Obsessive-Compulsive Disorder-- Sertraline is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

Panic Disorder-- Sertraline is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV.

Posttraumatic Stress Disorder (PTSD)-- Sertraline hydrochloride is indicated for the treatment of posttraumatic stress disorder.

Premenstrual Dysphoric Disorder (PMDD)-- Sertraline is indicated for the treatment of premenstrual dysphoric disorder (PMDD).

Social Anxiety Disorder-- Sertraline hydrochloride is indicated for the treatment of social anxiety disorder, also known as social phobia.

CONTRAINDICATIONS:

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. Concomitant use in patients taking pimozide is contraindicated.

Sertraline is contraindicated in patients with a hypersensitivity to Sertraline or any of the inactive ingredients in Sertraline.

CLINICAL PHARMACOLOGY:

 Pharmacodynamics

The mechanism of action of Sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that Sertraline blocks the uptake of serotonin into human platelets.

Pharmacokinetics

Systemic Bioavailability--Mean peak plasma concentrations (Cmax) of Sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma Sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state Sertraline plasma levels should be achieved after approximately one week of once-daily dosing.

For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours.

Metabolism-- Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for Sertraline is N-demethylation. N-desmethylSertraline has a plasma terminal elimination half-life of 62 to 104 hours. About 40-45% of the administered Sertraline radioactivity was recovered in urine in 9 days. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged Sertraline.

Protein Binding-- Sertraline is highly bound to serum proteins (98%).

Age-- Sertraline steady-state should be achieved after 2 to 3 weeks in older patients.

Liver Disease-- Use of Sertraline in patients with liver disease must be approached with caution.

Renal Disease-- Thus Sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment.

Cases of serious sometimes fatal reactions have been reported in patients receiving Sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Sertraline should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Sertraline before starting an MAOI.

PRECAUTIONS:

 General

Activation of Mania/Hypomania-- During premarketing testing, hypomania or mania occurred in approximately 0.4% of Sertraline hydrochloride treated patients.

Weight Loss-- Significant weight loss may be an undesirable result of treatment with Sertraline for some patients.

Seizure-- Sertraline should be introduced with care in patients with a seizure disorder.

Suicide-- The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Prescriptions for Sertraline should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Weak Uricosuric Effect-- Sertraline hydrochloride is associated with a mean decrease in serum uric acid of approximately 7%.

Use in Patients with Concomitant Illness-- Caution is advisable in using Sertraline in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

In patients with chronic mild liver impairment, Sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life.

Interference with Cognitive and Motor Performance-- Sertraline did not cause sedation and did not interfere with psychomotor performance.

Hyponatremia-- Several cases of hyponatremia have been reported and appeared to be reversible when Sertraline was discontinued.

Pregnancy--Pregnancy Category C, There are no adequate and well-controlled studies in pregnant women. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers-- Because many drugs are excreted in human milk, caution should be exercised when Sertraline is administered to a nursing woman.

Pediatric Use-- The efficacy of Sertraline in pediatric patients with major depressive disorder, panic disorder, PTSD, PMDD or social anxiety disorder has not been systematically evaluated. As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of Sertraline.

Geriatric Use-- No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.

As with other SSRIs, Sertraline has been associated with cases of clinically significant hyponatremia in elderly patients.

Drug Interactions:

Because Sertraline is tightly bound to plasma protein, the administration of Sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) 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. Accordingly, prothrombin time should be carefully monitored when Sertraline therapy is initiated or stopped.

CNS Active Drugs-- It is recommended that plasma lithium levels be monitored following initiation of Sertraline therapy with appropriate adjustments to the lithium dose.

Due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of Sertraline and pimozide should be contraindicated.

Caution is advised if the concomitant administration of Sertraline and CNS active drugs is required.

The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

Monoamine Oxidase Inhibitors--

Drugs Metabolized by P450 3A4-- These data indicate that Sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that Sertraline 200 mg (q.d.) induces the metabolism of cisapride.

Drugs Metabolized by P450 2D6-- Concomitant use of a drug metabolized by P450 2D6 with Sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever Sertraline is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.

Sumatriptan-- If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, Sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)-- Caution is indicated in the co-administration of TCAs with Sertraline, because Sertraline may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.

Hypoglycemic Drugs-- Sertraline administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.

Microsomal Enzyme Induction-- Sertraline induces hepatic microsomal enzymes.

Alcohol-- The concomitant use of Sertraline and alcohol is not recommended.

SIDE EFFECTS:

Physical and Psychological Dependence-- 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.

OVERDOSAGE:

The most common signs and symptoms associated with non-fatal Sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. 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. Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for Sertraline are known.

DOSAGE AND ADMINISTRATION:

 Dosage for Adults

Major Depressive Disorder and Obsessive-Compulsive Disorder-- Sertraline treatment should be administered at a dose of 50 mg once daily.

Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder-- Sertraline treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.

Premenstrual Dysphoric Disorder-- Sertraline treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.

Dosage for Pediatric Population (Children and Adolescents)

Obsessive-Compulsive Disorder-- Sertraline treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).

Dosage for Hepatically Impaired Patients-- If Sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.

Maintenance/Continuation/Extended Treatment

Major Depressive Disorder-- It is not known whether the dose of Sertraline needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.

Posttraumatic Stress Disorder-- It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. It is not known whether the dose of Sertraline needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.

Social Anxiety Disorder-- Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

Obsessive-Compulsive Disorder and Panic Disorder-- It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Premenstrual Dysphoric Disorder-- Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients to or from a Monoamine Oxidase Inhibitor-- At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Sertraline. In addition, at least 14 days should be allowed after stopping Sertraline before starting an MAOI.

How Supplied: Each Package of Ruz-Sertraline 50 mg tablets contains 100 film coated tablets in 10 blisters.

storage: Store at 15°-30°C.

Reference: PDR 2000, page 2399-2404

                  USPDI Vol for Professional Health Care, 2004, Page 2530-2535

                  Martindale 2005, Page 317-9