SERTRALINE-25, SERTRALINE-50, SERTRALINE-100 Sertraline Hydrochloride Capsules Equivalent to 25, 50 and 100 mg Sertraline

ACTIONS AND CLINICAL PHARMACOLOGY

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 down-regulates 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 did not cause sedation and did not interfere with psychomotor performance.

Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (Cmax) of sertraline is 0.19 ug/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 ug/mL, the half-life 65 hours and the area under the curve 2.3 mg.hr/L. Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours. 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 SERTRALINE (sertraline hydrochloride) be administered with meals. 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. Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see PRECAUTIONS). 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. Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

The pharmacokinetic of sertraline in patients with significant hepatic or renal dysfunction have not been determined.

A comparative bioavailability study was performed in healthy human volunteers. The rate and extent of absorption of sertraline were measured and compared after a single oral 100 mg dose of SERTRALINE or Zoloft 100 mg capsules. The results from measured data are summarized as follows: Geometric Mean

SERTRALINE (sertraline hydrochloride) is indicated for the symptomatic relief of depressive illness. However, the antidepressant action of SERTRALINE in hospitalized depressed patients has not been adequately studied. A placebo-controlled European study carried out over 44 weeks, in patients who were responders to sertraline has indicated that sertraline may be useful in continuation treatment, suppressing reemergence of depressive symptoms. However, because of methodological limitations, these findings on continuation treatment have to be considered tentative at this time.

CONTRAINDICATIONS

SERTRALINE (sertraline hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.

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

WARNINGS

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

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

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

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.

Patients currently taking 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.

PRECAUTIONS

During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of sertraline 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.

Sertraline 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 in the development program for depression. SERTRALINE (sertraline hydrochloride) should be introduced with care in patients with a seizure disorder.

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 should be written for the smallest quantity of drug consistent with good patient management.

(see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

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.

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

Sertraline 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 in double blind trials were evaluated and the data indicate that sertraline 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 or placebo.

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.

Sertraline is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. The pharmacokinetics of sertraline 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, it should be used with caution in such patients.

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.

The safety of SERTRALINE 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. 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 treatment during breast feeding. However, causal relationship between sertraline treatment and the emergence of these events has not been established.

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

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

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.

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

: Sertraline (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 in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of SERTRALINE and such drugs is required.

: There is limited controlled experience regarding the optimal timing of switching from other antidepressants 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) 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 and tryptophan in depressed patients. Until further data are available, serotonergic drugs, such as fenfluramine, should not be used concomitantly with sertraline.

: In placebo-controlled trials in normal volunteers, the co-administration of lithium with sertraline did not 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.

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.

Many antidepressants, eg. 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, eg. 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 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 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 and the comparative SSRI, respectively. These trial results indicate that the effect of sertraline was significantly less pronounced than that of the two comparative SSRIs. Nevertheless, concomitant use of a drug metabolized by P450 2D6 with sertraline, may require lower doses than are usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.

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

: Although sertraline did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of SERTRALINE and alcohol in depressed patients has not been studied and is not recommended.

: There are no controlled clinical trials with sertraline in diabetic patients treated with insulin or oral hypoglycemic drugs.

In a placebo-controlled trial in normal volunteers, the administration of sertraline for 22 days (dose of sertraline 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, glibenclamide, haloperidol, bisacodyl, aspirin and flucloxacillin. The causal relationship to sertraline treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with SERTRALINE 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 for 17 days (dose of sertraline: 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.

: There is no experience with the use of sertraline in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of sertraline 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 versus the placebo group. These data suggest that sertraline 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 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.

: 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.

: 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 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.

: Sertraline 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.

: In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline, alprazolam, and d-amphetamine in humans, sertraline 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 did not reveal any drug-seeking behaviour. In animal studies, sertraline 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 misuse or abuse (e.g. development of tolerance, incrementation of dose, drug-seeking behaviour).

ADVERSE REACTIONS

In clinical development programs, sertraline has been evaluated in 1902 subjects with depression. The most commonly observed adverse events associated with the use of sertraline were: gastrointestinal complaints, including nausea, diarrhea/loose stool and dyspepsia; male sexual dysfunction (primarily ejaculatory delay); insomnia and somnolence; tremor; increased sweating and dry mouth; and dizziness. In the fixed dose placebo controlled study, the overall incidence of side effects was dose related with a majority occurring in the patients treated with 200 mg dose. The discontinuation rate due to adverse events was 15% in 2710 subjects who received sertraline in pre-marketing multiple dose clinical trials. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea and fatigue.

Incidence in Controlled Clinical Trials

Table 1 enumerates adverse events that occurred at a frequency of 1% or more among sertraline patients who participated in controlled trials comparing titrated sertraline with placebo.

TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED

CLINICAL TRIALS *

TABLE 1
	Percent of Patients Reporting		Difference Percentage
ADVERSE EXPERIENCE	SERTRALINE (N=861)	PLACEBO (N=853)	Difference Percentage
Autonomic Nervous System Disorders	16.3	9.3	7.0
Mouth Dry	16.3	9.3	7.0
Sweating Increased	8.4	2.9	5.0
Cardiovascular	3.5	1.6	1.9
Palpitations	3.5	1.6	1.9
Chest Pain	1.0	1.6	-0.6
Centr. & Periph. Nervous System Disorders	20.3	19.0	1.3
Headache	20.3	19.0	1.3
Dizziness	11.7	6.7	5.0
Tremor	10.7	2.7	8.0
Paresthesia	2.0	1.8	0.2
Hypoesthesia	1.7	0.6	1.1
Twitching	1.4	0.1	1.3
Hypertonia	1.3	0.4	0.9
Disorders of Skin and Appendages Rash	2.1	1.5	0.6

Gastrointestinal Disorders	26.1	11.8	14.3
Nausea	26.1	11.8	14.3
Diarrhea/Loose Stools	17.7	9.3	8.4
Constipation	8.4	6.3	2.1
Dyspepsia	6.0	2.8	3.2
Vomiting	3.8	1.8	2.0
Flatulence	3.3	2.5	0.8
Anorexia	2.8	1.6	1.2
Abdominal Pain	2.4	2.2	0.2
Appetite Increased	1.3	0.9	0.4
General	10.6	8.1	2.5
Fatigue	10.6	8.1	2.5
Hot Flushes	2.2	0.5	1.7
Fever	1.6	0.6	1.0
Back Pain	1.5	0.9	0.6
Metabolic and Nutritional Disorders Thirst	1.4	0.9	0.5
Musculo-skeletal System Disorders Myalgia	1.7	1.5	0.2

TABLE 1
	Percent of Patients Reporting		Difference Percentage
ADVERSE EXPERIENCE	SERTRALINE (N=861)	PLACEBO (N=853)	Difference Percentage
Psychiatric Disorders Insomnia Sexual Dysfunction - Male (1) Somnolence Agitation Nervousness Anxiety Yawning Sexual Dysfunction - Female (2) Concentration Impaired
	16.4	8.8	7.6
	15.5	2.2	13.3
	13.4	5.9	7.5
	5.6	4.0	1.6
	3.4	1.9	1.5
	2.6	1.3	1.3
	1.9	0.2	1.7
	1.7	0.2	1.5
	1.3	0.5	0.8
Reproduction Menstrual Disorder (2)	1.0	0.5	0.5
Respiratory System Disorders	2.0	1.5	0.5
Rhinitis	2.0	1.5	0.5
Pharyngitis	1.2	0.9	0.3
Special Senses	4.2	2.1	2.1
Vision Abnormal	4.2	2.1	2.1
Tinnitus	1.4	1.1	0.3
Taste Perversion	1.2	0.7	0.5
Urinary System Disorders	2.0	1.2	0.8
Micturition Frequency	2.0	1.2	0.8
Micturition Disorder	1.4	0.5	0.9

* Events reported by at least 1% of patients treated with sertraline are included.

% based on male patients only: 271 sertraline and 271 placebo patients. Male sexual dysfunction can be broken down into the categories of decreased libido, impotence and ejaculatory delay. In this data set, the percentages of males in the sertraline group with these complaints are 4.8%, 4.8% and 8.9% respectively. It should be noted that since some sertraline patients reported more than one category of male sexual dysfunction, the incidence of each category of male sexual dysfunction combined is larger than the incidence for the general category of male sexual dysfunction, in which each patient is counted only once.
% based on female patients only: 590 sertraline and 582 placebo patients.

