Sertraline (Sanis Health, PM 00070514) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

1 INDICATIONS ................................................................................................................... 4

1.1 Pediatrics ....................................................................................................................... 5 1.2 Geriatrics ....................................................................................................................... 5

2 CONTRAINDICATIONS ...................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 6

4 DOSAGE AND ADMINISTRATION ...................................................................................... 6

4.1 Dosing Considerations .................................................................................................. 6 4.2 Recommended Dose and Dosage Adjustment ............................................................. 6 4.4 Administration .............................................................................................................. 7

5 OVERDOSAGE .................................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....................................... 9

7 WARNINGS AND PRECAUTIONS ..................................................................................... 10

7.1 Special Populations ..................................................................................................... 17 7.1.1 Pregnant Women ........................................................................................................ 17 7.1.2 Breast-feeding ............................................................................................................. 18 7.1.4 Geriatrics ..................................................................................................................... 18

8 ADVERSE REACTIONS ..................................................................................................... 19

8.2 Clinical Trial Adverse Reactions .................................................................................. 19 8.2.1 Clinical Trial Adverse Reactions – Pediatrics ............................................................... 26 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data ........................................................................................................ 26 8.5 Post-Market Adverse Reactions .................................................................................. 26

9 DRUG INTERACTIONS ..................................................................................................... 28

9.1 Serious Drug Interactions............................................................................................ 28 9.3 Drug-Behavioural Interactions .................................................................................... 28 9.4 Drug-Drug Interactions ............................................................................................... 28 9.5 Drug-Food Interactions ............................................................................................... 38 9.6 Drug-Herb Interactions ............................................................................................... 38 9.7 Drug-Laboratory Test Interactions .............................................................................. 38

10 CLINICAL PHARMACOLOGY ............................................................................................ 38

10.1 Mechanism of Action .................................................................................................. 38

10.3 Pharmacokinetics ........................................................................................................ 39

11 STORAGE, STABILITY AND DISPOSAL .............................................................................. 40

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 40

PART II: SCIENTIFIC INFORMATION ...................................................................................... 41

13 PHARMACEUTICAL INFORMATION ................................................................................. 41

14 CLINICAL TRIALS ............................................................................................................. 42

14.1 Clinical Trials by Indication.......................................................................................... 42 14.3 Comparative Bioavailability Study .............................................................................. 43

15 MICROBIOLOGY ............................................................................................................. 43

16 NON-CLINICAL TOXICOLOGY........................................................................................... 44

17 SUPPORTING PRODUCT MONOGRAPHS ......................................................................... 54

PATIENT MEDICATION INFORMATION ................................................................................. 55

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

SERTRALINE (sertraline hydrochloride capsules) is indicated for:

Adults

• Depression

  SERTRALINE (sertraline hydrochloride) is indicated for the symptomatic relief of depressive illness. However, the antidepressant action of sertraline hydrochloride 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 hydrochloride has indicated that sertraline hydrochloride 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.

• Panic Disorder

  SERTRALINE is indicated for the symptomatic relief of panic disorder, with or without agoraphobia. The efficacy of sertraline hydrochloride was established in 10-week and 12-week controlled trials of patients with panic disorder as defined according to DSM-III-R criteria.

  The effectiveness of sertraline hydrochloride in long-term use for the symptomatic relief of panic disorder (i.e., for more than 12 weeks) has not been systematically evaluated in placebo-controlled trials. Therefore, the health professional who elects to use SERTRALINE for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

• Obsessive-Compulsive Disorder

  SERTRALINE is indicated for the symptomatic relief of obsessive-compulsive disorder (OCD). The obsessions or compulsions must be experienced as intrusive, markedly distressing, time-consuming, or significantly interfering with the person’s social or occupational functioning.

