PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 9 DRUG INTERACTIONS 18 DOSAGE AND ADMINISTRATION 22 OVERDOSAGE 23 ACTION AND CLINICAL PHARMACOLOGY 24 STORAGE AND STABILITY 27 DOSAGE FORMS, COMPOSITION AND PACKAGING 27

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION 28 CLINICAL TRIALS 29 DETAILED PHARMACOLOGY 29 TOXICOLOGY 33

PART III: CONSUMER INFORMATION 47

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NOVO-SERTRALINE

Sertraline Hydrochloride Capsules

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to NOVO-SERTRALINE (sertraline hydrochloride) 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: Cases of serious, sometimes fatal, reactions have been reported in patients receiving sertraline hydrochloride in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI, selegiline and the reversible MAOI (reversible inhibitor of monoamine oxidase -RIMA), moclobemide. Some cases presented with features resembling the serotonin syndrome. Similar cases, have been reported with other antidepressants during combined treatment with an MAOI and in patients who have recently discontinued an antidepressant and have been started on an MAOI. Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. Therefore, NOVO-SERTRALINE should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should elapse after discontinuing NOVO-SERTRALINE treatment before starting an MAOI.

Pimozide: The concomitant use of NOVO-SERTRALINE and pimozide is contraindicated as sertraline hydrochloride has been shown to increase plasma pimozide levels. Elevation of pimozide blood concentration may result in QT interval prolongation and severe arrhythmias including Torsade de Pointes. (See WARNINGS AND PRECAUTIONS and PART III CONSUMER INFORMATION sections.)

WARNINGS AND PRECAUTIONS

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRI and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increase 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 sertraline hydrochloride 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.

Monoamine Oxidase Inhibitors: (See CONTRAINDICATIONS section.)

General

Discontinuation of Treatment with NOVO-SERTRALINE:

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, fatigue, confusion, headache, 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).

Occupational Hazards:

Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.

Use in Patients with Concomitant Illness:

General:

Clinical experience with NOVO-SERTRALINE in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using NOVO-SERTRALINE in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Carcinogenesis and Mutagenesis

In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown.

Cardiovascular

Sertraline hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. However, the electrocardiograms of 1006 patients who received sertraline hydrochloride in double-blind trials were evaluated and the data indicate that sertraline hydrochloride is not associated with the development of clinically significant ECG abnormalities. In placebo-controlled trials, the frequency of clinically noticeable changes (+- 15-20 mmHg) in blood pressure was similar in patients treated with either sertraline hydrochloride or placebo.

Dependence/Tolerance

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline hydrochloride, alprazolam and d-amphetamine in humans, sertraline hydrochloride did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with sertraline hydrochloride did not reveal any drug-seeking behaviour. In animal studies sertraline hydrochloride does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of NOVO- SERTRALINE misuse or abuse (e.g. development of tolerance, incrementation of dose, drug- seeking behaviour).

Hematologic

Hyponatremia:

Several cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

Platelet Function

:

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride, it is unclear whether sertraline hydrochloride had a causative role.

Hepatic

Sertraline is extensively metabolized by the liver. A single dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and increased AUC in comparison to normal subjects. The use of sertraline in patients with hepatic disease must be approached with caution. If NOVO-SERTRALINE is administered to patients with hepatic impairment, a lower or less frequent dose should be considered. (See ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections).

Neurologic

Seizure:

Sertraline hydrochloride has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride in the development program for depression. However, 4 patients out of approximately 1800 (220<18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, NOVO-SERTRALINE should be introduced with care in patients with a seizure disorder.

Psychiatric

Activation of Mania/Hypomania:

During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of sertraline hydrochloride treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants.

Suicide:

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. It should be noted that a causal role for SSRIs and other newer anti-depressants in inducing self harm or harm to others has not been established. In order to minimize the opportunity for overdosage, prescriptions for NOVO-SERTRALINE should be written for the smallest quantity of drug consistent with good patient management (See WARNINGS AND PRECAUTIONS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM). Because of the well-established co-morbidity between both obsessive-compulsive disorder and depression and panic disorder and depression, the same precautions should be observed when treating patients with obsessive-compulsive disorder and panic disorder.

Renal

Sertraline hydrochloride is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. In patients with mild to moderate renal impairment (creatinine clearance 30-60 ml/min) or moderate to severe renal impairment (creatinine clearance 10-29 ml/min), multiple-dose pharmacokinetic parameters (AUC0-24 or Cmax) were not significantly different compared with controls. Half-lives were similar and there were no differences in plasma protein binding in all groups studied. This study indicates that, as expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment.

Special Populations

Pregnant Women:

The safety of NOVO-SERTRALINE during pregnancy has not been established and therefore, it should not be used in women of childbearing potential, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Post-marketing reports indicate that some neonates exposed to SERTRALINE, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants 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 WARNINGS AND PRECAUTIONS - Monoamine Oxidase Inhibitors). When treating a pregnant woman with NOVO-SERTRALINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (see DOSAGE AND ADMINISTRATION section). The effect of sertraline hydrochloride on labour and delivery in humans is unknown.

Nursing Women:

The safety of NOVO-SERTRALINE during lactation has not been established and therefore, it should not be used in nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Pediatrics (< 18 years of age):

The safety and effectiveness of NOVO-SERTRALINE in children below the age of 18 have not been established.

Geriatrics (>= 65 years of age): 462 elderly patients ( $ 65 years) with depressive illness have participated in multiple dose therapeutic studies with sertraline hydrochloride. The pattern of adverse reactions in the elderly was comparable to that in younger patients.

DRUG INTERACTIONS

Overview

Microsomal Enzyme Induction:

Sertraline hydrochloride was shown to induce hepatic enzymes as determined by the decrease of the antipyrine half-life. This degree of induction reflects a clinically insignificant change in hepatic metabolism.

