PRODUCT MONOGRAPH

Prphl-SERTRALINE

(Sertraline Hydrochloride Capsules) 25 mg, 50 mg & 100 mg

Antidepressant/Antipanic/Antiobsessional Agent

Pharmel Inc. Date of Preparation:

8699, 8e Ave. November 18, 2003 Montreal, Quebec, Canada Date of Revision: H1Z 2X4 August 8, 2005

Control No.:

PRODUCT MONOGRAPH

Prphl-SERTRALINE (Sertraline Hydrochloride Capsules) 25 mg, 50 mg & 100 mg

CONTRAINDICATIONS

Sertraline hydrochloride capsules is contraindicated in patients with known hypersensitivity to the drug.

Monoamine Oxidase Inhibitors:

Cases of serious, sometimes fatal, reactions have been reported in patients receiving Sertraline hydrochloride capsules 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, Sertraline hydrochloride 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 Sertraline hydrochloride treatment before starting an MAOI.

Pimozide: The concomitant use of Sertraline hydrochloride 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 PRECAUTIONS and INFORMATION FOR THE CONSUMER sections.)

WARNINGS

POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with 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 phl-SERTRALINE 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.)

PRECAUTIONS

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 the marketed antidepressants.

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, Sertraline hydrochloride capsules should be introduced with care in patients with a seizure disorder.

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. In order to minimize the opportunity for overdosage, prescriptions for Sertraline hydrochloride 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).

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

Discontinuation of Treatment with Sertraline hydrochloride: 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 Sertraline hydrochloride capsules in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Sertraline hydrochloride capsules in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular Conditions:

Sertraline hydrochloride capsules 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 capsules in double-blind trials were evaluated and the data indicate that Sertraline hydrochloride capsules 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.

Hepatic Dysfunction:

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 sertraline is administered to patients with hepatic impairment, a lower or less frequent dose should be considered.

Renal Dysfunction:

Sertraline hydrochloride is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. The pharmacokinetics of Sertraline hydrochloride have not been studied in patients with renal impairment and, until adequate numbers of patients with mild, moderate or severe renal impairment have been evaluated during chronic treatment with Sertraline hydrochloride, it should be used with caution in such patients.

Carcinogenesis:

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.

Use in Pregnancy and Nursing Mothers:

The safety of Sertraline hydrochloride during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, 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 antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Monoamine Oxidase Inhibitors). When treating a pregnant woman with SERTRALINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See DOSAGE AND ADMINISTRATION section).

There have been isolated reports of reactions such as tremors, jitteriness, restlessness, hypertonia, hyperreflexia and difficulty breathing in neonates whose mothers had been treated with sertraline during pregnancy and in an infant whose mother discontinued Sertraline hydrochloride treatment during breast feeding. However, causal relationship between Sertraline hydrochloride treatment and the emergence of these events has not been established.

Labor and Delivery:

The effect of Sertraline hydrochloride on labor and delivery in humans is unknown.

Use in Children:

The safety and effectiveness of Sertraline hydrochloride in children below the age of 18 have not been established.

Use in Elderly:

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.

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 several patients taking Sertraline hydrochloride, it is unclear whether Sertraline hydrochloride had a causative

role.

Interactions:

CNS Active Drugs:

Sertraline hydrochloride capsules (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 Sertraline hydrochloride and such drugs is required.

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 sertraline and pimozide is contraindicated (see CONTRAINDICATIONS and INFORMATION FOR THE CONSUMER 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 re-uptake inhibitor (SSRI) to another has not been established.

Co-administration with tryptophan may lead to a high incidence of serotonin-associated side effects.

There is no experience with the concomitant use of Sertraline hydrochloride and tryptophan in depressed patients or patients with panic disorder. Until further data are available, serotonergic drugs, such as fenfluramine, should not be used concomitantly with sertraline.

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

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. As with other SSRIs, caution is recommended when co-administering sertraline with medications, such as lithium, which may act via serotonergic mechanisms.

Monoamine Oxidase Inhibitors

- See CONTRAINDICATIONS section.

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 carbarnazepine. 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 SSRls, 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 coadministration 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 coadministration 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 Sertraline hydrochloride, may require lower doses than are usually prescribed for the other drug. Furthermore, whenever Sertraline hydrochloride is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.

Electroconvulsive Therapy:

There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and Sertraline hydrochloride.

Alcohol:

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

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 hydrochloride treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with Sertraline hydrochloride and oral hypoglycemic drugs or insulin is recommended.

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.

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 $-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

$

-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.

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.

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 Sertraline hydrochloride 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.

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.

Physical and Psychological Dependence:

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 behavior. 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 Sertraline hydrochloride misuse or abuse (e.g. development of tolerance, incrementation of dose, drug-seeking behavior).

Precautions when taking phl-SERTRALINE

:

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.

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.

phl-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 phl-SERTRALINE. Contact your physician before stopping or reducing your dosage of phl-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 phl-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 phl-SERTRALINE to alleviate the symptoms. Post-marketing reports indicate that some newborns whose mother took an SSRI (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants, such as SERTRALINE, during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support, and tube feeding. Reported symptoms include: 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 antidepressant 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 antidepressant, 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.

What to do in case of 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.

How to store phl-SERTRALINE

:

Store at room temperature (15o to 30oC) in a dry place. Keep the container tightly closed. Keep out of reach of children. If your doctor decides to stop phl-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.

What phl-SERTRALINE contains

:

phl-SERTRALINE is available as 25 mg (yellow capsule), 50 mg (white and yellow capsule) and 100 mg (orange capsule). Sertraline hydrochloride is the active ingredient. Nonmedicinal ingredients include: cornstarch; lactose (anhydrous); magnesium stearate; sodium lauryl sulfate. Capsule shells contain gelatin, titanium dioxide and dye D&C Yellow #10. In addition, capsules 25 and 50 mg also contain dye FD&C Yellow #6 and capsules 100 mg also contain dye FD&C Red #40.

Who manufactures Phl-SERTRALINE

:

phl-SERTRALINE capsules are manufactured by Pharmel Inc..

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.

AVAILABILITY OF DOSAGE FORMS

The capsules are available as follows:

The drug is supplied in white high density polyethylene bottles of 100 capsules.

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 [1-14C] 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. Alpha-hydroxy ketone glucuronides diastereomeric pair are excreted as endproducts of this metabolic pathway. In man, the "-hydroxy ketone glucuronide diastereomers were the major but not the sole endproduct of the deamination pathway, as both the ketone and "-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-0-glucuronide. Sertraline carbamoyl-0-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.

TOXICOLOGY

Acute Toxicity:

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 asymptornatic. 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.

Peri- Post-Natal Studies

Peri- Post-Natal Study in Rats (Segment III) by the Oral Route

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. 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.

2. 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.

3. 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.

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

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

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

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

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