Dom-Sertraline Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

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

Like most clinically effective antidepressants, sertraline 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.

Pharmacokinetics: 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. 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.

Food appears to increase the bioavailability by about 40%: it is recommended that Dom-SERTRALINE capsules be administered with meals.

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

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

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.

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

Liver and Renal Disease: The pharmacokinetics of sertraline in patients with significant hepatic or renal dysfunction have not been determined (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

Clinical Trials

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

Obsessive-Compulsive Disorder: Five placebo-controlled clinical trials, in adults, of 8 to 16 weeks in duration have been performed to investigate the efficacy of sertraline hydrochloride in obsessive-compulsive disorder: four flexible dose studies (50-200 mg/day) and one fixed dose study (50, 100 and 200 mg/day). Results for three of the four flexible dose studies and the 50 and 200 mg dose groups of the fixed dose study were supportive of differences from placebo in favour of sertraline hydrochloride in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale (last observation carried forward analysis). No clear dose-dependency was demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies. In the flexible dose studies, the mean daily dose administered at the last week of treatment ranged from 124-180 mg.

Comparative Bioavailability Study

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

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Dom-SERTRALINE 100 mg capsules, Dominion Pharmacal ^† ZOLOFT^® 100 mg capsules, Pfizer Canada Inc. ^§ Expressed as the arithmetic mean (CV %) only.

INDICATIONS AND CLINICAL USE

Adults

Depression

Dom-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 re-emergence of depressive symptoms.

However, because of methodological limitations, these findings on continuation treatment have to be considered tentative at this time.

Panic Disorder

Dom-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 physician who elects to use Dom-SERTRALINE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive-Compulsive Disorder

Dom-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 physician who elects to use Dom-SERTRALINE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Pediatrics (<18 years of age)

Dom-SERTRALINE is not indicated for use in children under 18 years of age (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM; ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

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

Monoamine Oxidase Inhibitors

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

Pimozide

The concomitant use of Dom-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 PRECAUTIONS and PART III: CONSUMER INFORMATION sections.)

WARNINGS

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

• Pediatrics: Placebo-Controlled Clinical Trial Data:

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

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

• Adults and Pediatrics: Additional Data:

  There are clinical trial and post-marketing reports with SSRIs and other newer 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, and depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

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 behaviour with antidepressants compared to placebo.

Families and caregivers of patients being treated with Dom-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 behaviour, 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.

Discontinuation Symptoms

Patients currently taking Dom-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.

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS.

Bone Fracture Risk

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 Dom-SERTRALINE. Elderly patients 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. 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, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

PRECAUTIONS

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.

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 DRUG INTERACTIONS, Drugs Affecting Platelet Function). Caution is also advised in patients with a history of bleeding disorders or predisposing conditions (e.g., thrombocytopenia).

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.

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.

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 (TdP)

Sertraline has been demonstrated to cause a concentration-dependent prolongation of the QTc interval (see ADVERSE REACTIONS, Cardiac Electrophysiology). Cases of QTc prolongation and Torsade de Pointes (TdP) 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 also DRUG INTERACTIONS, as well as OVERDOSAGE).

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 haemorrhage, 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.

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.

Discontinuation of Treatment with Sertraline Hydrochloride

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

Electroconvulsive Therapy

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

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 Dom-SERTRALINE in patients with hepatic disease must be approached with caution. If Dom-SERTRALINE is administered to patients with hepatic impairment, a lower or less frequent dose should be considered (see ACTION and DOSAGE AND ADMINISTRATION sections).

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 Use in Elderly). 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.

Occupational Hazards

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.

Ophthalmologic

Angle-Closure Glaucoma

As with other antidepressants, Dom-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.

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. Pre-marketing clinical experience with sertraline hydrochloride did not reveal any drug-seeking behaviour. In animal studies, sertraline hydrochloride does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of sertraline hydrochloride misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behaviour).

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 PRECAUTIONS, Abnormal Bleeding).

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.