Other events observed during the pre-marketing evaluation of sertraline: During its pre-marketing assessment, multiple doses of sertraline were administered to 2710 subjects. The conditions and duration of exposure to sertraline varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for indications other than depression. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. All events are included except those already listed in the previous table or in the PRECAUTIONS section, and those reported in terms so general as to be uninformative. It is important to emphasize that although the events reported occurred during treatment with sertraline, they were not necessarily caused by it. Autonomic Nervous System Disorders: Infrequent:flushing, mydriasis, increased saliva, cold clammy skin; Rare:pallor. Cardiovascular: Infrequent:postural dizziness, hypertension, hypotension, postural hypotension, edema, dependent edema, periorbital edema, peripheral edema, peripheral ischemia, syncope, tachycardia; Rare:precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, varicose veins. Central and Peripheral Nervous System Disorders: Frequent:confusion; Infrequent:ataxia, abnormal coordination, abnormal gait, hyperesthesia, hyperkinesia, hypokinesia, migraine, nystagmus, vertigo; Rare:local anesthesia, coma, convulsions, dyskinesia, dysphonia, hyporeflexia, hypotonia, ptosis. Disorders of Skin and Appendages: Infrequent:acne, alopecia, pruritus, erythematous rash, maculopapular rash, dry skin; Rare:bullous eruption, dermatitis, erythema multiforme, abnormal hair texture, hypertrichosis, photosensitivity reaction, follicular rash, skin discoloration, abnormal skin odor, urticaria. Endocrine Disorders: Rare:exophthalmos, gynecomastia. Gastrointestinal Disorders: Infrequent:dysphagia, eructation; Rare:diverticulitis, fecal incontinence, gastritis, gastroenteritis, glossitis, gum hyperplasia, hemorrhoids, hiccup, melena, hemorrhagic peptic ulcer, proctitis, stomatitis, ulcerative stomatitis, tenesmus, tongue edema, tongue ulceration. General: Frequent:asthenia; Infrequent:malaise, generalized edema, rigors, weight decrease, weight increase; Rare:enlarged abdomen, halitosis, otitis media, aphthous stomatitis. Hematopoietic and Lymphatic: Infrequent:lymphadenopathy, purpura; Rare:anemia, anterior chamber eye hemorrhage. Metabolic and Nutritional Disorders: Rare:dehydration, hypercholesterolemia, hypoglycemia. Musculo-Skeletal System Disorders: Infrequent:arthralgia, arthrosis, dystonia, muscle cramps, muscle weakness; Rare:hernia. Psychiatric Disorders: Infrequent:abnormal dreams, aggressive reaction, amnesia, apathy, delusion, depersonalization, depression, aggravated depression, emotional lability, euphoria, hallucination, neurosis, paranoid reaction, suicide attempt (including suicidal ideation), teeth- grinding, abnormal thinking; Rare:hysteria, somnambulism, withdrawal syndrome. Reproductive: Infrequent:dysmenorrhea (2), intermenstrual bleeding (2); Rare:amenorrhea (2), balanoposthitis (1), breast enlargement (2), female breast pain (2), leukorrhea (2), menorrhagia (2), atrophic vaginitis (2).

- % based on male subjects only: 1005
- % based on female subjects only: 1705

Respiratory System Disorders: Infrequent:bronchospasm, coughing, dyspnea, epistaxis;

Rare:

bradypnea, hyperventilation, sinusitis, stridor.

Special Senses: Infrequent:abnormal accommodation, conjunctivitis, diplopia, earache, eye pain, xerophthalmia; Rare:abnormal lacrimation, photophobia, visual field defect. Urinary System Disorders: Infrequent:dysuria, face edema, nocturia, polyuria, urinary incontinence; Rare:oliguria, renal pain, urinary retention.

Laboratory Tests

: In man, asymptomatic elevations in serum hepatic transaminases (SGOT [or AST] and SGPT [or ALT]) to a value >= 3 times the upper limit of normal have been reported infrequently (approximately 0.6% and 1.1%, respectively) in association with sertraline administration. The proportion of patients having these elevations was greater in the sertraline group than in the placebo group. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

Sertraline therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%).

Uricosuric Effect

Sertraline is associated with a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance. There have been no reports of acute renal failure with sertraline.

Other Events Observed During the Postmarketing Evaluation of Sertraline

Adverse events not listed above which have been reported in temporal association with sertraline since market introduction include: increased coagulation times, bradycardia, AV block, atrial arrhythmias, hypothyroidism, leukopenia, thrombocytopenia, hyperglycemia, priapism, galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like events, psychosis, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events. The causal relationship between sertraline treatment and the emergence of these events has not been established. The clinical features of hepatic events (which in the majority of cases appeared to be reversible with discontinuation of sertraline) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death. There have been spontaneous reports of symptoms such as dizziness, paresthesia, nausea, headache, anxiety, fatigue, and agitation following the discontinuation of sertraline treatment.

SYMPTOMS AND TREATMENT OF OVERDOSE

On the evidence available, sertraline has a wide margin of safety in overdose. Overdoses of sertraline alone of up to 6 g have been reported. Symptoms of overdose with sertraline alone included somnolence, nausea, vomiting, tachycardia, ECG changes, anxiety and dilated pupils. Treatment was primarily supportive and included monitoring and use of activated charcoal, gastric lavage or cathartics and hydration. Although there were no reports of death when sertraline was taken alone, there were 4 deaths involving overdoses of sertraline in combination with other drugs and/or alcohol. Therefore, any overdosage should be treated aggressively.

Management of Overdoses

: Establish and maintain an airway, ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.

