ADVERSE REACTIONS

Depression: In clinical development programs, ZOLOFT (sertraline hydrochloride) has been evaluated in 1902 subjects with depression. The most commonly observed adverse events associated with the use of ZOLOFT were: gastrointestinal complaints, including nausea, diarrhea/loose stools 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 ZOLOFT in premarketing 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 ZOLOFT patients who participated in controlled trials comparing titrated ZOLOFT with placebo.

TABLE 1

TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN

PLACEBO-CONTROLLED CLINICAL TRIALS IN ADULTS *

	Percent of Patients Reporting
ADVERSE EXPERIENCE	ZOLOFT (N=861)	PLACEBO (N=853)
Autonomic Nervous System Disorders	16.3	9.3
Mouth Dry
Sweating Increased	8.4	2.9
Cardiovascular	3.5	1.6
Palpitations
Chest Pain	1.0	1.6
Centr. & Periph. Nerv. System Disorders	20.3	19.0
Headache
Dizziness	11.7	6.7
Tremor	10.7	2.7
Paresthesia	2.0	1.8
Hypoesthesia	1.7	0.6
Twitching	1.4	0.1
Hypertonia	1.3	0.4
Disorders of Skin and Appendages Rash	2.1	1.5
Gastro-Intestinal Disorders	26.1	11.8
Nausea
Diarrhea/Loose Stools	17.7	9.3
Constipation	8.4	6.3
Dyspepsia	6.0	2.8
Vomiting	3.8	1.8
Flatulence	3.3	2.5
Anorexia	2.8	1.6
Abdominal Pain	2.4	2.2
Appetite Increased	1.3	0.9
General	10.6	8.1
Fatigue
Hot Flushes	2.2	0.5
Fever	1.6	0.6
Back Pain	1.5	0.9
	Percent of Patients Reporting
ADVERSE EXPERIENCE	ZOLOFT (N=861)	PLACEBO (N=853)
Metabolic and Nutritional Disorders Thirst	1.4	0.9
Musculo-Skeletal System Disorders Myalgia	1.7	1.5
Psychiatric Disorders	16.4	8.8
Insomnia
Sexual Dysfunction - Male (1)	15.5	2.2
Somnolence	13.4	5.9
Agitation	5.6	4.0
Nervousness	3.4	1.9
Anxiety	2.6	1.3
Yawning	1.9	0.2
Sexual Dysfunction - Female (2)	1.7	0.2
Concentration Impaired	1.3	0.5
Reproduction Menstrual Disorder (2)	1	0.5
Respiratory System Disorders	2.0	1.5
Rhinitis
Pharyngitis	1.2	0.9
Special Senses	4.2	2.1
Vision Abnormal
Tinnitus	1.4	1.1
Taste Perversion	1.2	0.7
Urinary System Disorders	2.0	1.2
Micturition Frequency
Micturition Disorder	1.4	0.5

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

%based on male patients only: 271 ZOLOFT 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 ZOLOFT group with these complaints are 4.8%, 4.8% and 8.9%, respectively. It should be noted that since some ZOLOFT 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 patient only: 590 ZOLOFT and 582 placebo patients.

Panic Disorder: In placebo-controlled clinical trials, 430 patients with panic disorder were treated with ZOLOFT in doses of 25 - 200 mg/day. During treatment, most patients received doses of 50 - 200 mg/day. Adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: diarrhea, ejaculation failure (primarily ejaculatory delay), anorexia, constipation, libido decreased, agitation, and tremor. In the total safety data base for panic disorder, 14% of patients discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.6%), insomnia (2.3%), somnolence (2.3%), and agitation (2.1%).

Obsessive-Compulsive Disorder: In placebo-controlled clinical trials for OCD, adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: nausea, insomnia, diarrhea, decreased libido, anorexia, dyspepsia, ejaculation failure (primarily ejaculatory delay), tremor, and increased sweating. In placebo-controlled clinical trials for OCD, 10% of patients treated with ZOLOFT discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.8%), insomnia (2.6%), and diarrhea (2.1%).

Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at a frequency of 2% or more among patients on ZOLOFT who participated in controlled trials comparing ZOLOFT with placebo in the treatment of panic disorder and obsessive-compulsive disorder. Only those adverse events which occurred at higher rate during ZOLOFT treatment than during placebo treatment are included.

TABLE 2

TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS FOR PANIC AND OBSESSIVE-COMPULSIVE DISORDER IN ADULTS *

	(Percent of Patients Reporting)
ADVERSE EXPERIENCE	PANIC DISORDER		OBSESSIVE COMPULSIVE DISORDER
	ZOLOFT (N=430)	Placebo (N=275)	ZOLOFT (N=533)	Placebo (N=373)
Autonomic Nervous System Disorders	15	10	146	91
Mouth Dry
Sweating Increased	5	1
Cardiovascular	-	-	33	22
Palpitations
Chest Pain	-	-
Centr. & Periph. Nerv. System Disorders Tremor Paresthesia Headache Dizziness Hypertonia	5 4 - - -	1 3 - - -	8330172	112491
Disorders of Skin and Appendages Rash	4	3	2	1
Gastrointestinal Disorders	29	18	30241061134	1110442111
Nausea
Diarrhea	20	9	3
Dyspepsia	10	8
Constipation	7	3
Anorexia	7	2
Vomiting	6	3
Flatulence	-	-
Appetite Increased	-	-
General Fatigue Hot Flushes Pain Back Pain	11 3 - -	6 1 - -	14232	10111
Metabolic and Nutritional Disorders Weight Increase	-	-	3	0
Musculoskeletal System Disorders Arthralgia	2	1	-	-
	(Percent of Patients Reporting)
ADVERSE EXPERIENCE	PANIC DISORDER		OBSESSIVE COMPULSIVE DISORDER
	ZOLOFT (N=430)	Placebo (N=275)	ZOLOFT (N=533)	Placebo (N=373)
Psychiatric Disorders	25	18	28	12
Insomnia
Somnolence	15	9	15	8
Nervousness	9	5	7	6
Libido Decreased	7	1	11	2
Agitation	6	2	6	3
Anxiety	4	3	8	6
Concentration Impaired	3	0	-	-
Depersonalization	2	1	3	1
Paroniria	-	-	2	1
Respiratory System Disorders Pharyngitis	-	-	4	2
Special Senses Tinnitus Vision Abnormal Taste Perversion	4 - -	3 - -	-43	-21
Urogenital	19	1	175	21
Ejaculation Failure (1)
Impotence (2)	2	1

* Events reported by at least 2% of patients treated with ZOLOFT are included, except for the following events which

had an incidence on placebo greater than or equal to ZOLOFT [Panic Disorder]: headache, dizziness, malaise, abdominal pain, respiratory disorder, pharyngitis, flatulence, vision abnormal, pain, upper respiratory tract infection, and paroniria. [OCD]: abdominal pain, respiratory disorder, depression, and amnesia.

1. - Primarily ejaculatory delay; % based on male patients only: Panic Disorder: 216 ZOLOFT and 134 placebo patients, OCD: 296 ZOLOFT and 219 placebo patients.

2. % based on male patients only: Panic Disorder: 216 ZOLOFT and 134 placebo patients, OCD: 296 ZOLOFT and 219 placebo patients.

Suicidality-related adverse events from clinical trials in major depressive disorder in the pediatric population In the safety analysis from controlled clinical trials in children and adolescents with major depressive disorder aged 6 to 17 years, both the number and percentage of patients for whom suicide attempts were reported was the same for the sertraline arm (2/189, 1.1%) as for the placebo arm (2/184, 1.1%), while the corresponding event rates of suicide attempts were 1.1% (2 attempts in 2/189 patients) in sertraline-treated patients versus 1.6% in placebo-treated patients (3 attempts in 2/184 patients). For the additional category of "other events possibly related to self-harm", which includes suicidal ideation and self-injurious behaviors such as cutting, event rates were 2.1% (4 events in 189 patients) in sertraline-treated patients and 0% in placebo-treated patients. Overall, the total reported event rates for both suicide attempts and other events possibly related to self-harm are as follows: 3.2% or 6 /189 for sertraline versus 1.6% or 3/184 for placebo. (See WARNINGS, POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.)

