Zoloft (Sertraline HCl)

ZOLOFT™

Pfizer

Sertraline HCl

Antidepressant – Antipanic – Antiobsessional Agent

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 and beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites.

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

Pharmacokinetics: Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (Cmax) of sertraline is 0.19 g/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time curve is 2.8 mg h/L. For desmethylsertraline, Cmax is 0.14 g/mL, the half-life 65 hours and the area under the curve 2.3 mg h/L. Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours. Linear dose proportionality has been demonstrated over the clinical dose range of 50 to 200 mg/day.

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

Sertraline is extensively metabolized to N-desmethylsertraline, which shows negligible pharmacological activity. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. Biliary excretion of metabolites is significant. Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see Precautions).

The pharmacokinetics of sertraline itself appear to be similar in young and elderly subjects. Plasma levels of N-desmethylsertraline show a 3-fold elevation in the elderly following multiple dosing, however, the clinical significance of this observation is not known.

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

Liver and Renal Disease: The pharmacokinetics of sertraline in patients with significant hepatic or renal dysfunction have not been determined.

Clinical Trials: Panic Disorder: Four placebo-controlled clinical trials have been performed to investigate the efficacy of sertraline in panic disorder: 2 flexible-dose studies and 2 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 favor of sertraline 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 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 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 group. The mean daily dose administered at the last week of treatment was approximately 120 mg (range: 25 to 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 of 8 to 16 weeks in duration have been performed to investigate the efficacy of sertraline in obsessive-compulsive disorder: 4 flexible-dose studies (50 to 200 mg/day) and 1 fixed-dose study (50, 100 and 200 mg/day). Results for 3 of the 4 flexible-dose studies and the 50 and 200 mg dose groups of the fixed-dose study were supportive of differences from placebo in favor of sertraline 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 to 180 mg.

Indications And Clinical Uses: Depression: For the symptomatic relief of depressive illness. However, the antidepressant action of sertraline in hospitalized depressed patients has not been adequately studied.

A placebo-controlled European study carried out over 44 weeks, in patients who were responders to sertraline has indicated that sertraline may be useful in continuation treatment, suppressing 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: For the symptomatic relief of panic disorder, with or without agoraphobia.

The efficacy of sertraline 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 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 sertraline for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive-Compulsive Disorder: 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 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 sertraline for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: In patients with known hypersensitivity to the drug.

MAO Inhibitors: Cases of serious, sometimes fatal, reactions have been reported in patients receiving sertraline in combination with an MAO inhibitor, including the selective MAO inhibitor, selegiline and the reversible MAO inhibitor (reversible inhibitor of MAO-RIMA), moclobemide. Some cases presented with features resembling the serotonin syndrome. Similar cases, have been reported with other antidepressants during combined treatment with an MAO inhibitor and in patients who have recently discontinued an antidepressant and have been started on an MAO inhibitor. Symptoms of a drug interaction between an SSRI and an MAO inhibitor 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 MAO inhibitor or within 14 days of discontinuing treatment with an MAO inhibitor. Similarly, at least 14 days should elapse after discontinuing sertraline treatment before starting an MAO inhibitor.

Manufacturers’ Warnings In Clinical States: MAO Inhibitors: See Contraindications.

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

Seizure: Sertraline has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product’s premarket testing. No seizures were observed among approximately 3 000 patients treated with sertraline in the development program for depression. However, 4 patients out of approximately 1 800 (220
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for sertraline should be written for the smallest quantity of drug consistent with good patient management.

Because of the well-established comorbidity 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.

Occupational Hazards: Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.

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

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

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

Hepatic Dysfunction: Sertraline is extensively metabolized by the liver. A single dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and increased AUC in comparison to normal subjects. The use of sertraline in patients with hepatic disease must be approached with caution. If sertraline is administered to patients with hepatic impairment, a lower or less frequent dose should be considered.

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

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.

Pregnancy and Lactation: The safety of sertraline during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus. There have been isolated reports of reactions such as tremors, jitteriness, restlessness, hypertonia, hyperreflexia and difficulty breathing in neonates whose mothers had been treated with sertraline during pregnancy and in an infant whose mother discontinued sertraline treatment during breast-feeding. However, causal relationship between sertraline treatment and the emergence of these events has not been established.