Cardiac and vital signs monitoring are recommended along with general symptomatic and supportive measures. There are no specific antidotes for SERTRALINE (sertraline hydrochloride). Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. In managing overdosage, the possibility of multiple drug involvement must be considered.

DOSAGE AND ADMINISTRATION

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

General:

SERTRALINE (sertraline hydrochloride) should be administered with food once daily preferably with the evening meal, or, if administration in the morning is desired, with breakfast.

Initial Treatment

: 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.

Titration

: 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, the dosage should be maintained at the lowest effective dose and patients should be periodically reassessed to determine the need for continued treatment.

Renal/Hepatic Impairment

As with many other medications, SERTRALINE should be used with caution in patients with renal and/or hepatic impairment (see PRECAUTIONS).

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 SERTRALINE. In addition, at least 14 days should be allowed after stopping SERTRALINE before starting an MAOI (see CONTRAINDICATIONS section).

Children:

(see: WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

PHARMACEUTICAL INFORMATION

Drug Substance

Proper/Common Name: sertraline hydrochloride Chemical Name: (IS,cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1- naphthalenamine hydrochloride Structural Formula: Molecular Formula: C17H17NCl2HCl Molecular Weight: 342.7 Description: 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. Melting point: 243-245degC.

Composition

In addition to sertraline hydrochloride, each capsule contains the non-medicinal ingredients croscarmellose sodium, stearic acid, colloidal silicon dioxide and corn starch. The capsule shells, imprinted with edible black ink, contain the non-medicinal ingredients gelatin, silicon dioxide, titanium dioxide, sodium lauryl sulfate, D&C yellow #10, FD&C yellow #6 (25 mg and 50 mg only) and FD&C red #40 (100 mg capsule).

Stability and Storage Recommendations

Store at room temperature (15deg to 30degC). Protect unit dose packages from high humidity.

AVAILABILITY OF DOSAGE FORMS

SERTRALINE-25 mg:

Each yellow, size #4 capsule, imprinted PRO 25, contains sertraline hydrochloride equivalent to 25 mg sertraline. Available in bottles of 100, unit dose packages of 30, 60 and 100.

SERTRALINE-50 mg:

Each yellow and white, size #4 capsule, imprinted PRO 50, contains sertraline hydrochloride equivalent to 50 mg sertraline. Available in bottles of 100, 250 and 500, unit dose packages of 30, 60 and 100.

SERTRALINE-100 mg:

Each orange, size #2 capsule, imprinted PRO 100, contains sertraline hydrochloride equivalent to 100 mg sertraline. Available in bottles of 100, 250 and 500, unit dose packages of 30 and 100.

INFORMATION FOR THE PATIENT

Please read this information before you start to take your medicine, even if you have taken this drug before. What you should know about SERTRALINE: SERTRALINE (sertraline hydrochloride) belongs to a family of medicines called SSRIs; Selective Serotonin Reuptake Inhibitors. SERTRALINE has been prescribed to you by your doctor to relieve your symptoms of depression. 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 you should tell your doctor before taking SERTRALINE:

All your medical conditions, including a history of seizures, liver or kidney disease; Any medications (prescription or nonprescription) which you are taking especially monoamine oxidase inhibitor antidepressants

(e.g. phenelzine sulfate, tranylcypromine sulfate or moclobemide) or any other antidepressants, drugs used to treat diabetes, drugs used to thin the blood (anticoagulants) or drugs containing tryptophan; If you are pregnant or thinking about becoming pregnant, or if you are breast feeding; Your habits concerning alcohol consumption.

How to take SERTRALINE:

It is very important for you to take SERTRALINE exactly as your doctor has instructed. The usual starting dose is 50 mg of SERTRALINE/day. Your doctor may decide to increase the dose to 200 mg/day.

Never increase the amount of SERTRALINE you are taking unless your doctor tells you to. 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. SERTRALINE should be taken with food; either in the morning or evening. You should swallow the capsule whole; do not chew it. Keep taking 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. If you miss taking a dose of 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 SERTRALINE.

When not to use SERTRALINE:

Do not use SERTRALINE if you are allergic to it or to any of the components of its formulation. Stop taking the drug and contact your doctor immediately if you experience an allergic reaction or any severe or unusual side effect.

Precautions when taking 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, consult your doctor immediately; do not discontinue your medication on your own.

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 SERTRALINE.

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 center immediately, even though you may not feel sick.

How to store SERTRALINE: Store at room temperature (15 to 30degC) in a dry place. Keep the container tightly closed. Keep out of the reach of children. If your doctor decides to stop 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 SERTRALINE contains:

SERTRALINE is available as 25 mg (yellow capsule), 50 mg (white and yellow capsule) and 100 mg (orange capsule). Sertraline is the active ingredient.