Other events observed during the premarketing evaluation of ZOLOFT (sertraline hydrochloride): During its premarketing assessment, multiple doses of ZOLOFT were administered to 2710 subjects. The conditions and duration of exposure to ZOLOFT 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

ZOLOFT

, they were not necessarily caused by it.

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.

Gastro-Intestinal Disorders

- Infrequent:dysphagia, eructation; Rare:diverticulitis, fecal incontinence, gastritis, gastroenteritis, glossitis, gum hyperplasia, hemorrhoids, hiccup, gastrointestinal bleeding, melena, hemorrhagic peptic ulcer, proctitis, stomatitis, ulcerative stomatitis, tenesmus, tongue edema, tongue ulceration.

General

- Frequent:allergic reaction, allergy, 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 reactions.

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 ZOLOFT administration. The proportion of patients having these elevations was greater in the ZOLOFT 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.

ZOLOFT

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

Uricosuric Effect:

ZOLOFT

is associated with a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.

Other Events Observed During the Postmarketing Evaluation of ZOLOFT: Adverse events not listed above which have been reported in temporal association with ZOLOFT since market introduction include: muscle contractions involuntary, acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias), hypothyroidism, syndrome of inappropriate ADH secretion, agranulocytosis, aplastic anemia, pancytopenia, hematuria, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, priapism, galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome - like events, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome, epidermal necrolysis, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events. The causal relationship between ZOLOFT 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 ZOLOFT) 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 ZOLOFT treatment.

Adverse Reactions following Discontinuation of Treatment (or Dose Reduction): There have been reports of adverse reactions upon the discontinuation of ZOLOFT (particularly when abrupt), including but not limited to the following: 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION sections). Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self- limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

SYMPTOMS AND TREATMENT OF OVERDOSE

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

SYMPTOMS

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

TREATMENT

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

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

GENERAL:

ZOLOFT

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

INITIAL TREATMENT:

Depression and Obsessive-Compulsive Disorder:

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

ZOLOFT

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

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

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

HEPATIC IMPAIRMENT: As with many other medications, ZOLOFT should be used with caution in patients with hepatic impairment (See PRECAUTIONS section).

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

TREATMENT OF PREGNANT WOMEN DURING THE THIRD TRIMESTER:

Post-marketing reports indicate that some neonates exposed to ZOLOFT, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS section). When treating a pregnant woman with ZOLOFT during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering ZOLOFT in the third trimester.

SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR:

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with ZOLOFT. In addition, at least 14 days should be allowed after stopping ZOLOFT before starting an MAOI (see CONTRAINDICATIONS section).

DISCONTINUATION OF ZOLOFT TREATMENT: Symptoms associated with the discontinuation or dosage reduction of ZOLOFT have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (See PRECAUTIONS and ADVERSE REACTIONS sections). A gradual reduction in the dose over several weeks rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See PRECAUTIONS and ADVERSE REACTIONS sections).

PHARMACEUTICAL INFORMATION

Drug Substance

Tradename: ZOLOFT

Generic Name

: sertraline hydrochloride

Code Name

: CP-51,974-01

Chemical Name: (lS,cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1- naphthalenamine hydrochloride

Structural Formula: Molecular Formula: C17H17NCl2HCl Molecular Weight: 342.7 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.

Composition

: Capsules are formulated to contain sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline.

