem to be a group at risk.

Pregnancy and Nursing Mothers

The safety of citalopram hydrobromide during pregnancy and lactation has not been established. Therefore, citalopram hydrobromide 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.

Citalopram hydrobromide is excreted in human milk. Citalopram hydrobromide 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. Pediatric Use

Safety and effectiveness in patients below the age of 18 have not been established.

Geriatric Use

In premarketing clinical trials, 800 elderly patients ($65 years of age) have been treated with citalopram hydrobromide. 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 hydrobromide 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

Clinical Trials under ACTION AND CLINICAL PHARMACOLOGY). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE

AND ADMINISTRATION).

Hepatic Impairment

In subjects with hepatic impairment, citalopram hydrobromide clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased

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

Renal Impairment

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 hydrobromide in patients with severely reduced renal function (creatinine clearance <20 mL/min), citalopram hydrobromide should be used with caution in these patients.

Use in Patients with Cardiac Disease

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 hydrobromide in clinical trials, indicate that citalopram hydrobromide was not associated with the development of clinically significant ECG abnormalities.

In clinical trials, citalopram hydrobromide 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.

Use in Diabetic Patients

Citalopram hydrobromide 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 hydrobromide affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram hydrobromide should be used with caution in diabetic patients on insulin or other antidiabetic drugs.

Interference with Cognitive and Motor Performance

In studies in normal volunteers, citalopram hydrobromide 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 hydrobromide does not affect them adversely.

Electroconvulsive Therapy (ECT)

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

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, acetylsalicyclic acid, and non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders.

Drug Interactions

Monoamine Oxidase Inhibitors (MAOI)

For interactions between citalopram hydrobromide and MAOI, see CONTRAINDICATIONS.

General

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 hydrobromide 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.

Metoprolol

Coadministration of citalopram hydrobromide (40 mg/day for 22 days) and the $-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a twofold increase in the plasma levels of metoprolol. However, the effect of metoprolol on blood pressure and heart rate was not affected.

Warfarin

Administration of citalopram hydrobromide (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 hydrobromide (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram hydrobromide were slightly lower in the presence of digoxin.

Imipramine

Coadministration of citalopram hydrobromide (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 hydrobromide, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that citalopram hydrobromide 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 hydrobromide and imipramine/desipramine should be undertaken with caution.

Levomepromazine

Coadministration of citalopram hydrobromide (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 hydrobromide (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 hydrobromide 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 hydrobromide was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of citalopram hydrobromide 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 hydrobromide (40 mg/day) for an additional 14 days.

Citalopram hydrobromide 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 hydrobromide should be considered if the two drugs are given concomitantly.

Cytochrome P450 Isozymes

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 CYP1A2.

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 hydrobromide is administered with a potent inhibitor of

CYP3A4 (e.g., ketoconazole, intraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should be considered.

Alcohol

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

Other Drugs

No pharmacodynamic interactions have been noted in clinical trials where citalopram hydrobromide 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.

ADVERSE REACTIONS

During the premarketing clinical development, 3652 patients received 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 hydrobromide are in general mild and transient. They usually attenuate during the first one or two weeks of treatment.

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 hydrobromide- 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 hydrobromide 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 hydrobromide 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 hydrobromide, and for which the incidence in patients treated with citalopram hydrobromide 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

* Events included are those occurring in 2% or more of patients treated with citalopram hydrobromide, and for which the incidence in patients treated with citalopram hydrobromide 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 hydrobromide; N=245 for Placebo). ³ Denominator used was for males only (N=404 for citalopram hydrobromide; N=181 for Placebo).

The following events had an incidence on placebo $citalopram hydrobromide: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision. Most Frequent Adverse Events

Adverse events that occurred in citalopram hydrobromide-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 hydrobromide and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received citalopram hydrobromide 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 hydrobromide (N=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving citalopram hydrobromide

(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 hydrobromide in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

ECG

Respective analyses of electrocardiograms in citalopram hydrobromide-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 hydrobromide 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 hydrobromide 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 hydrobromide (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)

Additional Adverse Events Observed During the Premarketing Evaluation of

Citalopram hydrobromide

The events listed below include all adverse events that were reported in the overall development program of citalopram hydrobromide (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 hydrobromide, 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 Disorder- 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, esophaitis, 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 Disorder- 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.