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.

PHARMACOLOGY

Sertraline is a highly selective and potent inhibitor of neuronal 5HT uptake, both in vitro and in

. 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 p.o. 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.

Data from pharmacokinetic studies in the mouse, rat and dog are contained in Table 2. 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 2). 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 2). 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 2).

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

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 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 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.

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

* t1/2, VD and Cl 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.

TOXICOLOGY

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
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
36 Day Diet Study in Mice
CD-1 Mice	Diet	0 10 40 80	10/sex	36 Days	Drug and desmethyl metabolite serum levels drug related: Serum Concentration (ng/mL) Drug Metabolite Dose Male Female Male Female (mg/kg/day) 10 22 17 40 23 40 52 16 181 <10 80 142 63 307 169 Some degree of alopecia occurred in three mid-dose animals and one high-dose animal. Fatty change occurred in the livers of 8/10 high-dose males compared to 3/10 control males. On the basis of these findings, daily doses of 10, 20 and 40 mg sertraline hydrochloride base/kg were proposed for the 2-year feeding study.
2 Year Diet Study in Mice
CD-1 Mice	Diet	0 0 10 20 40	50/sex	24 Months	Survival of drug treated females was slightly less than control. Bronchioalveolar adenomas occurred in 9/49, 1/50, and 12/50 low-, mid-, and high-dose females compared to 6/50 and 2/50 in females of the two control groups. Hepatocellular adenomas were observed in 8/50, 8/50 and 12/50 low-, mid-, and high-dose males compared to 3/50 and 4/50 males in the two control groups. These tumors were benign and the type usually occurring spontaneously in this strain of mouse. There were no treatment-related increases in tissue specific or total malignant tumors.
16 Day P.O. Study in Rats
Sprague Dawley Rats	Gavage	0 40 80 160	5/sex	16 Days	Anorexia and transient body weight gain inhibition; latter effect was high in high-dose females. Dose-related increase in liver weights due to microsomal enzyme induction; centrilobular degeneration at all dose levels and slightly elevated SGPT and SGOT at 160 mg/kg only.
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
6 Week Diet Study in Rats
Sprague Dawley Rats	Diet	0 10 40 80	10/sex	6 Weeks	Minimal effect on body weight gain of males and slight inhibition of body weight (<10%) in mid- and high-dose females. Liver weight increase in mid- and high-dose males and females; hepatocellular hypertrophy and minimal midzonal fatty change in high-dose males and females and mid-dose males accompanied by slight elevations in serum SDH, GOT and 5'NT in some animals. No adverse effect level: 10 mg/kg/day.
3 Month P.O. Study in Rats
Sprague Dawley Rats	Gavage	0 10 40 80	15M 10F	3 Months	Dose related plasma levels at 10 and 40 mg/kg. Plasma Levels ( u g/mL) of Drug 2 h Post-Dose on Days 1, 5 and 30 Dose (mg/kg/day) Sex Day 1 Day 5 Day 30 80 M Mean 0.63 0.31 0.46 +- SD 0.19 0.05 0.20 F Mean 0.75 0.37 0.84 +- SD 0.19 0.10 0.48 40 M Mean 0.70 0.20 0.32 +- SD 0.11 0.06 0.18 F Mean 0.42 0.33 0.92 +- SD 0.14 0.05 0.28 10 M Mean 0.25 0.10 0.10 +- SD 0.10 0.03 0.03 F Mean 0.19 0.14 0.27 +- SD 0.06 0.03 0.08 Dose related increases in absolute and relative liver weights due to induction of microsomal enzymes: increases associated with centrilobular hepatocellular hypertrophy; mild midzonal fatty changes observed in 10/15 males and 1/10 females at 80 mg/kg.
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
2 Year Diet Study in Rats
Long Evans Rats	Diet	0 10 20 40	65/sex	24 Months	Interim sacrifice (15/sex) at 6 months : Kidney/body weight was increased. Increase in mean absolute and relative liver weights in males and females at high dose and in females at mid-dose. 2 years sacrifice : Deaths were dose-related; inhibition of weight gain was dose-related in males and present at high dose only in females. Slight elevations of serum 5'nucleotidase (5'NT) activity in the high and mid-dose groups occurred throughout the study. Increase of liver and kidney/body weight ratios. These effects are considered to be related to drug-metabolizing enzyme induction. Hepatocytes with large clear fat-containing vacuoles were observed; number of affected animals in groups was dose related in females but distribution was more erratic in males. In no case was there evidence of necrosis or of an inflammatory response. There were no treatment related effects on the number of tumor bearing animals, total malignant tumors or total benign tumors in either sex. Hence, there was no evidence of oncogenic potential.
Rat (Special Toxicology Study) I.V.