The following excipients are used in the manufacture of ZOLOFT capsules: Lactose, anhydrous Corn Starch Magnesium Stearate Sodium Lauryl Sulfate Hard Gelatin Capsule Shells

Stability and Storage Recommendations:

ZOLOFT

capsules are packaged in opaque high density polyethylene bottles and PVC blisters and are stored at controlled room temperature between 50deg and 86degF (15deg to 30degC).

INFORMATION TO THE CONSUMER

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 ZOLOFT

:

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

ZOLOFT Treatment with these types of medications is most safe and effective when you and your doctor have good communication about how you are feeling.

has been prescribed to you by your doctor to relieve your symptoms of depression, panic disorder or obsessive-compulsive disorder.

What you should tell your doctor before taking ZOLOFT:

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, pimozide (an antipsychotic drug), 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; Any natural or herbal products you are taking (e.g. St. John's Wort).

How to take ZOLOFT:

It is very important for you to take ZOLOFT exactly as your doctor has instructed.The usual starting dose is 50 mg of ZOLOFT/day for depression and obsessive-compulsive disorder. If you are taking ZOLOFT for panic disorder, your doctor may start you at 25 mg/day. Your doctor may decide to increase the dose up to 200 mg/day. Never increase or decrease the amount of ZOLOFT you, or those in your care if you are a caregiver or guardian, are taking unless your doctor tells you to and do not stop taking this medication without consulting your doctor (see under Precautions when taking ZOLOFT). 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.

ZOLOFT

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

Keep taking ZOLOFT 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 ZOLOFT, 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 ZOLOFT. You should avoid taking St. John's Wort if you are taking ZOLOFT.

When not to use ZOLOFT:

Do not use ZOLOFT if you are allergic to it or to any of the components of its formulation (see list of components at the end of this section). 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 ZOLOFT:

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.

ZOLOFT

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 ZOLOFT. Contact your physician before stopping or reducing your dosage of ZOLOFT. 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 ZOLOFT. 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 ZOLOFT 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 ZOLOFT, 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 center immediately, even though you may not feel sick.

How to store ZOLOFT:

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

ZOLOFT

is available as 25 mg (yellow capsule), 50 mg (white and yellow capsule) and 100 mg (orange capsule). Sertraline 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. Capsules 25 and 50 mg also contain dye FD & C Yellow #6 and capsules 100 mg also contain dye FD& C Red #40. The capsules do not contain tartrazine or gluten.

Who manufactures ZOLOFT:

ZOLOFT

capsules are manufactured by: Pfizer Canada 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

The capsules are available as follows:

Strengths (Capsules)	Sizes	Colors (Body/Cap)
25 mg	#4	yellow/yellow
50 mg	#4	white/yellow
100 mg	#2	orange/orange

Capsule shells contain gelatin, titanium dioxide and dye D & C Yellow #10. Capsules 25 and 50 mg also contain dye FD & C Yellow #6, and capsules 100 mg also contain FD & C Red #40. They are Tartrazine free. The drug is supplied in white high density polyethylene bottles of 100 capsules. Also, the 50 and 100 mg strengths are available in bottles of 250 capsules each.

Animal Pharmacology:

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.

TABLE 3

SUMMARY OF PHARMACOKINETICS FOR SERTRALINE AND THE PRIMARY AMINE METABOLITE IN THE

MOUSE, RAT, DOG AND MAN

Sertraline * Primary Amine *
	Sertraline Dose
	(mg/kg) and	t 1/2	V D	Cl	% Oral	Cmax	AUC	t 1/2	Cmax	AUC
Species	Route of	(hr)	(l/kg)	(mL/min/kg)	Bioavail	( : g/mL)	(mg	(hr)	( : g/mL)	(mg

Administration hr/l) hr/l)

Rat	5 (IV and PO)
Rat Dog	25 (IP and PO) 5 (IV) and 10

Mouse 29 (SC and PO) 2.5 -- -- 70 0.31 1.6 7.4 0.41 5.3

4.5 23 59 36 0.062

14 0.051 0.71
	(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

a

6.5 -- -- -- 0.31 4.5 10.5 0.11 1.8

*

T1/2, VD

and C1 in mouse, rat and dog were based on data from parenteral route of sertraline hydrochloride

administration, while Cmax and AUC were based on data following oral administration.