Drugs Metabolized by P450 System

Drugs Metabolized by P450 3A4:

In two separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine or carbamazepine, under steady-state conditions. The results of these studies demonstrated that sertraline co-administration did not increase plasma concentrations of terfenadine or carbamazepine. These data suggest that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Drugs Metabolized by P450 2D6:

Many antidepressants, e.g. the SSRIs, including sertraline and most tricyclic antidepressants, inhibit the biochemical activity of the drug metabolizing isozyme, cytochrome P450 2D6 (debrisoquin hydroxylase) and thus may increase the plasma concentration of co-administered drugs that are metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressants and the type Ic antiarrhythmics, propafenone and flecainide. There is variability among the antidepressants in the extent of clinically important P450 2D6 inhibition. In two drug interaction clinical trials using desipramine and the recommended starting SSRI doses in normal volunteers, the effect of sertraline hydrochloride was compared to two other SSRIs. In the first study, mean desipramine steady state AUC (24) increased by 23% and 380% during co-administration with sertraline hydrochloride and the comparative SSRI, respectively. In a second study using a different comparative SSRI, mean desipramine steady state AUC (24) increased by 37% and 421% during co-administration with sertraline hydrochloride and the comparative SSRI, respectively. These trial results indicate that the effect of sertraline hydrochloride was significantly less pronounced than that of the two comparative SSRIs. Nevertheless, concomitant use of a drug metabolized by P450 2D6 with NOVO-SERTRALINE, may require lower doses than are usually prescribed for the other drug. Furthermore, whenever NOVO-SERTRALINE is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.

The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Drug-Drug Interactions

Alcohol:

Although sertraline hydrochloride did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of NOVO-SERTRALINE and alcohol in depressed, panic disorder or OCD patients has not been studied and is not recommended.

Beta Blockers:

There is no experience with the use of sertraline hydrochloride in hypertensive patients controlled by beta blockers. In a placebo-controlled crossover study in normal volunteers, the effect of sertraline hydrochloride on the b-adrenergic blocking activity of atenolol was assessed. The mean CD25's (the doses of isoproterenol required to increase heart rate by 25 bpm, the chronotropic dose 25 or CD25) and the average decreases in heart rate seen with atenolol during exercise test were not statistically different in the sertraline hydrochloride versus the placebo group. These data suggest that sertraline hydrochloride does not alter the b-blocking action of atenolol.

Cimetidine:

In a placebo-controlled crossover study in normal volunteers, the potential of cimetidine to alter the disposition of a single 100 mg dose of sertraline hydrochloride was assessed. The mean sertraline Cmax and AUC were significantly higher in the cimetidine-treated group, as were the mean desmethylsertraline Tmax and AUC. These data suggest that concomitant administration of cimetidine may inhibit the metabolism of sertraline and its metabolite, desmethylsertraline, and may result in a decrease in the clearance and first pass metabolism of sertraline, with a possible increase in drug-related side effects.

CNS Active Drugs:

Sertraline hydrochloride (200 mg daily) did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects, however the risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of NOVO-SERTRALINE and such drugs is required.

Diazepam:

In a normal volunteer, double-blind, placebo-controlled study comparing the disposition of intravenously administered diazepam before and after administration of sertraline (200 mg/day final dose) to steady state or placebo, there was a statistically significant 13% decrease relative to baseline in diazepam clearance for the sertraline group over that of the placebo group. These changes are of unknown clinical significance.

Digoxin:

In a parallel placebo controlled trial in normal volunteers (10 subjects per group), the administration of sertraline hydrochloride for 17 days (dose of sertraline hydrochloride: 200 mg for the last 10 days) did not cause changes in the total plasma concentrations of digoxin except a decrease of Tmax as compared to baseline.

Electroconvulsive Therapy:

There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and NOVO-SERTRALINE.

Hypoglycemic Drugs:

There are no controlled clinical trials with sertraline hydrochloride in diabetic patients treated with insulin or oral hypoglycemic drugs. In a placebo-controlled trial in normal volunteers, the administration of sertraline hydrochloride for 22 days (dose of sertraline hydrochloride was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an I.V. dose of 1000 mg. In a placebo-controlled study in normal volunteers, glibenclamide (5 mg) was given before and after administration of sertraline (200 mg/day final dose) to steady state or placebo. No significant changes were observed in the total plasma concentration of glibenclamide. Hypoglycemia requiring dextrose infusion was observed in one patient treated with sertraline hydrochloride, glibenclamide, haloperidol, bisacodyl, acetylsalicylic acid, and flucloxacillin. The causal relationship to sertraline treatment hydrochloride was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with NOVO-SERTRALINE and oral hypoglycemic drugs or insulin is recommended.

Lithium:

In placebo-controlled trials in normal volunteers, the co-administration of sertraline with lithium did not significantly alter lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. When co-administering sertraline with medications, such as lithium, which may act via serotonergic mechanisms, patients should be appropriately monitored. Monoamine Oxidase Inhibitors - See CONTRAINDICATIONS section.

Phenytoin:

It is recommended that plasma phenytoin concentrations be monitored following initiations of sertraline therapy, with appropriate adjustments to the phenytoin dose. The pharmacokinetic and pharmacodynamic effects have not been adequately characterized.

Pimozide:

In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co- administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%. Although these increases were not identified in the trial as being associated with clinically important effects on QT intervals, the trial design was not optimal for the investigation of pharmacodynamic effects in the clinical setting. For ethical considerations, a trial with higher doses could not be done. Since the highest recommended pimozide dose (12 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of NOVO-SERTRALINE and pimozide is contraindicated (see CONTRAINDICATIONS and CONSUMER INFORMATION sections).