Sprague	I.V.	0	10/sex	15 Days	Hemoglobinuria, identifiable only be reagent test strip as
Dawley	0.125	16 Days	early as 5 minutes after injection, the only treatment related
Rats	0.250	17 Days	clinical pathology finding, was not dose-related. It is
0.500	18 Days	analogous to the in vitro hemolytic effects of sertraline
hydrochloride in the concentrations utilized in this study, i.e.,
0.125, 0.25, and 0.5 mg/mL. No hemolysis was detected in
vitro when red cells were exposed to 0.005 mg/mL sertraline
hydrochloride. In vitro studies have also demonstrated
incompatibility (cloudiness) of plasma exposed to equal
volumes of 0.25 and 0.5 mg sertraline hydrochloride/mL.
These data suggest that intravenous sertraline hydrochloride
solutions should be administered by drip rather than by bolus
injections. A total of 3 high-dose and 12 control rats had
perivascular hemorrhage and/or chronic perivasculitis at the
injection site in the tail.
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
7 Day Oral Study in Dogs
Beagle	Oral (Capsule)	0 15 45	2 Males	7 Days	Slight anorexia, body weight loss and hind limb weakness at high dose. Plasma drug levels suggested good oral absorption. Plasma Concentrations of Drug 3 h Post Dose on Days 1 and 7 ==================================== Plasma Concentration ( u g/mL) Dose Dog No. Day 1 Day 7 (mg/kg/day) 45 832255 2.28 2.48 832259 2.04 0.82 15 832258 1.12 0.13 832260 0.42 0.68 Apparent losses of small lymphocytes from thymus was observed; lymphoid depletion in spleen, mesenteric lymph nodes and ileum were seen in one high dose dog.
14 Day Oral Study in Dogs
Beagle	Oral (Capsule)	0 40 80 160	1/sex	14 Days	Dose related anorexia and body weight loss. Increase of serum alkaline phosphatase at high dose and of SGPT in the high dose females. Depletion of small lymphocytes from spleen in the 80 mg male and from spleen and ileum in the high dose male.
3 Month Oral Study in Dogs
Beagle	Oral (Capsule)	0 10 40 80	3/sex	3 Months	Dose-related CNS stimulation during the first one or two weeks of treatment. One high-dose animal died of convulsions 5.5 hours after drug administration on the first day of treatment. Necropsy of this animal revealed generalized congestion and lymphoid depletion of the thymus, spleen and mesenteric lymph node consistent with the cause of death. Elevated alkaline phosphatase (ALP) values were measured in all dogs of the high-dose group and in 2 males and 2 females of the mid-dose group. The ALP elevation together with a trend toward increased liver weights reflect the ability of sertraline hydrochloride to induce drug metabolizing enzymes at 40 and 80 mg/kg. Slight SGPT elevations in the high-dose animals were not associated with histopathological changes.
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
6 Month Oral Study in Dogs
Beagle	Oral (Capsule)	0 10 30 90	4/sex	6 Months	Pronounced clinical signs of CNS stimulation were observed at high dose; they diminished in intensity or completely disappeared after 1 to 2 weeks of dosing. At the 90 mg/kg dose level increase in absolute and relative liver weights, proliferation of smooth endoplasmic reticulum and mild serum alkaline phosphatase elevations were all consistent with sertraline hydrochloride being an enzyme inducer. This was demonstrated by a shortening of the plasma half-life of antipyrine at the high-dose level only (30 min. compared to 54 min. ). A few dogs at 30 mg/kg had slight sporadic alkaline phosphatase elevations. Some dogs at the high-dose level only had SGPT elevations. The mild bile duct hyperplasia detected in two high-dose males could have been drug-related; however, this lesion sometimes is observed in control beagle dogs.
1 Year Oral Study in Dogs
Beagle	Oral (Capsule)	0 10 30 90	4/sex	1 Year	Dose-related incidences of central and autonomic nervous system clinical signs during the first few weeks of the study were observed. Slight to moderate elevations in serum alkaline phosphatase activity occurred in 1/8, 4/8 and 7/8 low-, mid- and high- dose dogs, respectively. SGPT levels were increased in 2/8 high-dose animals. Liver/body weight ratios were increased in high-dose males (25%) and females (32%) and in mid- dose females (25%). Sertraline hydrochloride was previously shown to be an inducer of hepatic microsomal drug metabolizing enzymes, a phenomenon often associated with elevated liver weights and serum alkaline phosphatase activity in dogs. There were no gross or microscopic histologic changes in the liver or in other tissues. Plasma levels of sertraline hydrochloride and its desmethyl metabolite, CP-62,508, confirmed dose-related systemic exposure throughout the study: C m ax OF DRUG AND 0-24 HOUR AUC OF METABOLITE C max AUC CP-51,974 CP-62,508 (mcg/mL) (mg.hr/L) (mg/kg) Day 1 Day 99 Day 274 Day 1 Day 99 Day 274 10 Mean 0.344 0.218 0.262 3.4 2.6 3.0 S.D. 0.165 0.142 0.190 1.7 0.8 1.0 30 Mean 0.723 0.643 1.26 4.9 8.8 11.6 S.D. 0.454 0.299 0.90 2.3 4.4 5.0 90 Mean 1.33 1.06 2.16 11.8 12.2 39.9 S.D. 0.81 0.61 1.24 6.2 5.0 25.1