Serotonin Syndrome/Neuroleptic Malignant Syndrome

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of sertraline hydrochloride particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs and other dopamine antagonists. As these syndromes may result in potentially life-threatening conditions, treatment with Dom-SERTRALINE should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium, and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome, Dom-SERTRALINE should not be used in combination with MAO inhibitors (including the antibiotic linezolid and methylthioninium chloride (methylene blue)) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution and avoided whenever possible in patients receiving other serotonergic drugs (amphetamines, triptans, fenfluramine, lithium, tramadol, St. John’s Wort (Hypericum perforatum), most tricyclic antidepressants, other antidepressants, and fentanyl), neuroleptics/antipsychotics or other antidopaminergic agents (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Seizure

Sertraline hydrochloride has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product’s pre-market 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, Dom-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. Dom-SERTRALINE should be discontinued in any patient who develops seizures.

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 antidepressants in inducing self-harm or harm to others has not been established. In order to minimize the opportunity for overdosage, prescriptions for Dom-SERTRALINE should be written for the smallest quantity of drug consistent with good patient management (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

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.

Special Populations

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.

Use in Pregnancy and Nursing Mothers

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

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 20^th 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 PRECAUTIONS-Monoamine Oxidase Inhibitors). When treating a pregnant woman with Dom-SERTRALINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION section).

Labour and Delivery

The effect of sertraline hydrochloride on labour and delivery in humans is unknown.

Use in Children

The safety and effectiveness of sertraline hydrochloride in children below the age of 18 have not been established and its use is not recommended.

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 TOXICOLOGY, Chronic Toxicity/Oncogenicity – Rat (juvenile animal study).

Use in Elderly

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

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 PRECAUTIONS, Hyponatremia).

Use in Patients with Concomitant Illness

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

DRUG INTERACTIONS

CNS Active Drugs

Sertraline hydrochloride (200 mg daily) did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the risk of using sertraline hydrochloride in combination with other CNS active drugs has not been

systematically evaluated. Consequently, caution is advised if the concomitant administration of Dom-SERTRALINE and such drugs is required.

Pimozide

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

Serotonergic Drugs

There is limited controlled experience regarding the optimal timing of switching from other antidepressants and antipanic agents to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) or Tricyclic Antidepressants (TCAs) etc. to another has not been established.

Co-administration with tryptophan, TCAs and other antidepressants may lead to a higher incidence of serotonin-associated side effects.

Rare post-marketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of a selective serotonin reuptake inhibitor (SSRI) and 5-HT1 agonists (triptans). If concomitant treatment with Dom-SERTRALINE and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs with serotonergic activity including but not limited to amphetamines, fentanyl (and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine), fenfluramine and tryptophan is clinically warranted, appropriate observation of the patient for acute and long-term adverse events is advised.

QTc-Prolonging Drugs

Pharmacokinetic and pharmacodynamic studies of sertraline combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of sertraline and these medicinal products cannot be excluded. Therefore, co-administration of sertraline with medicinal products that have a clear QT interval prolonging effect is discouraged. Drugs that have been associated with QTc interval prolongation and/or Torsade de Pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some,

although not necessarily all, class members have been implicated in QTc prolongation and/or Torsade de Pointes:

• Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone);
• Class 1C antiarrhythmics (e.g., flecainide, propafenone);
• antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone);
• antidepressants (e.g., citalopram, fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline);
• opioids (e.g., methadone);
• macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus);
• quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
• antimalarials (e.g., quinine, chloroquine);
• azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
• domperidone;
• 5-HT3 receptor antagonists (e.g., dolasetron, ondansetron);
• tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib);
• histone deacetylase inhibitors (e.g., vorinostat);
• beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

Drugs that Affect Electrolytes

The concomitant use of sertraline hydrochloride with drugs that can disrupt electrolyte levels is discouraged. Drugs that decrease electrolyte levels include, but are not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high-dose corticosteroids.

The above lists of potentially interacting drugs are not comprehensive (see also PRECAUTIONS, Cardiovascular).

St. John’s Wort

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

Lithium

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

Phenytoin

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

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS section.