  The effectiveness of sertraline hydrochloride in long-term use for the symptomatic relief of OCD (i.e., for more than 12 weeks) has not been systematically evaluated in placebo-controlled trials. Therefore, the health professional who elects to use SERTRALINE for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

1.1 Pediatrics

Pediatrics (< 18 years of age): SERTRALINE is not indicated for use in children under 18 years of age (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; 8.2.1 Clinical Trial Adverse Reactions – Pediatrics).

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness (see 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

• SERTRALINE is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

• Monoamine Oxidase Inhibitors

  Cases of serious, sometimes fatal, reactions have been reported in patients receiving sertraline hydrochloride in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI, selegiline and the reversible MAOI (reversible inhibitor of monoamine oxidase - RIMA), moclobemide and linezolid, an antibiotic which is a reversible non-selective MAOI and methylthioninium chloride (methylene blue), which is a MAOI. 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.

• Pimozide

  The concomitant use of SERTRALINE and pimozide is contraindicated as sertraline hydrochloride has been shown to increase plasma pimozide levels. Elevation of pimozide blood concentration may result in QT interval prolongation and severe arrhythmias including Torsade de Pointes (see 7 WARNINGS AND PRECAUTIONS).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

Increased risk of self-harm, harm to others, suicidal thinking and behavior with antidepressants use. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of agitation-type and/or suicidal thoughts and behaviors (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

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 2 CONTRAINDICATIONS).

4.2 Recommended Dose and Dosage Adjustment

Depression and Obsessive-Compulsive Disorder

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

Panic Disorder

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

Titration

In depression, OCD and panic disorder, a gradual increase in dosage may be considered if no clinical improvement is observed. Based on pharmacokinetic parameters, steady-state sertraline plasma levels are achieved after approximately 1 week of once daily dosing; accordingly, dose changes, if necessary, should be made at intervals of at least one week. Doses should not exceed a maximum of 200 mg/day.

The full therapeutic response may be delayed until 4 weeks of treatment or longer. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.

Maintenance

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

Special Populations

• Hepatic Impairment: As with many other medications, SERTRALINE should be used with caution in patients with hepatic impairment (see 7 WARNINGS AND PRECAUTIONS). The effects of sertraline hydrochloride in patients with moderate and severe hepatic impairment have not been studied.

• Pediatrics (< 18 years): Health Canada has not authorized an indication for pediatric use.

  (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

• Treatment of Pregnant Women During the Third Trimester: Post-marketing reports indicate that some neonates exposed to sertraline hydrochloride, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see 7.1.1 Pregnant Women). When treating a pregnant woman with sertraline hydrochloride during the third trimester, the health professional should carefully consider the potential risks and benefits of treatment. The health professional may consider tapering SERTRALINE in the third trimester.

Discontinuation of SERTRALINE Treatment

Symptoms associated with the discontinuation or dosage reduction of sertraline hydrochloride have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction.

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 7 WARNINGS AND PRECAUTIONS, General, Discontinuation Symptoms; 8.5 Post-Market Adverse Reactions).

4.4 Administration

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

5 OVERDOSAGE

Of 2,288 cases of overdose involving sertraline hydrochloride worldwide (circa 2012), alone or with other drugs, there were 244 cases with fatal outcome.

Deaths have been reported involving overdoses of sertraline, alone or in combination with other drugs and/or alcohol. Therefore, any overdosage should be treated aggressively.

The largest reported overdose of sertraline alone from which a patient recovered is 13.5 g. The lowest reported fatal case of overdose involving sertraline alone is 750 mg.

Symptoms

Symptoms of overdose include serotonin-mediated side effects such as somnolence, gastrointestinal disturbance (such as nausea, vomiting, diarrhea), tachycardia, tremor, agitation and dizziness, anxiety, dilated pupils, and ECG changes including QT-interval prolongation and Torsade de Pointes. 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, 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.

Monitoring of cardiac rhythm and vital signs is recommended along with general symptomatic and supportive measures. There are no specific antidotes for sertraline hydrochloride.