Fertility and Reproductive Performance
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
A Study of the Reproduction and Fertility of Rats. Segment I (Extended to Produce F 2 Litters)
Rat	Oral (Gavage)	0 10 40 80	F 0 =30F/ dose F 0 =15M/ dose		F 0 males were treated in the 64 days prior to mating and throughout mating. F 0 females were treated in the 14 days prior to mating and during mating and gestation. Offspring (F 1 generation) were raised for 3 months free of
drug treatment and then mated to produce an F 2 generation
which, together with F 1 dams were sacrificed 21 - 24 days
post-partum. The F 0 treated dams showed decreased
pregnancy rates, most marked at 80 mg/kg. The pregnancy
rates were 47%, 83%, 92% and 100% respectively in the
high, mid, low dose and control groups. Survival of F 1 pups
to Day 4 post-partum was also depressed in a dose-related
order. High-dose F 1 pups showed evidence of earlier
behavioral development.
Fetotoxicity and Fertility Study (FDA Protocol, Segment I) in Rats by Oral Administration
Rat	Oral	0	20M		Males were treated for 71 days before mating. Females
(Gavage)	10	40F	were treated for 2 weeks before mating, during mating and
20	throughout gestation. Four additional groups of 20 undosed
80	females were mated with the same males to test their
fertility. Drug treatment produced inhibition (approximately
20 g) during pregnancy in all treated females and reduced
birth weights of pups at Day 1 post-partum (males: <= 0.15 g,
females <= 0.3 g). At Days 4 and 21 of age, the weights of
the pups treated also led to a lower neonatal survival rate at
the two highest doses (survival was 61% and 69%
respectively at high- and mid-dose groups compared with a
survival of 94% in the low-dose group and 98% in controls
at 21 days). Some of this mortality was attributed to a
higher incidence of hemoperitoneum in 18 high dose and 12
mid-dose than in 6 low dose and 1 control F 1 neonates.
Hemoperitoneum was not seen in newborn pups in any of
the other studies. In behavioral tests, some early
hyperactivity observed in pups of the treated groups was
consistent with the pharmacology of the drug. No adverse
effects were observed in the F 2 generation.

Teratology
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
Fetotoxicity Study (Segment II) in Rat by the Oral Route
Rat	Oral (Gavage)	0 10 20 80	20F		Drug was administered to inseminated females at Days 6 - 15 post-insemination. Treatment caused transient aggressiveness at the beginning of the treatment period and reduced body weight gain (an average of 26 g) of the high- dose dams. A slight delay in ossification of fetuses appears to be related to lower fetal weights in the mid- and high- dose groups which were probably functions of maternal toxicity (Ex: delay in ossification of metacarpus in 20 pups among 1181 at 80 mg/kg and in 13 pups among 1825 in the control group.
Fetotoxicity Study (FDA Segment II) in Rabbits by the Oral Route
Rabbit	Oral (Gavage)	0 5 20 40	20F		Sertraline hydrochloride was administered to pregnant rabbits during organogenesis (Days 7 to 18 post insemination). At the highest dose level of 40 mg/kg, the compound induced severe maternal toxicity which in turn delayed the ossification processes of the fetuses (Ex: delay in ossification in hyoid bone: control = 20%, 40 mg/kg = 36%; in Talus bone: control = 27%, 40 mg/kg = 44%.