Drugs Metabolized by P450 System

Drugs Metabolized by P450 3A4

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

Drugs Metabolized by P450 2D6

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

Alcohol

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

Hypoglycemic Drugs

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

In a placebo-controlled trial in normal volunteers, the administration of sertraline hydrochloride for 22 days (dose of sertraline hydrochloride was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an IV dose of 1,000 mg. In a placebo-controlled study in normal volunteers, glibenclamide (5 mg) was given before and after administration of sertraline (200 mg/day final dose) to steady-state or placebo. No significant changes were observed in the total plasma concentration of glibenclamide. Hypoglycemia requiring dextrose infusion was observed in one patient treated with sertraline hydrochloride, glibenclamide, haloperidol, bisacodyl, acetylsalicylic acid and flucloxacillin. The causal relationship to sertraline hydrochloride treatment was not firmly established. Nevertheless, close monitoring of glycaemia in patients treated with sertraline hydrochloride and oral hypoglycemic drugs or insulin is recommended since their dosage of insulin and/or concomitant oral hypoglycemia drug may need to be adjusted (see PRECAUTIONS, Diabetes/Loss of Glycemic Control).

Digoxin

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

Beta Blockers

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

Cimetidine

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

Diazepam

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

Drugs Affecting Platelet Function (e.g., NSAIDs, ASA and other anticoagulants)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Dom-SERTRALINE is initiated or discontinued (see PRECAUTIONS, Abnormal Bleeding).

Warfarin

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Dom-SERTRALINE is initiated or discontinued.

In a placebo-controlled study in healthy men comparing prothrombin time AUC (0-120 hr) following single dosing with warfarin (0.75 mg/kg) before and after dosing to steady state with either sertraline (200 mg/day final dose) or placebo, there was a statistically significant mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo. The normalization of prothrombin time for the sertraline group was delayed compared to the placebo group. The clinical significance of these changes is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped in patients receiving warfarin (see PRECAUTIONS, Abnormal bleeding).

Because sertraline is highly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.

ADVERSE REACTIONS

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); 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 pre-marketing multiple-dose clinical trials. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea and fatigue. Table 1 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 1: 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 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 2 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 2: 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.

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 behaviours 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 BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.)

Cardiac Electrophysiology

In a randomized, 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 hrs 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 hr 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.

Other Events Observed During the Pre-marketing Evaluation of Sertraline Hydrochloride

During its pre-marketing 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 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 discolouration, abnormal skin odour, 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.

Other Events Observed During the Post-marketing Evaluation of Sertraline Hydrochloride

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

Hepatobiliary 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 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).

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, and 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 physician should consider contacting a poison control center for additional information on the treatment of any overdose.

DOSAGE AND ADMINISTRATION

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

General

Dom-SERTRALINE 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.

Panic Disorder

Dom-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.

Hepatic Impairment

As with many other medications, Dom-SERTRALINE should be used with caution in patients with hepatic impairment (see PRECAUTIONS section). The effects of sertraline hydrochloride in patients with moderate and severe hepatic impairment have not been studied.

Children

(See INDICATIONS: Pediatrics (<18 years of age); WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM; ADVERSE REACTIONS).

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 PRECAUTIONS section). When treating a pregnant woman with Dom-SERTRALINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Dom-SERTRALINE in the third trimester.

Switching Patients to or from a Monoamine Oxidase Inhibitor

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

Discontinuation of Dom-SERTRALINE Treatment

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

Trade name: Dom-SERTRALINE

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: C₁₇H₁₇NCl₂^.HCl

Molecular Mass: 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

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

Capsules: 25 mg, 50 mg and 100 mg.

Composition

Capsules are formulated to contain sertraline hydrochloride equivalent to 25 mg, 50 mg and 100 mg of sertraline and the following non-medicinal ingredients: Corn Starch, Lactose, Magnesium Stearate and Sodium Lauryl Sulfate. In addition, the capsule shells contain the following additional ingredients:

The 25 mg capsules: D&C Yellow #10, FD&C Yellow #6, Gelatin, Titanium Dioxide. The 50 mg capsules: D&C Yellow #10, FD&C Yellow #6, Gelatin, Titanium Dioxide. The 100 mg capsules: D&C Yellow #10, FD&C Red #40, Gelatin, Titanium Dioxide.