Due to the large volume of distribution of sertraline hydrochloride, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

In managing overdosage, the possibility of multiple drug involvement must be considered. The health professional should consider contacting a poison control centre for additional information on the treatment of any overdose.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

SERTRALINE contains sertraline hydrochloride equivalent to 25 mg, 50 mg and 100 mg of sertraline.

Packaging

SERTRALINE capsules are packaged in white high-density polyethylene bottles of: 25 mg: 100 and 1400 capsules

50 mg: 100, 250 and 1400 capsules

100 mg: 100, 250 and 800 capsules

7 WARNINGS AND PRECAUTIONS

General

Discontinuation Symptoms: 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 antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g., dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see 8.5_Post-Market_Adverse_Reactions). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see 4.2 Recommended Dose and Dosage Adjustment; 8.5 Post-Market Adverse Reactions).

Monoamine Oxidase Inhibitors: See 2 CONTRAINDICATIONS.

Use in Patients with Concomitant Illness: Clinical experience with sertraline hydrochloride 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.

Carcinogenesis

In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown (see 16 NON-CLINICAL TOXICOLOGY).

Cardiovascular

Sertraline hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. However, the electrocardiograms of 1,006 patients who received sertraline hydrochloride in double-blind trials were evaluated and the data indicate that sertraline hydrochloride is not associated with the development of clinically significant ECG abnormalities.

In placebo-controlled trials, the frequency of clinically noticeable changes (±15-20 mmHg) in blood pressure was similar in patients treated with either sertraline hydrochloride or placebo.

QTc Prolongation/Torsade de Pointes: Sertraline has been demonstrated to cause a concentration-dependent prolongation of the QTc interval (see 8.4 Abnormal Laboratory

Findings: Hematologic, Clinical Chemistry and Other Quantitative Data). Cases of QTc prolongation and Torsade de Pointes have been reported during post-marketing use of sertraline, including at therapeutic doses.

Torsade de Pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de Pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.

The majority of reports occurred in patients with other risk factors such as concomitant illness, concomitant medications known to cause electrolyte imbalance or increase QT interval, and overdose.

Caution should be exercised when sertraline is prescribed in patients with an increased risk of QT prolongation including but not limited to those who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug, or in patients with cardiovascular disease or family history of QT prolongation, or in patients taking medicines known to increase QT interval, especially for patients with increased risk of QT prolongation (see 5 OVERDOSAGE; 9.4 Drug-Drug Interactions).

Risk factors for torsade de pointes in the general population include, but are not limited to, the following: female gender; age 65 years or older; baseline prolongation of the QT/QTc interval; presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at < 50 years; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease); history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation); electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) or conditions that can lead to electrolyte disturbances (e.g., eating disorders); bradycardia (< 50 beats per minute); acute neurological events (e.g., intracranial or subarachnoid hemorrhage, stroke, intracranial trauma); diabetes mellitus; autonomic neuropathy.

When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.

Dependence/Tolerance

Physical and Psychological Dependence: In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline hydrochloride, alprazolam, and d-amphetamine in humans, sertraline hydrochloride did not produce the positive subjective

effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with sertraline hydrochloride did not reveal any drug-seeking behavior. In animal studies, sertraline hydrochloride does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, health professionals 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 behavior).

Driving and Operating Machinery

Any psychoactive drug may impair judgement, 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.

Endocrine and Metabolism

Diabetes/Loss of Glycemic Control: Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including sertraline hydrochloride. Loss of glycemic control including both hyperglycemia and hypoglycemia has also been reported in patients with and without pre-existing diabetes. Patients should therefore be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycemic drug may need to be adjusted.

Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs or SNRIs including sertraline. In many cases, hyponatremia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also patients taking diuretics or who are otherwise volume-depleted may be at greater risk (see 7.1.4 Geriatrics). Several cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Discontinuation of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

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

Hematologic

Abnormal Bleeding: SSRIs and SNRIs, including sertraline hydrochloride, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. SSRIs/SNRIs, including sertraline hydrochloride, may increase the risk of postpartum hemorrhage (7.1.1 Pregnant Women).

Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g., thrombocytopenia). Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride and NSAIDs, ASA or other drugs that affect coagulation (see 9.4 Drug-Drug Interactions, Drugs Affecting Platelet Function).

Platelet Function: There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride, it is unclear whether sertraline hydrochloride had a causative role (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding).

Hepatic/Biliary/Pancreatic

Hepatic Dysfunction: Sertraline hydrochloride 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 effects of sertraline hydrochloride in patients with moderate and severe hepatic impairment have not been studied. 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 (see 4.2 Recommended Dose and Dosage Adjustment, Special Populations; 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency; and Renal Insufficiency ).

Musculoskeletal

Bone Fracture Risk: Elderly patients and patients with osteoporosis and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal.

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of

treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with SERTRALINE. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long-term treatment with SSRIs/SNRIs, including sertraline hydrochloride, cannot be excluded.

Neurologic

Serotonin Toxicity/Neuroleptic Malignant Syndrome: Serotonin toxicity, also known as serotonin syndrome, is a potentially life-threatening condition and has been reported with SNRIs and SSRIs, including sertraline hydrochloride.

Serotonin toxicity is characterized by neuromuscular excitation, autonomic stimulation (e.g., tachycardia, flushing) and altered mental state (e.g., anxiety, agitation, hypomania). In accordance with the Hunter criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed:

• Spontaneous clonus
• Inducible clonus or ocular clonus with agitation and diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature > 38°C and ocular clonus or inducible clonus

Neuroleptic malignant syndrome has also been rarely reported with sertraline hydrochloride, particularly during combined use with neuroleptic/antipsychotic drugs. The clinical manifestations of neuroleptic malignant syndrome often overlap with those of serotonin toxicity, including hyperthermia, hypertonia, altered mental status, and autonomic instability. In contrast to serotonin toxicity, patients with neuroleptic malignant syndrome may present with “lead pipe” muscle rigidity as well as hyporeflexia.

The concomitant use of sertraline hydrochloride with monoamine oxidase inhibitors, including linezolid and methylthioninium chloride (methylene blue), or serotonergic precursors, L-tryptophan, oxitriptan is contraindicated (see 2 CONTRAINDICATIONS). SERTRALINE should be used with caution in patients receiving other serotonergic drugs including amphetamines, triptans, opioids (e.g., fentanyl, tramadol) fenfluramine, lithium, St. John’s Wort, most tricyclic antidepressants, other antidepressants, antipsychotics/neuroleptics. If concomitant treatment with SERTRALINE and other serotonergic drugs and/or antipsychotics/neuroleptics is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 9.4 Drug-Drug Interactions). Serotonin toxicity and neuroleptic malignant syndrome may result in potentially life-threatening conditions. If serotonin toxicity or neuroleptic malignant syndrome is suspected, discontinuation of

SERTRALINE should be considered.

Seizure: Sertraline hydrochloride has not been evaluated in patients with seizure disorders.

These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3,000 patients treated with sertraline hydrochloride in the development program for depression. However, 4 patients out of approximately 1,800 (220 < 18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, SERTRALINE should be introduced with care in patients with a seizure disorder and should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. SERTRALINE should be discontinued in any patient who develops seizures.

Ophthalmologic

Angle-Closure Glaucoma: As with other antidepressants, SERTRALINE can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

Psychiatric

Potential Association with Behavioral and Emotional Changes, Including Self-Harm.

• Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRI and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioral and emotional changes, including an increased risk of suicidal ideation and behavior over that of placebo.

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

• Adults and Pediatrics: Additional data

  There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type adverse 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 behavior is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioral changes.

An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo.