Peri- Post-Natal Studies
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
Peri- Post-Natal Study in Rats (Segment III) by the Oral Route
Rat	Oral	0 10 20 80	20F		Sertraline hydrochloride was administered by gavage to inseminated rats from Day 15 post-insemination until parturition and throughout the whole lactation period. The treatment produced some adverse effects in dams and pups at the two higher dose levels; a dose-related delay in body weight gain of the dams during gestation and lactation in mid- and high-dose groups was observed. In some animals in each of these groups, hyperactivity was observed during the first few days of treatment. Food and water consumption was also affected in these two dose groups. Statistically significant decreases in mean litter size were observed at the high dose level on Day 1 post-partum, at the mid- and high-dose levels on Day 4 post-partum; this effect was dose related on Day 21 post-partum. The mean body weights of pups were lower in both sexes at both of the higher dose level groups when compared to controls on Days 1 post-partum but there were no statistically significant differences between the groups on Day 21 post- partum. No external or visceral anomalies were observed in the pups that died during the lactation phase or were sacrificed at weaning. The post-natal development of pups was also affected by the treatment of dams: fewer pups showed positive responses on the last day when reflexes were tested and the appearance of the incisors was retarded. This was most evident at the high-dose, but also to some extent at the mid-dose. Post-weaning examination revealed no treatment related changes.
Experiment (Segment III) to Further Investigate the Effect of Sertraline on Neonates
Rat	Oral (Gavage)	80			A second Segment III Study was carried out to further investigate the effects of sertraline hydrochloride on the neonates. In this study, pups from dams treated at 80 mg base/kg were fostered by untreated dams and vice versa, pups from untreated dams were fostered by drug treated dams. As observed in previous studies, sertraline hydrochloride affected the weight gain of the dams (body weight difference between control and high dose group: at 20 days of pregnancy = 34 g, at 21 days post-partum = 19 g). The effects observed on the progeny can be separated into two categories: Those directly related to the in utero exposure of fetuses: perinatal mortality and pup weight impairment on Day 1; those related to the exposure during lactation: post-natal growth impairment and delay in development. Vision and hearing, evaluated after weaning, were not affected.
SPECIES	ROUTE	DOSE mg/kg/day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
Experiment to Delineate the Prenatal Period of Fetal Vulnerability
Rat	Oral	0	20		Sertraline hydrochloride administered to pregnant rats
(Gavage)	80	20 X 4	throughout or during late gestation, has been shown to exert
deleterious effects on neonatal growth and survival to Day 4
post-partum. Another experiment was done in which
sertraline hydrochloride (80 mg base/kg/day) was
administered in 0.1% methylcellulose by oral gavage to 4
groups of pregnant dams (20/group) from Day 0 to Days 5,
10, or 15 and throughout gestation, respectively, in order to
delineate the prenatal period of fetal vulnerability. Pup
survival was unaffected by sertraline hydrochloride treatment
during the first 5, 10 or 15 days of gestation. Mortality of
live-born pups in these groups during the first 4 days of life
ranged from 0.8% to 3% compared with 2% for the controls
whereas 56% of pups born alive to dams treated throughout
the gestational period did not survive their first 4 days of life.
However, survival of pups from Day 4 to Day 21 (lactation
index) was comparable in all treatment and control groups.
Pups born to mothers dosed throughout gestation also
weighed less than control on Days 1 and 4 post partum, but
body weights of pups were comparable to control by Day 14.
This experiment demonstrates that the immediate prenatal
period, gestation Days 16 - 21, is the period of vulnerability of
the neonatal pup for survival from the in utero effects of a
high dose (80 mg/kg) of sertraline hydrochloride.

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.

648	635	102.1
682 (33)	663 (31)

AUC l	732	717	102.1
(ng.hr/mL)	774 (35)	754 (33)

T ma x (hr)	7.52 (29)	6.52 (22)	-
t 1/ 2 (hr)	21.0 (17)	20.6 (16)	-

Mouse	29 (SC and PO)	2.5	--	--	70	0.31	1.6	7.4	0.41	5.3
Rat	5 (IV and PO)	4.5	23	59	36	0.062	0.51	14	0.051	0.71
Rat	25 (IP and PO)	6.5	--	--	--	0.31	4.5	10.5 a	0.11	1.8
Dog	5 (IV) and 10 (PO)	5.2	25	49	22	0.15	1.4	7.1 a	0.16	4.6
Dog b	10 (PO)	--	--	--	--	0.32	2.3	--	0.21	3.0
Dog b	30 (PO)	--	--	--	--	0.93	8.6	--	0.49	7.8
Dog b	90 (PO)	--	--	--	--	3.1	33.6	--	1.8	29.5
Man c	3 (PO)	26	--	--	--	0.19	2.8	65	0.14	2.3

Species	Sex	LD 50 (mg Sertraline base/kg)		Max Mortality (hr)
		Oral	IP	Oral	IP
Mice	M	548 (495-612)	73 (66-79)	2 1/4	1
	F	419 (371-465)		1 3/4
Rats	M	1591 (1348-1847)	79 (70-90)	24	24
	F	1327 (1071-1562)		4.5

PRODUCT MONOGRAPH

THERAPEUTIC CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY

CONTRAINDICATIONS

WARNINGS

PRECAUTIONS

ADVERSE REACTIONS

PHARMACOLOGY

TOXICOLOGY

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

ANIMAL PER DOSE LEVEL

FINDINGS

REFERENCES