Serotonergic Drugs:

There is limited controlled experience regarding the optimal timing of switching from other antidepressants and antipanic agents to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) or Tricyclic Antidepressants (TCAs) etc. to another has not been established. Co-administration with tryptophan, TCAs and other antidepressants may lead to a higher incidence of serotonin-associated side effects. Rare postmarketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of a selective serotonin reuptake inhibitor (SSRI) and 5-HT1 agonists (triptans). If concomitant treatment with NOVO-SERTRALINE and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs with serotonergic activity (including but not limited to fenfluramine and tryptophan) is clinically warranted and appropriate observation of the patient for acute and long-term adverse events is advised.

Warfarin:

In a placebo-controlled study in healthy men comparing prothrombin time AUC (0-120 hr) following single dosing with warfarin (0.75 mg/kg) before and after dosing to steady state with either sertraline (200 mg/day final dose) or placebo, there was a statistically significant mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo. The normalization of prothrombin time for the sertraline group was delayed compared to the placebo group. The clinical significance of these changes are unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped in patients receiving warfarin. Because sertraline is highly bound to plasma protein, the administration of NOVO- SERTRALINE to a patient taking another drug which is tightly bound to protein may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.

Drug-Food Interactions

Food appears to increase the bioavailability by about 40%: it is recommended that NOVO- SERTRALINE (sertraline hydrochloride) be administered with meals.

Drug-Herb Interactions

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

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

NOVO-SERTRALINE (sertraline hydrochloride) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS: POTENTIAL ASSOCIATIONS WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

NOVO-SERTRALINE should be administered with food once daily preferably with the evening meal, or, if administration in the morning is desired, with breakfast. As with many other medications, NOVO-SERTRALINE should be used with caution in patients with hepatic impairment (See WARNINGS AND PRECAUTIONS section).

TREATMENT OF PREGNANT WOMEN DURING THE THIRD TRIMESTER: Post-marketing reports indicate that some neonates exposed to sertraline hydrochloride, SSRIs and other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalizations, respiratory support, and tube feeding (see WARNINGS AND PRECAUTIONS section). When treating a pregnant woman with NOVO-SERTRALINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering NOVO-SERTRALINE in the third trimester.

SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with NOVO-SERTRALINE. In addition, at least 14 days should be allowed after stopping NOVO-SERTRALINE before starting an MAOI (see CONTRAINDICATIONS section).

Recommended Dose and Dosage Adjustment INITIAL TREATMENT:

Depression and Obsessive-Compulsive Disorder:

As no clear dose-response relationship has been demonstrated over a range of 50-200 mg/day, a dose of 50 mg/day is recommended as the initial dose.

Panic Disorder:

NOVO-SERTRALINE treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily depending on tolerability and clinical response. No clear dose-response relationship has been demonstrated over a range of 50-200 mg/day.

TITRATION: In depression, OCD and panic disorder, a gradual increase in dosage may be considered if no clinical improvement is observed. Based on pharmacokinetic parameters, steady-state sertraline plasma levels are achieved after approximately 1 week of once daily dosing; accordingly, dose changes, if necessary, should be made at intervals of at least one week. Doses should not exceed a maximum of 200 mg/day. The full therapeutic response may be delayed until 4 weeks of treatment or longer. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.

MAINTENANCE: During long-term therapy for any indication, the dosage should be maintained at the lowest effective dose and patients should be periodically reassessed to determine the need for continued treatment.

DISCONTINUATION OF NOVO-SERTRALINE TREATMENT: Symptoms associated with the discontinuation or dosage reduction of sertraline hydrochloride have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS sections). 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 WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS sections).

Missed Dose

Missed dose of NOVO-SERTRALINE should be taken as soon as possible unless it is almost time for the next dose. In that case missed dose should be skipped and the regular schedule should be followed. Doses must not be doubled.

OVERDOSAGE

On the evidence available, sertraline has a wide margin of safety in overdose. Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999). Reported overdoses of sertraline alone of up to 13.5 g have been documented. However, an overdose of 2.5 g of sertraline alone had a fatal outcome.

Symptoms

Symptoms of overdose include serotonin-mediated side effects such as somnolence, gastrointestinal disturbance (such as nausea, vomiting, diarrhea), tachycardia, tremor, agitation and dizziness, ECG changes, anxiety and dilated pupils. Less frequently reported was coma. Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include alopecia, decreased libido, ejaculation disorder, fatigue, insomnia, bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.

Treatment

Establish and maintain an airway, ensure adequate oxygenation and ventilation, if necessary. Activated charcoal, which may be used with sorbitol, may be as or more effective than lavage, and should be considered in treating overdose. Induction of emesis is not recommended. Treatment was primary supportive and included monitoring and use of activated charcoal, gastric lavage or cathartics and hydration. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Cardiac and vital signs monitoring are recommended along with general symptomatic and supportive measures. There are no specific antidotes for NOVO-SERTRALINE. Due to the large volume of distribution of sertraline hydrochloride, 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

The mechanism of action of sertraline is presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets. Like most clinically effective antidepressants, sertraline downregulates brain norepinephrine and serotonin receptors in animals. In receptor binding studies, sertraline has no significant affinity for adrenergic (alpha1, alpha2 & beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites. In placebo-controlled studies in normal volunteers, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance.