Events Observed During the Post-Marketing Evaluation of Citalopram hydrobromide

Adverse events which have been reported to be temporally (but not necessarily causally)

associated with citalopram hydrobromide 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.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Citalopram hydrobromide has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of Citalopram hydrobromide either alone or in combination with other drugs and/or alcohol. Cases of overdoses of Citalopram hydrobromide 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 hydrobromide, had reversible ECG abnormalities, the most important of which was prolongation of QTc. Citalopram hydrobromide 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 hydrobromide up to 3920 mg.

Fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide (Manerix) and citalopram hydrobromide. The plasma concentrations of moclobemide were between 16 and 90 mg/L (therapeutic range: 1 to 3 mg/L) and those of citalopram hydrobromide between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L).

This indicates that a relatively low dose of citalopram hydrobromide, given with an overdose of moclobemide represents a serious risk for the patient.

Symptoms most often accompanying citalopram hydrobromide 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.

Management Of Overdosage

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 hydrobromide.

Due to the large volume of distribution of citalopram hydrobromide, 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.

DOSAGE AND ADMINISTRATION

General

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

Children:

RAN-CITALOPRAM (citalopram hydrobromide) is not indicated for use in children under 18 years of age. (see WARNINGS: POTENTIAL ASSOCIATION WITH THE

OCCURRENCE BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-

HARM)

Adults

RAN-CITALOPRAM (citalopram hydrobromide) 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.

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 hydrobromide in patients with severe renal impairment, citalopram hydrobromde should be used with caution in these patients.

Maintenance Treatment

Evaluation of citalopram hydrobromide 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 mg 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 a Monoamine Oxidase Inhibitor (MAOI)

At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with citalopram hydrobromide. Similarly, at least 14 days should be allowed after stopping citalopram hydrobromide before starting a MAOI (see CONTRAINDICATIONS).

Discontinuation of Citalopram Hydrobromide Treatment

Symptoms associated with the discontinuation or dosage reduction of citalopram hydrobromide 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).

PHARMACEUTICAL INFORMATION

Drug Substance:

Proper name: Citalopram hydrobromide

Chemical name: 1-[3-Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-

5-isobenzofuran carbonitrile, hydrobromide

Molecular formula: C₂₀H₂₁FN₂OHBr

Molecular weight: 405.35

Structural formula:

. HBr O

NC

N

CH₃ CH₃

F

Description: White to off-white, crystalline powder.

Melting point: 184°- 188°C

pH: 5.5-6.5 (0.4% solution)

pKa: 9.5 (microtitration)

Solubility: Water (sparingly soluble)

Ethanol (soluble)

Chloroform (freely soluble)

Diethylether (very slightly soluble) Partition Coefficient: Log P (octanol/phosphate buffer pH 7.4) - 1.57

Composition: RAN-CITALOPRAM tablets contains citalopram

hydrobromide corresponding to 20 mg and 40 mg citalopram, and the following non-medicinal ingredients: Colloidal Silicon Dioxide, Croscarmellose Sodium, Hydroxypropyl Methylcellulose, Lactose Monohydrate, Magnesium stearate, Microcrystalline Cellulose, Polydextrose, Polyethylene Glycol, Titanium Dioxide, and Triacetin.

Stability and storage: RAN-CITALOPRAM tablets should be stored in a dry place at room temperature between 15° and 30 °C.

AVAILABILITY OF DOSAGE FORMS

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

20 mg tablets: White colour, oval, biconvex film-coated tablet with bisect on one side and rph 285X on the other side. Available in bottles of 100 tablets and in blister packages of 30 tablets.

40 mg tablets: White colour, oval biconvex film-coated tablet with bisect on one side and rph 285Y on the other side. Available in bottles of 100 tablets and in blister packages of 30 tablets.