Packaging

Sertraline hydrochloride capsules are packaged in white high-density polyethylene bottles of 100 capsules (all strengths) and 250 capsules (50 mg and 100 mg strengths only).

STORAGE AND STABILITY

Store between 15°C and 30°C.

DETAILED PHARMACOLOGY

Animal Pharmacology

Sertraline is a highly selective and potent inhibitor of neuronal 5HT uptake, both in vitro and in vivo. Sertraline is highly active in several behavioural and biochemical models in which clinically effective antidepressants are also active. Sertraline has no significant effects on cardiac function and only transient effects on pulmonary function are seen with high intravenous doses. A transient reduction in K+ excretion was observed in conscious dogs, which dissipated after the second daily dose of 4 mg/kg p.o. Sertraline increases gastric acid secretion in rats but does not induce any pathological changes in the stomachs of dogs, even after several months of treatment. Sertraline is a mild inducer of hepatic microsomal cytochrome P450.

Rats receiving a 32 mg/kg oral dose of sertraline (5 to 10-fold the therapeutic dose in man) in combination with lithium (200 mg/kg) had increased plasma levels of lithium compared to saline-treated controls.

Characterization in animal test systems produced evidence that sertraline shares pharmacologic properties common to clinically effective antidepressant agents and lacks cardiovascular or anticholinergic effects.

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 end products of this metabolic pathway. In man, the α-hydroxy ketone glucuronide diastereomers were the major but not the sole end product of the deamination pathway, as both the ketone and α-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*

Species

Sertraline Dose

(mg/kg) and

Route of

Administration

t1/2

(hr)

VD

(L/kg)

Cl

(mL/min/

kg)

% Oral

Bioavail

Cmax (mcg/mL)

AUC

(mg

hr/L)

t1/2

(hr)

Cmax

(mcg/mL)

AUC (mg hr/L)

Mouse 29 (SC and PO) 2.5 -- -- 70 0.31 1.6 7.4 0.41 5.3 Rat 5 (IV and PO) 4.5 23 59 36 0.062 0.51 14 0.051 0.71 Rat 25 (IP and PO) 6.5 -- -- -- 0.31 4.5 10.5 ^a 0.11 1.8 Dog 5 (IV) and 10

(PO)

5.2 25 49 22 0.15 1.4 7.1 ^a 0.16 4.6

Dog ^b 10 (PO) -- -- -- -- 0.32 2.3 -- 0.21 3.0 Dog ^b 30 (PO) -- -- -- -- 0.93 8.6 -- 0.49 7.8 Dog ^b 90 (PO) -- -- -- -- 3.1 33.6 -- 1.8 29.5 Man ^c 3 (PO) 26 -- -- -- 0.19 2.8 65 0.14 2.3

* T_1/2 and V_D and C1 in mouse, rat and dog were based on data from parenteral route of sertraline hydrochloride administration, while C_max and AUC were based on data following oral administration.

^a Based on parenteral administration of primary amine metabolite.

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

^c Sertraline t1/2 based on data at doses of 50 to 400 mg/day. C_max and AUC for drug and metabolite were steady-state values (day

1. 14) of 200 mg dose subjects.

TOXICOLOGY

Acute Toxicity: mice and rats

Acute Oral and Intraperitoneal Toxicity Studies in Mice and Rats

Signs of toxicity observed in both mice and rats dosed orally and by intraperitoneal administration included hyperactivity, convulsions, depression, weakness, decreased food consumption, and weight gain inhibition. Oral administration in both mice and rats produced exophthalmia, soft stools, and laboured 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 hrs, but eating resumed late in the day after treatment and the dogs recovered uneventfully.

Chronic Toxicity/Oncogenicity

Reproduction and Teratology

Fertility and Reproductive Performance

Teratology

Peri- Post-Natal Studies

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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    Date of Revision: January 24, 2018, Control No.: 208736.