Pharmacodynamics Clinical Trials Panic Disorder: Four placebo-controlled clinical trials have been performed to investigate the efficacy of sertraline hydrochloride in panic disorder: two flexible dose studies and two fixed dose studies. At the last week of treatment (week 10 or 12), both flexible dose studies and one of the fixed dose studies showed statistically significant differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline in the total number of full panic attacks (last observation carried forward analysis). As the flexible dose studies were of identical protocol, data for these investigations can be pooled. The mean number of full panic attacks at baseline was 6.2/week (N = 167) in the sertraline hydrochloride group and 5.4/week in the placebo group (N = 175). At week 10 (last observation carried forward analysis), the mean changes from baseline were -4.9/week and -2.5/week for the sertraline hydrochloride and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 57% in the placebo group and 69% in the sertraline hydrochloride group. The mean daily dose administered at the last week of treatment was approximately 120 mg (range: 25-200 mg) in the flexible dose studies. No clear dose-dependency has been demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies. Obsessive Compulsive Disorder: Five placebo-controlled clinical trials, in adults, of 8 to 16 weeks in duration have been performed to investigate the efficacy of sertraline hydrochloride in obsessive-compulsive disorder: four flexible dose studies (50-200 mg/day) and one fixed dose study (50, 100 & 200 mg/day). Results for three of the four flexible dose studies and the 50 and 200 mg dose groups of the fixed dose study were supportive of differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale (last observation carried forward analysis). No clear dose- dependency was demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies. In the flexible dose studies, the mean daily dose administered at the last week of treatment ranged from 124-180 mg. One placebo-controlled clinical trial of 12 weeks duration, was performed in children and adolescents aged 6-17 years, to investigate the efficacy of sertraline hydrochloride in obsessive- compulsive disorder. The study used flexible dosing, starting with 25 mg/day in children 6-12 years old (sertraline hydrochloride n=53, placebo n=54) and with 50 mg/day in adolescents 13-17 years old (sertraline hydrochloride n=39, placebo n=41). In both age groups, sertraline hydrochloride was titrated up to a maximum 200 mg/day, over 4 weeks, as tolerated. The mean dose for completers (74/92 sertraline hydrochloride treated patients) was 178 mg/day. Results showed statistically significant differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline to endpoint (last observation carried forward analysis) on the Children's Yale-Brown Obsessive-Compulsive Scale (p=0.005), the National Institute of Mental Health Obsessive-Compulsive Scale (p=0.019) and the Clinical Global Impression Improvement Rating Scale (p=0.002).

Pharmacokinetics

Summary of NOVO-SERTRALINE's Pharmacokinetic Parameters

Absorption: Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (Cmax) of sertraline is 0.19 Fg/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time curve is 2.8 mg hr/l. For desmethylsertraline, Cmax is 0.14 Fg/mL, the half-life 65 hours and the area under the curve 2.3 mg hr/l. Linear dose proportionality has been demonstrated over the clinical dose range of 50 to 200 mg/day. Food appears to increase the bioavailability by about 40%: it is recommended that NOVO- SERTRALINE (sertraline hydrochloride) be administered with meals.

Distribution:

Approximately 98% of sertraline is plasma protein bound.

The interactions between sertraline and other highly protein bound drugs have not been fully evaluated. (See WARNINGS AND PRECAUTIONS section)

Metabolism:

Sertraline is extensively metabolized to N-desmethylsertraline, which shows negligible pharmacological activity. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. Biliary excretion of metabolites is significant.

Excretion:

Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours.

Special Populations and Conditions

Pediatrics:

The long term safety, including effects on growth and development, in patients under 18 years of age, has not been established.

Geriatrics:

The pharmacokinetics of sertraline itself appear to be similar in young and elderly subjects. Plasma levels of N-desmethylsertraline show a 3-fold elevation in the elderly following multiple dosing, however, the clinical significance of this observation is not known.

Gender:

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

Race:

Differences in pharmacokinetics based on race have not been established.

Hepatic Insufficiency: WARNINGS AND PRECAUTIONS DOSAGE AND ADMINISTRATION

The pharmacokinetics of sertraline in patients with significant hepatic dysfunction have been determined. (See

and

sections)

Renal Insufficiency: WARNINGS AND PRECAUTIONS DOSAGE AND ADMINISTRATION

The pharmacokinetics of sertraline in patients with significant renal dysfunction have been determined. (See

and

sections)

Genetic Polymorphism:

Differences in pharmacokinetics based on genetic polymorphism have not been established.

STORAGE AND STABILITY

NOVO-SERTRALINE capsules are packaged in white high density polyethylene bottles and are stored at controlled room temperature between 15deg to 30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-SERTRALINE Capsules are available as: 25 mg: Opaque yellow cap and opaque yellow body, hard gelatin capsules printed N and

in black ink on opposing cap and body portions of the capsules.

50 mg: Opaque yellow cap and opaque white body, hard gelatin capsules printed N and 50 in black ink on opposing cap and body portions of the capsules. 100 mg: Opaque orange cap and opaque orange body, hard gelatin capsules printed N and

in black ink on opposing cap and body portions of the capsules.

The drug is supplied in white high density polyethylene bottles of 100, 250, 500 and 1000 capsules.

Composition

25 mg and 50 mg: colloidal silicon dioxide, D&C Yellow #10, FD&C Yellow #6, gelatin, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulphate, and titanium dioxide. 100 mg: colloidal silicon dioxide, D&C Yellow #10, FD&C Red #40, gelatin, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulphate, and titanium dioxide. Capsules contain sertraline hydrochloride equivalent to 25, 50, or 100 mg of sertraline.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: sertraline hydrochloride Chemical name: (1S,cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1- naphthalenamine hydrochloride Molecular formula and molecular mass: C17H17NCl2HCl 342.7 Structural formula:

NHCH3 . HCl

Cl

Cl

Physicochemical properties: Sertraline hydrochloride is a white to off-white crystalline powder that is slightly soluble in water and isopropyl alcohol, very slightly soluble in 0.1N aqueous hydrochloric acid, practically insoluble in 0.1N aqueous sodium hydroxide, sparingly soluble in ethanol, and soluble in chloroform.