Families and caregivers of patients being treated with SERTRALINE should be alerted about the need to monitor patients for the emergence of agitation, anxiety, panic attacks, hostility, irritability, hypomania or mania, unusual changes in behavior, and other symptoms, as well as the emergence of suicidality particularly within several weeks of starting treatment or changing the dose. Such symptoms should be reported immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. It should be noted that a causal role for SSRIs and other newer anti-depressants in inducing self-harm or harm to others has not been established. In order to minimize the opportunity for overdosage, prescriptions for SERTRALINE should be written for the smallest quantity of drug consistent with good patient management (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Because of the well-established co-morbidity between both obsessive-compulsive disorder and depression and panic disorder and depression, the same precautions should be observed when treating patients with obsessive-compulsive disorder and panic disorder.

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

Akathisia: The use of sertraline has been associated with the development of akathisia (psychomotor restlessness), characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

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

Renal

Renal Dysfunction: Sertraline hydrochloride is extensively metabolized and excretion of

unchanged drug in the urine is a minor route of elimination. In patients with mild to moderate renal impairment (creatinine clearance 30-60 mL/min) or moderate to severe renal impairment (creatinine clearance 10-29 mL/min), multiple-dose pharmacokinetic parameters (AUC_0-24 or C_max) were not significantly different compared with controls. Half-lives were similar and there were no differences in plasma protein binding in all groups studied. This study indicates that, as expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment.

Reproductive Health: Female and Male Potential

• Fertility

Male Fertility

Animal data have shown that some SSRIs may affect sperm quality. In human case reports, some reversible changes in sperm quality have been reported with some SSRIs. An impact on human fertility has not been observed. (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology)

• Function

Sexual Dysfunction

Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs. (see 8.2 Clinical Trial Adverse Reactions)

7.1 Special Populations

7.1.1 Pregnant Women

The safety of sertraline hydrochloride during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the health professional, the potential benefits to the patient outweigh the possible hazards to the fetus.

Observational studies have provided evidence of an increased risk (less than 2-fold) of postpartum hemorrhage following exposure to SSRIs, including sertraline, especially within the month prior to birth (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding).

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants

who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs "in early pregnancy" and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs "in early pregnancy" and an antenatal SSRI prescription "in later pregnancy."

Post-marketing reports indicate that some neonates exposed to sertraline hydrochloride, SSRIs (Selective Serotonin Reuptake Inhibitors), or newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see 7 WARNINGS AND PRECAUTIONS, General, Monoamine Oxidase Inhibitors). When treating a pregnant woman with SERTRALINE during the third trimester, the health professional should carefully consider the potential risks and benefits of treatment (see 4.2 Recommended Dose and Dosage Adjustment).

Labor and Delivery: The effect of sertraline hydrochloride on labor and delivery in humans is unknown.

7.1.2 Breast-feeding

It is unknown if SERTRALINE is excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety and effectiveness of sertraline hydrochloride in children below the age of 18 have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

Only limited clinical evidence is available concerning long-term safety data in children and adolescents, including effects on growth, sexual maturation and cognitive and behavioural developments (see 16 NON-CLINICAL TOXICOLOGY, Chronic Toxicity/Oncogenicity – Rat (juvenile animal study).

7.1.4 Geriatrics

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

SSRIS and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyponatremia).

8 ADVERSE REACTIONS

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Depression

In clinical development programs, sertraline hydrochloride has been evaluated in 1,902 subjects with depression. The most commonly observed adverse events associated with the use of sertraline hydrochloride were: gastrointestinal complaints; including nausea, diarrhea/loose stools and dyspepsia; male sexual dysfunction (primarily ejaculatory delay) (see 7 WARNINGS AND PRECAUTIONS); 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 2,710 subjects who received sertraline hydrochloride 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. Table 2 enumerates adverse events that occurred at a frequency of 1% or more among sertraline hydrochloride patients who participated in controlled trials comparing titrated sertraline hydrochloride with placebo for depression in adults.