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

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

Geriatrics: 462 elderly patients (³65 years) with depressive illness have participated in multiple-dose therapeutic studies with sertraline. The pattern of adverse reactions in the elderly was comparable to that in younger patients.

Hyponatremia: Several cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of these occurences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume-depleted.

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

Drug Interactions: CNS Active Drugs: Sertraline (200 mg daily) did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects, however the risk of using sertraline in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline and such drugs is required.

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) to another has not been established.

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

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

Lithium: In placebo-controlled trials in normal volunteers, the coadministration of sertraline with lithium did not significantly alter lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. As with other SSRIs, caution is recommended when coadministering sertraline with medications, such as lithium, which may act via serotonergic mechanisms.

MAO Inhibitors: See Contraindications.

Drugs Metabolized by P450 System: Drugs Metabolized by P450 3A4: In 2 separate in vivo interaction studies, sertraline was coadministered 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 coadministered drugs that are metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressants and the type lc antiarrhythmics, propafenone and flecainide. There is variability among the antidepressants in the extent of clinically important P450 2D6 inhibition. In 2 drug interaction clinical trials using desipramine and the recommended starting SSRI doses in normal volunteers, the effect of sertraline was compared to 2 other SSRIs. In the first study, mean desipramine steady-state AUC increased by 23% and 380% during coadministration with sertraline and the comparative SSRI, respectively. In a second study using a different comparative SSRI, mean desipramine steady-state AUC increased by 37% and 421% during coadministration with sertraline and the comparative SSRI, respectively. These trial results indicate that the effect of sertraline was significantly less pronounced than that of the 2 comparative SSRIs. Nevertheless, concomitant use of a drug metabolized by P450 2D6 with sertraline, may require lower doses than are usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from cotherapy, an increased dose of the coadministered drug may be required.

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

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

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

In a placebo-controlled trial in normal volunteers, the administration of sertraline for 22 days (dose was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an i.v. dose of 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 1 patient treated with sertraline, glibenclamide, haloperidol, bisacodyl, ASA and flucloxacillin. The causal relationship to sertraline treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with sertraline and oral hypoglycemic drugs or insulin is recommended.

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

Beta-blockers: There is no experience with the use of sertraline in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of sertraline on the B-adrenergic blocking activity of atenolol was assessed. The mean CD25s (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 vs the placebo group. These data suggest that sertraline does not alter the B-blocking action of atenolol.

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

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

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

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

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

Physical and Psychological Dependence: In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline, alprazolam and d-amphetamine in humans, sertraline did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with sertraline did not reveal any drug-seeking behavior. In animal studies sertraline does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of sertraline misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Adverse Reactions: Depression: In clinical development programs, sertraline has been evaluated in 1 902 subjects with depression. The most commonly observed adverse events associated with the use of sertraline 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 in premarketing multiple dose clinical trials. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea and fatigue.

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

Panic Disorder: In placebo-controlled clinical trials, 430 patients with panic disorder were treated with sertraline in doses of 25 to 200 mg/day. During treatment, most patients received doses of 50 to 200 mg/day. Adverse events observed at an incidence of at least 5% for sertraline 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 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 discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.8%), insomnia (2.6%) and diarrhea (2.1%).

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

Other events observed during the premarketing evaluation of sertraline: During its premarketing assessment, multiple doses of sertraline were administered to 2 710 subjects. The conditions and duration of exposure to sertraline varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for indications other than depression. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

All events are included except those already listed in Table I and Table II or in the Precautions section, and those reported in terms so general as to be uninformative.

It is important to emphasize that although the events reported occurred during treatment with sertraline, they were not necessarily caused by it.

Autonomic Nervous System Disorders: Infrequent: flushing, mydriasis, increased saliva, cold clammy skin. Rare: pallor.

Cardiovascular: Infrequent: postural dizziness, hypertension, hypotension, postural hypotension, edema, dependent edema, periorbital edema, peripheral edema, peripheral ischemia, syncope, tachycardia. Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, varicose veins.