CLINICAL TRIALS

A comparative, two-way, single dose bioavailability study was performed on NOVO- SERTRALINE (sertraline hydrochloride) 100 mg Capsules and Zoloft(r) 100 mg Capsules. The pharmacokinetic data calculated for the two sertraline hydrochloride formulations are tabulated below:

*

Novo-Sertraline Tablet 100 mg (Novopharm Ltd., Canada)

+ Zoloft(r) 100 mg Tablet (Pfizer Inc., Canada), purchased in Canada

++ For drugs with a half-life greater than 24 hours AUCT should be replaced with AUC0-72.

SS

Expressed as the arithmetic mean (CV%) only.

Expressed as the arithmetic mean (CV%) only.

# Indicate % Confidence Interval (i.e., 90% or 95%) in the column heading and list for the AUCT, AUCI and CMAX (if required).

DETAILED PHARMACOLOGY

Animal Pharmacology: Sertraline is a highly selective and potent inhibitor of neuronal 5HT uptake, both in vitro and in vivo. Sertraline is highly active in several behavioral and biochemical models in which clinically effective antidepressants are also active. Sertraline has no significant effects on cardiac function and only transient effects on pulmonary function are seen with high intravenous doses. A transient reduction in K+ excretion was observed in conscious dogs, which dissipated after the second daily dose of 4 mg/kg po. Sertraline increases gastric acid secretion in rats but does not induce any pathological changes in the stomachs of dogs, even after several months of treatment. Sertraline is a mild inducer of hepatic microsomal cytochrome P450. Rats receiving a 32 mg/kg oral dose of sertraline (5 to 10 fold the therapeutic dose in man) in combination with lithium (200 mg/kg) had increased plasma levels of lithium compared to saline- treated controls. Characterization in animal test systems produced evidence that sertraline shares pharmacologic properties common to clinically effective antidepressant agents and lacks cardiovascular or anticholinergic effects.

Preclinical Pharmacokinetics: Data from the pharmacokinetic studies in the mouse, rat and dog are contained in Table 3. The elimination half-life of sertraline was 2.5 hours in the mouse and about 5 hours in the rat and dog. The plasma clearance of sertraline was estimated at 59 and 49 ml/min/kg in the rat and dog, respectively (Table 3). Plasma clearance represents metabolic clearance in rat and dog, since sertraline is not excreted unchanged in urine or bile. The oral bioavailability of sertraline was 70, 36 and 22% in the mouse, rat and dog, respectively (Table 3). In bile duct-cannulated rats and dogs receiving [1-14 C] sertraline by oral gavage, 62 to 94% of the dose was absorbed. Therefore, sertraline undergoes first-pass metabolism with oral absorption. The primary amine metabolite (desmethylsertraline), was present in the circulation of all species studied. This metabolite has no pharmacologic activity in vivo. Its elimination half- life is 2-3 times longer than that of sertraline in all species studied. The plasma protein binding of sertraline in rat, dog and man was 97.2, 98.9 and 98.6%, respectively, at 100 ng/ml plasma concentrations. Sertraline distributes extensively into tissues. The volume of distribution of sertraline in rat or dog was 23 or 25 l/kg (Table 3). Enzyme induction activity: Following a five day treatment in rats, 80 mg/kg/day of sertraline (oral dose) was approximately equivalent to 50 mg/kg/day of phenobarbital in inducing the in vitro O-demethylation of p-chloroanisole. Following a three week treatment of 90 mg/kg/day in dogs, the half-life of antipyrine decreased from a pretreatment value of 54 minutes to 30 minutes. Rat, dog and man form the primary amine metabolite (desmethylsertraline) by the N- demethylation of sertraline; form ketone by the oxidative deamination of sertraline and primary amine. Alphahydroxy ketone glucuronides diastereomeric pair are excreted as endproducts of this metabolic pathway. In man, the a-hydroxy ketone glucuronide diastereomers were the major but not the sole endproduct of the deamination pathway, as both the ketone and a-hydroxy ketone metabolites underwent reduction to some extent. Conjugates of the corresponding reductive metabolites, the alcohol and dihydroxy metabolite, were excreted in urine. Although not identified in excreta of rat or dog, the alcohol and dihydroxy metabolites were formed in vitro by incubation of ketone in hepatic microsomes from both species. Sertraline can alternatively be converted to N-hydroxy sertraline glucuronide or sertraline carbamoyl-O-glucuronide. Sertraline carbamoyl-O- glucuronide was the major excretory metabolite in the dog and also was formed by rat and man. N-hydroxy sertraline glucuronide was identified only in rat and dog. There was a greater excretion of metabolites in bile by the rat and dog than by man.

TABLE 3

Summary of Pharmacokinetics for Sertraline and the Primary Amine Metabolite in the Mouse, Rat, Dog and Man

Sertraline * Primary Amine *

* T1/2, VD and C1 in mouse, rat and dog were based on data from parenteral route of sertraline hydrochloride administration, while Cmax and AUC were based on data following oral administration.

1. Based on parenteral administration of primary amine metabolite.

2. Steady-state values (average of days 3 and 36) of toxicology study #82-375-08 (Pfizer Canada Inc.)

3. Sertraline t1/2 based on data at doses of 50 to 400 mg/day. Cmax and AUC for drug and metabolite were steady-state values (day 14) of 200 mg dose subjects.