Table 2 : Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials for Depression in Adults*

* Events reported by at least 1% of patients treated with sertraline hydrochloride are included. ⁽¹⁾ %based on male patients only: 271 sertraline hydrochloride 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 hydrochloride group with these complaints are 4.8%, 4.8% and 8.9%, respectively. It should be noted that since some sertraline hydrochloride 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.

⁽²⁾ % based on female patient only: 590 sertraline hydrochloride and 582 placebo patients.

Panic Disorder

In placebo-controlled clinical trials, 430 patients with panic disorder were treated with sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride 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 for Panic and Obsessive-compulsive disorder in adults

Table 3 enumerates adverse events that occurred at a frequency of 2% or more among patients on sertraline hydrochloride who participated in controlled trials comparing sertraline hydrochloride with placebo in the treatment of panic disorder and obsessive-compulsive disorder. Only those adverse events which occurred at higher rate during sertraline hydrochloride treatment than during placebo treatment are included.

Table 3: Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled – Clinical Trials for Panic and Obsessive-Compulsive Disorder in Adults*

ADVERSE EVENTS

* Events reported by at least 2% of patients treated with sertraline hydrochloride are included, except for the following events which had an incidence on placebo greater than or equal to sertraline hydrochloride [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 sertraline hydrochloride and 134 placebo patients, OCD: 296 sertraline hydrochloride and 219 placebo patients.

⁽²⁾ % based on male patients only: Panic Disorder: 216 sertraline hydrochloride and 134 placebo patients, OCD: 296 sertraline hydrochloride and 219 placebo patients.

Other events observed during the premarketing evaluation of sertraline hydrochloride

During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to 2,710 subjects. The conditions and duration of exposure to sertraline hydrochloride 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 7 WARNINGS AND 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 hydrochloride, 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.

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).

(1) - % based on male subjects only: 1,005

(2) - % based on female subjects only: 1,705

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: enuresis, 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 hydrochloride administration. The proportion of patients having these elevations was greater in the sertraline hydrochloride 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.

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

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

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

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

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 7 WARNINGS AND PRECAUTIONS, Psychiatric, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data

Clinical Trial Findings

Cardiac Electrophysiology: In a randomised, three-way crossover, double-blind, placebo- and positive-controlled ECG assessment study, healthy subjects (N = 50) were upward titrated over 6 days to a target 200 mg BID dose of sertraline that was administered from days 7-13, with a single 200 mg dose on day 14. Serial ECG data collected over 24 h on day 14 showed QTcF (QTcF=QT/RR^0.33) prolongation averaging approximately 6-10 ms, with a maximum difference from placebo in the mean change from baseline QTcF of 9.7 ms (90% CI 7.6, 11.7) at the 4 h time point. Exposure-response analysis demonstrated a statistically significant positive relationship between the change from baseline QTcF and sertraline plasma concentrations. The observed mean C_max (234 ng/mL) at the supratherapeutic 200 mg BID dose in this study is slightly higher than the mean C_max of 190 ng/mL reported for the maximum recommended therapeutic dose of 200 mg following once-daily doses.

8.5 Post-Market Adverse Reactions

Adverse events not listed above which have been reported in temporal association with sertraline hydrochloride since market introduction include:

Blood and Lymphatic Disorders: agranulocytosis, aplastic anemia, pancytopenia, leukopenia, thrombocytopenia

Cardiovascular Disorders: bradycardia, AV block, atrial arrhythmias, ventricular tachycardia (including torsade de pointes-type arrhythmias)

Endocrine Disorders: hypothyroidism, syndrome of inappropriate ADH secretion, hyperprolactinemia

Eye Disorders: blindness, cataract, oculogyric crisis

Gastrointestinal Disorders: pancreatitis

Hepatobilary Disorders: liver events

Immune System Disorders: anaphylactoid reaction, serum sickness

Investigations: increased coagulation times, QT interval prolongation

Metabolism and Nutrition Disorders: diabetes mellitus, hyperglycemia, hypoglycemia