1. Based on parenteral administration of primary amine metabolite.

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

1/2

Sertraline t

based on data at doses of 50 to 400 mg/day. Cmax and AUC for drug and metabolite were steady-state

values (day 14) of 200 mg dose subjects.

Acute Toxicity:

mice and rats

TOXICOLOGY

ACUTE ORAL AND INTRAPERITONEAL TOXICITY STUDIES IN MICE AND RATS

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

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 (mg/kg/day) 10 40 80	Male 22 52 142	Female 17 16 63	Male 40 181 307	Female 23 <10 169
					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.
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.

SPECIES	ROUTE	DOSE mg/kg/ day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
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 ( : 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 F	Mean + SD Mean + SD	0.63 0.19 0.75 0.19	0.31 0.05 0.37 0.10	0.46 0.20 0.84 0.48
					40	M F	Mean + SD Mean + SD	0.70 0.11 0.42 0.14	0.20 0.06 0.33 0.05	0.32 0.18 0.92 0.28
					10	M F	Mean + SD Mean + SD	0.25 0.10 0.19 0.06	0.10 0.03 0.14 0.03	0.10 0.03 0.27 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.
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.

SPECIES	ROUTE	DOSE mg/kg/ day	ANIMAL PER DOSE LEVEL	DURATION	FINDINGS
Rat (Special Toxicology Study) I.V.
Sprague Dawley Rats	I.V.	0 0.125 0.250 0.500	10/sex	days days days days	Hemoglobinuria, identifiable only by reagent test strip as early as 5 minutes after injection, the only treatment related clinical pathology finding, was not dose-related. It is 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.
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 ( : g/mL)
					Dose (mg/kg/day)	Dog No.	Day 1	Day 7
					45	832255 832259	2.28 2.04	2.48 0.82
					15	832258 832260	1.12 0.42	0.13 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:
					CMAX OF DRUG AND 0-24 HOUR AUC OF METABOLITE
					(mg/kg)		Cmax CP-51,974 ( : g/mL)			AUC CP-62,508 (mg.hr/l)
							DAY 1	DAY 99	DAY 274	DA Y 1	DAY 99	DA Y 274
					10	MEAN S.D.	0.344 0.165	0.218 0.142	0.262 0.190	3.4 1.7	2.6 0.8	3.0 1.0
					30	MEAN S.D.	0.723 0.454	0.643 0.299	1.26 0.90	4.9 2.3	8.8 4.4	11.6 5.0
					90	MEAN S.D.	1.33 0.81	1.06 0.61	2.16 1.24	11.8 6.2	12.2 5.0	39.9 25.1

Reproduction and Teratology

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	0	F 0 =30F/dose		F 0 males were treated in the 64 days prior to mating and
	(gavage)	10	F 0 =15M/dose		throughout mating. F 0 females were treated in the 14
		40			days prior to mating and during mating and gestation.
		80			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.
Foetotoxicity and Fertility Study (FDA Protocol, Segment I) in Rats by Oral Administration
Rat	Oral	10	20M		Males were treated for 71 days before mating. Females
	(gavage)	20	40F		were treated for 2 weeks before mating, during mating
		80			and throughout gestation. Four additional groups of 20
					undosed 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
Feototoxicity Study (Segment II) in Rat by the Oral Route
Rat	Oral (gavage)	10 20 80	20F		Drug 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).
Feototoxicity Study (FDA Segment II) in Rabbits by the Oral Route
Rabbit	Oral (gavage)	0 5 20 40	20F		Sertraline hydrochloride 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	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 day 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 (gavage)	80	20 20 x 4		Sertraline hydrochloride administered to pregnant rats 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: 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.

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