TOXICOLOGY

Acute Toxicity:

mice and rats

ACUTE ORAL AND INTRAPERITONEAL TOXICITY STUDIES IN MICE AND RATS

Signs of toxicity observed in both mice and rats dosed orally and by intraperitoneal administration included hyperactivity, convulsions, depression, weakness, decreased food consumption, and weight gain inhibition. Oral administration in both mice and rats produced exophthalmia, soft stools, and labored respiration. Orally dosed rats also showed marked salivation. Acute oral administration produced no gross pathological findings. Acute intraperitoneal administration, on the other hand, caused adhesion of the intestines or pancreas to the liver in 2 of 10 male mice and liver lobe adhesions which were dose-related in rats. Sertraline was also given in single doses of 10, 20, 30, and 50 mg base/kg p.o. (in capsules) to two female beagle dogs at each dose. At the lowest level, dogs were mydriatic and anorectic but otherwise asymptomatic. At higher doses, increased salivation, tremors and twitches were observed, along with the mydriasis and anorexia. None of the dogs at any dose level exhibited motor stimulation, circling or stereotypy. The duration of the anorexia was 12 to 15 hr., but eating resumed late in the day after treatment and the dogs recovered uneventfully.

Chronic Toxicity/Oncogenicity

Fertility and Reproductive Performance

Reproduction and Teratology

Teratology

Genotoxicity: Genotoxicity studies including Ames Salmonella and mouse lymphoma TK+/TK- assays for point mutations, tests for cytogenetic aberrations in vivo on mouse bone marrow and on human lymphocytes in vitro with and without metabolic activation were uniformly negative. Sertraline did not induce mutations at the gene level in the Ames microbial assay with and without metabolic activation against Salmonella typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 nor at the chromosomal level in bone marrow of mice treated with 80 mg/kg p.o. (in vivo cytogenetic assay) or in human lymphocytes (in vitro cytogenetic assay) at 0.5 to 25 mg/mL in culture. Sertraline produced no significant increase in mutant frequency in L5178Y mouse lymphoma (TK+/-) cells either in the presence or absence of exogenous metabolic activation by normal rat liver S9 microsomes.

REFERENCES

1. Anonymous. Sertraline. Drugs Future 1986; 11: 345.

2. Anonymous. Sertraline. Drugs Future 1985; 10: 349.

3. Anonymous. Sertraline. Drugs Future 1984; 9(4): 277-8.

4. Bisserbe JC, Wiseman R, Flament M, Goldberg M, Lane R. A Double-Blind Comparison of Sertraline and Clomipramine in Outpatients with Obsessive-Compulsive Disorder. European Psychiatry 12: 82-93, 1997.

5. Burrows GD, McIntyre IM, Judd FK, et al. Clinical effects of serotonin reuptake inhibitors in the treatment of depressive illness. J Clin Psychiatry 1988; 49(8Suppl):18-22.

6. Butler J, Leonard BE. Acute and chronic effects of the novel antidepressant sertraline on platelet and synaptosomal uptake of 3H-5HT in rat brain. Br Assoc Psychopharmacol; Cambridge, U.K., 6/86.

7. Butler J, Leonard BE, The platelet serotonergic system in depression and following sertraline treatment. Int Clin Psychopharmacol 1988; 3(4):343-7.

8. Byerley WF, McConnell EJ, McCabe RT, et al. Chronic administration of sertraline, a selective serotonin uptake inhibitor, decreased the density of b-adrenergic receptors in rat frontoparietal cortex. Brain Res 1987; 421(1-2): 377-81.

9. Cohn CK, Shrivastava R, Mendels J, et al. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin Psychiatry 1990; 51(12Suppl):28-33.

10. Cohn J, Katon W, Richelson E. Choosing the right antidepressant. Patient Care 1990; 15:88-116.

11. Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry. In press.

12. Doogan DP, Caillard V. Sertraline in the prevention of relapse in major depression. (abstract). Psychopharmacology 1988; 96(Suppl) :271 (abstract #31.02.16).

13. Doogan DP. Sertraline in the prevention of depression. Br J Psychiatry. In press.

14. Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry 1988; 49(8Suppl):46-51.

15. Fontaine R et al. The efficacy and safety of sertraline versus imipramine in outpatients with major depression: a six month double-blind, parallel multicenter study (Abstract). In: Proceedings of the 4th European College of Neuropsychopharmacology Congress, Monaco, 6-9 Oct., 1991. J Eur Coll Neuropsychopharmacology. In press.

16. Greist J, Jefferson JW, Kobak KA, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz MR, Lydiard B, McElroy S, Mendels J, Rasmussen S, White K, Flicker C. A 1 Year Double-Blind Placebo-Controlled Fixed Dose Study of Sertraline in the Treatment of Obsessive-Compulsive Disorder. International Clinical Psychopharmacology 10:57-65, 1995.

17. Greist J, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz M, Lydiard RB, Rasmussen S, White K, Sikes C. Double-Blind Parallel Comparison of Three Dosages of Sertraline and Placebo in Outpatients With Obsessive-Compulsive Disorder. Archives of General Psychiatry 52:289-295, 1995.

18. Guy W, Manov G, Wilson WH. Double-blind dose determination study of a new antidepressant- sertraline. Drug Dev Res 1986; 9(4): 267-72.

19. Heym J, Reynolds LS. Inhibition of serotonergic unit activity by sertraline: a new and highly selective inhibitor of serotonin uptake. Soc Neurosci Abstr 1986; 12: 473.

20. Heym J, Koe BK. Pharmacology of sertraline: a review. J Clin Psychiatry 1988; 49(8Suppl):40-5.

21. Hindmarch I, Shillingford J, Shillingford C. The effects of sertraline on psychomotor performance in elderly volunteers. J Clin Psychiatry 1990; 51(12SupplB):34-6.

22. Hindmarch I, Bhatti JZ. Psychopharmacological effects of sertraline in normal healthy volunteers. Eur J Clin Pharmacol 1988; 35(2):221-3.