Musculoskeletal System Disorders: Muscle contractions involuntary, Lupus-like syndrome, trismus, bone fractures, rhabdomyolysis

Nervous System Disorders: cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and call-fleming syndrome), optic neuritis, neuroleptic malignant syndrome, extrapyramidal symptoms, serotonin syndrome

Psychiatric Disorders: psychosis

Reproductive System Disorders: priapism, galactorrhea

Respiratory Disorders: pulmonary hypertension

Skin Disorders: angioedema, severe skin reactions such as Stevens-Johnson syndrome, epidermal necrosis, photosensitivity, other severe cutaneous disorders

Urinary System Disorders: acute renal failure, hematuria

Vascular Disorders: vasculitis

The causal relationship between sertraline hydrochloride 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 hydrochloride) 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 hydrochloride treatment.

Adverse Reactions following Discontinuation of Treatment (or Dose Reduction) There have been reports of adverse reactions upon the discontinuation of sertraline hydrochloride (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 4.2 Recommended Dose and Dosage Adjustment; 7 WARNINGS AND PRECAUTIONS, General, Discontinuation Symptoms).

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 4.2 Recommended Dose and Dosage Adjustment; 7 WARNINGS AND PRECAUTIONS General, Discontinuation Symptoms).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Monoamine Oxidase Inhibitors: See 2 CONTRAINDICATIONS
• Pimozide: See 2 CONTRAINDICATIONS

9.3 Drug-Behavioural Interactions

Alcohol

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

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e.

those identified as contraindicated).

Table 4 – Established or Potential Drug-Drug Interactions

¹ Currently not marketed in Canada for human use

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Food appears to increase the bioavailability by about 40%: it is recommended that SERTRALINE be administered with meals (see 4.4 Administration).

9.6 Drug-Herb Interactions

St. John’s Wort

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

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The mechanism of action of sertraline is presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets.

Like most clinically effective antidepressants, sertraline downregulates brain norepinephrine and serotonin receptors in animals. In receptor binding studies, sertraline has no significant affinity for adrenergic (alpha1, alpha₂ & beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5- HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites.

In placebo-controlled studies in normal volunteers, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance.

10.3 Pharmacokinetics

Absorption

Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (C_max) of sertraline is 0.19 mcg/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time curve is 2.8 mg hr/L. Food appears to increase the bioavailability by about 40%: it is recommended that SERTRALINE be administered with meals. For desmethylsertraline, C_max is 0.14 mcg/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.

Distribution

Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see 9.4 Drug-Drug Interactions).

Metabolism

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

Elimination

Biliary excretion of metabolites is significant.

Special Populations and Conditions

• Geriatrics

  The pharmacokinetics of sertraline itself appears 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.

• Sex

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

• Hepatic Insufficiency

  The pharmacokinetics of sertraline in patients with significant hepatic dysfunction has not been determined (see 4.2 Recommended Dose and Dosage Adjustment; 7 WARNINGS AND PRECAUTIONS Hepatic/Biliary/Pancreatic).

• Renal Insufficiency

  The pharmacokinetics of sertraline in patients with significant renal dysfunction has not been determined (see 4.2 Recommended Dose and Dosage Adjustment; 7 WARNINGS AND PRECAUTIONS, Renal).

11 STORAGE, STABILITY AND DISPOSAL

Store between 15°C and 30°C. Keep out of the reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

No special handling is necessary for this product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Sertraline Hydrochloride

Code Name: CP-51,974-01

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

Molecular Formula and molecular mass: C₁₇H₁₇NCl₂^.HCl, 342.7 g / mol

Structural Formula:

Physicochemical Properties:

Description: Sertraline hydrochloride is a white to off-white crystalline powder

Solubility: 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.