Central and Peripheral Nervous System Disorders: Frequent: confusion. Infrequent: ataxia, abnormal coordination, abnormal gait, hyperesthesia, hyperkinesia, hypokinesia, migraine, nystagmus, vertigo. Rare: local anesthesia, coma, convulsions, dyskinesia, dysphonia, hyporeflexia, hypotonia, ptosis.

Disorders of Skin and Appendages: Infrequent: acne, alopecia, pruritus, erythematous rash, maculopapular rash, dry skin. Rare: bullous eruption, dermatitis, erythema multiforme, abnormal hair texture, hypertrichosis, photosensitivity reaction, follicular rash, skin discoloration, abnormal skin odor, urticaria.

Endocrine Disorders: Rare: exophthalmos, gynecomastia.

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

General: Frequent: asthenia. Infrequent: malaise, generalized edema, rigors, weight decrease, weight increase. Rare: enlarged abdomen, halitosis, otitis media, aphthous stomatitis.

Hematopoietic and Lymphatic: Infrequent: lymphadenopathy, purpura. Rare: anemia, anterior chamber eye hemorrhage.

Metabolic and Nutritional Disorders: Rare: dehydration, hypercholesterolemia, hypoglycemia.

Musculoskeletal 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: oliguria, renal pain, urinary retention.

Laboratory Tests: In man, asymptomatic elevations in serum hepatic transaminases (AST and ALT) to a value ³3 times the upper limit of normal have been reported infrequently (approximately 0.6% and 1.1%, respectively) in association with sertraline administration. The proportion of patients having these elevations was greater in the sertraline group than in the placebo group. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

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

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

Other Events Observed During the Postmarketing Evaluation of Sertraline: Adverse events not listed above which have been reported in temporal association with sertraline since market introduction include: increased coagulation times, bradycardia, AV block, atrial arrhythmias, hypothyroidism, leukopenia, thrombocytopenia, hyperglycemia, priapism, galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like events, psychosis, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events. The causal relationship between sertraline treatment and the emergence of these events has not been established. The clinical features of hepatic events (which in the majority of cases appeared to be reversible with discontinuation of sertraline) occurring in 1 or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death. There have been spontaneous reports of symptoms such as dizziness, paresthesia, nausea, headache, anxiety, fatigue and agitation following the discontinuation of sertraline treatment.

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

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

Cardiac and vital signs monitoring are recommended along with general symptomatic and supportive measures. There are no specific antidotes for sertraline.

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

In managing overdose, the possibility of multiple drug involvement must be considered.

Dosage And Administration: General: 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 to 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 1 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 to 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 1 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.

Renal/Hepatic Impairment: As with many other medications, sertraline should be used with caution in patients with renal and/or hepatic impairment (see Precautions).

Switching Patients to or From an MAO Inhibitor: At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of therapy with sertraline. In addition, at least 14 days should be allowed after stopping sertraline before starting an MAO inhibitor (see Contraindications).

Availability And Storage: 25 mg: Each yellow capsule contains: sertraline HCl equivalent to 25 mg of sertraline. Nonmedicinal ingredients: cornstarch, lactose (anhydrous), magnesium stearate and sodium lauryl sulfate. Capsule shell: D&C Yellow No. 10, FD&C Yellow No. 6, gelatin and titanium dioxide. Tartrazine-free. White high density polyethylene bottles of 100.

50 mg: Each white and yellow capsule contains: sertraline HCl equivalent to 50 mg of sertraline. Nonmedicinal ingredients: cornstarch, lactose (anhydrous), magnesium stearate and sodium lauryl sulfate. Capsule shell: D&C Yellow No. 10, FD&C Yellow No. 6, gelatin and titanium dioxide. Tartrazine-free. White high density polyethylene bottles of 100 and 250.

100 mg: Each orange capsule contains: sertraline HCl equivalent to 100 mg of sertraline. Nonmedicinal ingredients: cornstarch, lactose (anhydrous), magnesium stearate and sodium lauryl sulfate. Capsule shell: D&C Yellow No. 10, FD&C Red No. 40, gelatin and titanium dioxide. Tartrazine-free. White high density polyethylene bottles of 100 and 250.

Store at controlled room temperature between 15 and 30°C.

ZOLOFT™ Pfizer Sertraline HCl Antidepressant – Antipanic – Antiobsessional Agent

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