23. Itil TM, Mukherjee S, Dayican G, et al. Mode of action and dose finding of sertraline, a new antidepressant based on CEEG-brain mapping technology (abstract). Psychopharmacology 1988; 96(Suppl):281.

24. Kennett GA, Dourish CT, Curzon G. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol 1987; 134(3): 265-74.

25. Koe BK, Weissman A, Welch WM, et al. Sertraline: 1S,4S-N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 1983; 226(3): 686-700.

26. Koe BK, Weissman A, Welch WM, et al. Sertraline: a new selective inhibitor of serotonin uptake. Psychopharmacol Bull 1983; 19(4): 687-91.

27. Koe BK. Preclinical pharmacology of sertraline: a potent and specific inhibitor of serotonin reuptake. J Clin Psychiatry 1990; 51(12SupplB):13-7.

28. Koe BK, Koch SW, Lebel LA, et al. Sertraline, a selective inhibitor of serotonin uptake, induces subsensitivity of beta-adrenoceptor system of rat brain. Eur J Pharmacol 1987; 141 (2): 187-94.

29. March JS, Biederman J, Wolkow R, Safferman A, Mardekian J, Cook EH et al. Sertraline in Children and Adolescents with Obsessive-Compulsive Disorder: A Multicenter Randomized Controlled Trial. JAMA 1998 Nov. 25, 280(20):1752-6.

30. Mattila MJ, Saarialho-Kere U, Mattila M. Acute effects of sertraline, amitriptyline, and placebo on the psychomotor performance of healthy subjects over 50 years of age. J Clin Psychiatry 1988; 49(8suppl):52-8.

31. Reimherr FW, Chouinard G, Cohn CK, et al. Antidepressant efficacy of sertraline: a doubleblind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry 1990; 51(12SupplB):18-27.

32. Reimherr FS, Byerley WF, Ward MF, et al. Sertraline, a selective inhibitor of serotonin uptake, for the treatment of outpatients with major depressive disorder. Psychopharmacol Bull 1988; 24(1):200-5.

33. Rickels K, Schweizer E. Clinical overview of serotonin reuptake inhibitors. J Clin Psychiatry 1990; 51 (12SupplB):9-12.

34. Saletu B, Grunberger J, Linzmayer L. On central effects of serotonin re-uptake inhibitors: quantitative EEG and psychometric studies with sertraline and zimelidine. J Neural Transm 1986; 67(3-4): 241-66.

35. Saletu B, Grunberger J. Drug profiling by computed electroencephalography and brain maps, with special consideration of sertraline and its psychometric effects. J Clin Psychiatry 1988; 49(8Suppl):59-71.

36. Sanders-Bush E, Tsutsumi M. Serotonin 5HT-2 receptor binding and function after chronic sertraline treatment. Fed Proc 1987; 46: 391.

37. Welch WM, Harbert CA, Koe BK, et al. Antidepressant derivatives of cis-4-phenyl- 1,2,3,4-tetrahydro-1-naphthalenamine and pharmaceutical compositions thereof. Eur Pat Appl EP 30081, 6/10/81, 54 pp.

38. Welch WM, Vivieros DM. Synthesis of 1-14C-(1S,4S)-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4 -tetrahydro-1-naphthalenamine L- mandelate (1-14C- sertraline mandelate). J Label Compounds Radiopharm 1987; 24(8): 987-93.

39. Welch WM, Kraska AR, Sarges R, et al. Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4- aryltetralins. J Med Chem 1984; 27(11): 1508-15.

40. Woolley DW, Shaw E. Some neurophysiological aspects of serotonin. Br Med J 1954; 2: 122-6.

41. Product Monograph for Zoloft(r) Capsules. Pfizer Canada Inc., Kirkland, Quebec, Canada.

November 10, 2004. A Randomized, Two-Way Crossover, Single-Dose, Blinded Study to Evaluate the Relative Bioavailability of a Test Capsule Formulation of Sertraline HCl (100 mg), Compared to an Equivalent Dose of a Commercially Available Reference Drug Product (Zoloft(r), Pfizer Inc., Canada) in 30 Fed, Healthy, Male Subjects. Completed December 9, 1998. Data on file at Novopharm Limited.

PART III: CONSUMER INFORMATION

Pr

NOVO-SERTRALINE

(Sertraline Hydrochloride Capsules)

This leaflet is part III of a three-part "Product Monograph" published when NOVO-SERTRALINE was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about NOVO-SERTRALINE. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

NOVO-SERTRALINE has been prescribed to you by your doctor to relieve your symptoms of depression, panic disorder or obsessive-compulsive disorder. Treatment with these types

of medications is most safe and effective when you and your doctor have good communication about how you are feeling.

What it does:

NOVO-SERTRALINE (sertraline hydrochloride) belongs to a family of medicines called SSRIs; Selective Serotonin Reuptake Inhibitors.

NOVO-SERTRALINE is thought to work by increasing the levels of a chemical in the brain called serotonin (5- hydroxytryptamine).

When it should not be used:

• Do not use NOVO-SERTRALINE if you are allergic to it or to any of the components of its formulation (see What the non medicinal ingredients are). Stop taking the drug and contact your doctor immediately if you experience an allergic reaction or any severe or unusual side effect.

• Do not use with a monoamine oxidase inhibitor (MAOI) (i.e. phenelzine sulphate, moclobemide) or within 14 days after stopping treatment with an MAOI.

• Do not use with pimozide. What the medicinal ingredient is:

Sertraline hydrochloride

What the nonmedicinal ingredients are:

Nonmedicinal ingredients include: lactose monohydrate; magnesium stearate; pregelatinized starch; sodium lauryl sulfate.