. HCl H NHCH₃

H

Cl

Cl

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Panic Disorder

Summary of patient demographics for clinical trials in panic disorder: Four placebo-controlled clinical trials have been performed to investigate the efficacy of sertraline hydrochloride in panic disorder: two flexible dose studies and two fixed dose studies.

Results of studies in panic disorder: At the last week of treatment (week 10 or 12), both flexible dose studies and one of the fixed dose studies showed statistically significant differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline in the total number of full panic attacks (last observation carried forward analysis). As the flexible dose studies were of identical protocol, data for these investigations can be pooled. The mean number of full panic attacks at baseline was 6.2/week (n = 167) in the sertraline hydrochloride group and 5.4/week in the placebo group (n = 175). At week 10 (last observation carried forward analysis), the mean changes from baseline were -4.9/week and -2.5/week for the sertraline hydrochloride and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 57% in the placebo group and 69% in the sertraline hydrochloride group. The mean daily dose administered at the last week of treatment was approximately 120 mg (range: 25-200 mg) in the flexible dose studies. No clear dose-dependency has been demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies.

Obsessive-Compulsive Disorder

Summary of patient demographics for clinical trials in obsessive-compulsive disorder: Five placebo-controlled clinical trials, in adults, of 8 to 16 weeks in duration have been performed to investigate the efficacy of sertraline hydrochloride in obsessive-compulsive disorder: four flexible dose studies (50-200 mg/day) and one fixed dose study (50, 100 & 200 mg/day).

Results of studies in obsessive-compulsive disorder: Results for three of the four flexible dose studies and the 50 and 200 mg dose groups of the fixed dose study were supportive of differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale (last observation carried forward analysis). No clear dose- dependency was demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies. In the flexible dose studies, the mean daily dose administered at the last week of treatment ranged from 124-180 mg.

14.3 Comparative Bioavailability Study

A comparative bioavailability study was performed in the fasting state to compare the pharmacokinetic parameters of SERTRALINE 100 mg capsules (Sanis Health Inc.) versus ZOLOFT^® 100 mg capsules (Pfizer Canada Inc.). The results of the study are shown in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* SERTRALINE 100 mg capsules, Sanis Health Inc.

^† ZOLOFT^® 100 mg capsules, Pfizer Canada Inc.

^§ Expressed as the arithmetic mean (CV %) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity: mice and rats

Table 5 – Acute Oral and Intraperitoneal Toxicity Studies in Mice and Rats

Signs of toxicity observed in both mice and rats dosed orally and by intraperitoneal administration included hyperactivity, convulsions, depression, weakness, decreased food consumption, and weight gain inhibition. Oral administration in both mice and rats produced exophthalmia, soft stools, and labored respiration. Orally dosed rats also showed marked salivation. Acute oral administration produced no gross pathological findings. Acute intraperitoneal administration, on the other hand, caused adhesion of the intestines or pancreas to the liver in 2 of 10 male mice and liver lobe adhesions which were dose-related in rats.

Sertraline was also given in single doses of 10, 20, 30, and 50 mg base/kg p.o. (in capsules) to two female beagle dogs at each dose. At the lowest level, dogs were mydriatic and anorectic but otherwise asymptomatic. At higher doses, increased salivation, tremors and twitches were observed, along with the mydriasis and anorexia. None of the dogs at any dose level exhibited motor stimulation, circling or stereotypy. The duration of the anorexia was 12 to 15 hr, but eating resumed late in the day after treatment and the dogs recovered uneventfully.

Chronic Toxicity/Oncogenicity: mice, rats and dogs

Table 6 – Chronic Toxicity/Oncogenicity

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.

Reproductive and Developmental Toxicology

Table 7 – Fertility and Reproductive Performance

Table 8 – Teratology

Table 9 – Peri- Post-Natal Studies

17 SUPPORTING PRODUCT MONOGRAPHS

^PrZOLOFT^® (capsules, 25 mg 50 mg and 100 mg), submission control number 265271, Product Monograph, Upjohn Canada ULC (October 19, 2022).