Capsule shells contain colloidal silicon dioxide, gelatin, sodium lauryl sulfate, titanium dioxide and dye D&C Yellow

#10. Capsules 25 mg and 50 mg also contain dye FD&C Yellow #6 and capsules 100 mg also contain dye FD&C Red

#40. The capsules do not contain tartrazine or gluten.

What dosage forms it comes in:

NOVO-SERTRALINE is available as 25 mg (yellow capsule), 50 mg (white and yellow capsule) and 100 mg (orange capsule).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions Particularly in the first few weeks or when doses are

adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety,

or have impulsive or disturbing thoughts such as thoughts

of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately; do not discontinue your medication on your own.

BEFORE you use NOVO-SERTRALINE talk to your doctor or pharmacist:

• All your medical conditions, including a history of seizures, liver or kidney disease

• If you are pregnant or thinking about becoming pregnant, or if you are breast-feeding

• Your habits concerning alcohol consumption

NOVO-SERTRALINE does not usually affect people's normal activities. However, some people feel sleepy while taking it, in which case they should not drive or operate machinery.

Avoid alcoholic drinks while taking NOVO-SERTRALINE. Post-marketing reports indicate that some newborns whose

mothers took an SSRI (Selective Serotonin Reuptake Inhibitor)

or other newer anti-depressant, such as sertraline hydrochloride, during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support, and tube feeding. Reported symptoms included: feeding and/or breathing difficulties, seizures, tense or overly relaxed muscles, jitteriness and constant crying. In most cases, the newer antidepressant was taken during the third trimester of pregnancy. These symptoms are consistent with either a direct adverse effect of the anti-depressant on the baby, or possibly a discontinuation syndrome caused by sudden withdrawal from the drug. These symptoms normally resolve over time. However, if your baby experiences any of these symptoms, contact your doctor as soon as you can.

If you are pregnant and taking an SSRI, or other newer anti- depressant, you should discuss the risks and benefits of the various treatment options with your doctor. It is very

important that you do NOT stop taking these medications without first consulting your doctor.

INTERACTIONS WITH THIS MEDICATION

Before you use NOVO-SERTRALINE talk to your Doctor or Pharmacist if you use:

• Any medications (prescription or non-prescription) which you are taking especially monoamine oxidase inhibitor antidepressants (e.g. phenelzine sulphate, tranylcypromine sulphate or moclobemide) or any other antidepressants, pimozide (an antipsychotic drug), drugs used to treat diabetes, drugs used to thin the blood (anticoagulants) or drugs containing tryptophan

• Any natural or herbal products you are taking (e.g. St.

John's Wort).

PROPER USE OF THIS MEDICATION

Usual dose:

It is very important for you to take NOVO-SERTRALINE exactly as your doctor has instructed. The usual starting dose is 50 mg of NOVO-SERTRALINE/day for depression and obsessive-compulsive disorder. If you are taking NOVO- SERTRALINE for panic disorder, your doctor may start you at 25 mg/day.

Your doctor may decide to increase the dose up to 200 mg/day. Never increase or decrease the amount of NOVO-

SERTRALINE you, or those in your care if you are a caregiver

or guardian, are taking unless your doctor tells you to and do not stop taking this medication without consulting your doctor (see under Precautions when taking NOVO- SERTRALINE).

You should continue to take your medicine even if you do not feel better, as it may take approximately four weeks for your medicine to work.

NOVO-SERTRALINE should be taken with food; either in the morning or evening. You should swallow the capsule whole; do not chew it.

Keep taking NOVO-SERTRALINE until your doctor tells you to stop. Your doctor may tell you to continue to take your medicine for several months. Continue to follow your doctor's instructions.

Overdose:

If you have taken a large number of capsules all at once, contact either your doctor, hospital emergency department or nearest poison control centre immediately, even though you may not feel sick.

Missed Dose:

If you miss taking a dose of NOVO-SERTRALINE, do not worry, just take the next dose when you normally do. Do not take 2 doses at once. It is important to discuss with your doctor

what you should do if you miss several doses of NOVO-

SERTRALINE.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

You may experience some side effects such as nausea, headache, dry mouth, diarrhea, sleep disturbance and loss of appetite. Other effects may include drowsiness, sexual problems, nervousness and tremor. Consult your doctor if you experience these or other side effects, as the dose may have to be adjusted.

Contact your physician before stopping or reducing your dosage of NOVO-SERTRALINE. Symptoms such as dizziness, abnormal dreams, electric shock sensations, agitation, anxiety, difficulty concentrating, headache, tremor, nausea, vomiting, sweating or other symptoms may occur after stopping or reducing the dosage of NOVO-SERTRALINE. Such symptoms may also occur if a dose is missed. These symptoms usually disappear without needing treatment. Tell your doctor immediately if you have these or any other symptoms. Your doctor may adjust the dosage of NOVO- SERTRALINE to alleviate the symptoms.

* If you think you have these side effects, it is important that

you seek medical advice from your doctor straight away.

This is not a complete list of side effects. For any unexpected effects while taking NOVO-SERTRALINE, contact your doctor or pharmacist.

HOW TO STORE IT

Store at room temperature (15 to 30EC) in a dry place. Keep the container tightly closed.

Keep out of reach of children.

If your doctor decides to stop NOVO-SERTRALINE treatment, return any leftover medicine to your pharmacist to safely dispose of it. Keep it only if your doctor tells you to do so.

Reminder: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be obtained by contacting Novopharm Limited at:

1-800-268-4127 ext. 5005

or druginfo @novopharm.com

This leaflet was prepared by: Novopharm Limited

30 Novopharm Court Toronto, Ontario

Canada, M1B 2K9

Last revised: November 23, 2005.