Apo-Sertraline

Sertraline hydrochloride.

Each capsule/tablet contains sertraline hydrochloride equivalent to 50mg of sertraline base.

Pharmacology: Pharmacodynamics: Sertraline is a potent and specific inhibitor of neuronal serotonin (5-HT) uptake in vitro which results in the potentiation of the effects of 5-HT in animals. It has only very weak effects on norepinephrine and dopamine neuronal re-uptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets. It is devoid of stimulant, sedative or anticholinergic activity or cardiotoxicity in animals. In controlled studies in normal volunteers, sertraline did not cause sedation and did not interfere with psychomotor performance. In accord with its selective inhibition of 5-HT uptake, sertraline does not enhance catecholaminergic activity. Sertraline has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA or benzodiazepine receptors. The chronic administration of sertraline in animals was associated with down-regulation of brain norepinephrine receptors as observed with other clinically effective antidepressant and antiobsessional drugs.
No weight gain was observed in controlled clinical trials with sertraline treatment for depression or OCD; some patients may experience a reduction in body weight with sertraline.
Sertraline has not demonstrated potential for abuse. 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 positive subjective effects indicative of abuse potential. In contrast, subjects rated both alprazolam and d-amphetamine significantly greater than placebo on measures of drug liking, euphoria and abuse potential. Sertraline did not produce either the stimulation and anxiety associated with d-amphetamine or the sedation and psychomotor impairment associated with alprazolam. Sertraline does not function as a positive reinforcer in rhesus monkeys trained to self-administer cocaine, nor does it substitute as a discriminative stimulus for either d-amphetamine or pentobarbital in rhesus monkeys.
Pharmacokinetics: Sertraline exhibits dose proportional pharmacokinetics over the range of 50-200 mg. In man, following oral once-daily dosing over the range of 50-200 mg for 14 days, peak plasma concentrations (C_max) of sertraline occur at about 4.5-8.4 hrs post-dosing. The pharmacokinetic profile in either adolescents or the elderly is not significantly different from that in adults between 18 and 65 years. The mean half-life of sertraline for young and elderly men and women ranges from 22-36 hrs. Consistent with the terminal elimination half-life, there is an approximately 2-fold accumulation up to steady-state concentration, which are achieved after 1 week of once-daily dosing. Approximately 98% of the circulating drug is bound to plasma proteins. Animal studies indicate that sertraline has a large apparent volume of distribution.
Sertraline undergoes extensive first-pass hepatic metabolism. The principal metabolite in plasma, N-desmethylsertraline, is substantially less active than sertraline (about 20 times) in vitro and there is no evidence of activity in in vivo models of depression. The half-life of N-desmethylsertraline is in the range of 62-104 hrs. Sertraline and N-desmethylsertraline are both extensively metabolized in man and the resultant metabolites excreted in feces and urine in equal amounts. Only a small amount (<0.2%) of unchanged sertraline is excreted in the urine.
Food does not significantly change the bioavailability of sertraline.
Toxicology: Preclinical Safety Data: Extensive chronic safety evaluation studies in animals show that sertraline is generally well tolerated at doses that are appreciable multiples of those that are clinically effective. Sertraline has also been shown to be devoid of mutagenic effects.

Treatment of symptoms of depression, including depression accompanied by symptoms of anxiety, in patients with or without history of mania. Following satisfactory response, continuation with sertraline therapy is effective in preventing relapse of the initial episode of depression or recurrence of further depressive episodes.
Treatment of obsessive-compulsive disorders (OCD). Following initial response, sertraline has been associated with sustained efficacy, safety and tolerability in up to 2 years of treatment of OCD.
Treatment of panic disorder, with or without agoraphobia; posttraumatic stress disorder (PTSD).

Sertraline should be administered once daily, either in the morning or evening. Sertraline can be administered with or without food.
Initial Treatment: Depression and OCD: 50 mg/day.
Panic Disorder and PTSD: Therapy should be initiated at 25 mg/day. After 1 week, the dose should be increased to 50 mg once daily. This dosage regimen has been shown to reduce the frequency of early treatment emergent side effects characteristic of panic disorder.
Titration: Depression, OCD, Panic Disorder and PTSD: Patients not responding to a 50-mg dose may benefit from dose increases. Dose changes should be made at intervals of at least 1 week, up to a maximum of 200 mg/day. Changes in dose should not be made more frequently than once per week given the 24-hr elimination half-life of sertraline.
The onset of therapeutic effect may be seen within 7 days. However, longer periods are usually necessary to demonstrate therapeutic response, especially in OCD.
Maintenance: Dosage during long-term therapy should be kept at the lowest effective level, with subsequent adjustment depending on therapeutic response.
Elderly: The same dose range as in younger patients may be used in the elderly. Over 700 elderly patients (>65 years) have participated in clinical studies which demonstrated the efficacy of sertraline in this patient population. The pattern and incidence of adverse reactions in the elderly was similar to that in younger patients.
Hepatic Insufficiency: The use of sertraline in patients with hepatic disease should be approached with caution. A lower or less frequent dose should be used (see Precautions).
Renal Insufficiency: Sertraline is extensively metabolized. Excretion of unchanged drug in urine is a minor route of elimination. As expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment (see Precautions).

SYMPTOMS AND TREATMENT OF OVERDOSAGE: On the evidence available, sertraline has a wide margin of safety in overdose. Overdoses of sertraline alone of up to 13.5 g have been reported. Deaths involving overdoses of sertraline primarily in combination with other drugs and/or alcohol have been reported. Therefore, any overdosage should be treated aggressively. Symptoms of overdose include serotonin-mediated side effects eg, somnolence, gastrointestinal disturbances (eg, nausea and vomiting), tachycardia, tremor, agitation and dizziness. Less frequently reported was coma.
There are no specific antidotes to sertraline. Establish and maintain an airway, ensure adequate oxygenation and ventilation, if necessary. Activated charcoal, which may be used with a cathartic, may be as or more effective than lavage, and should be considered in treating overdose. Induction of emesis is not recommended. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

Patients with known hypersensitivity to sertraline. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) (see Precautions).
Tablet: Concomitant use in patients taking pimozide is contraindicated (see Interactions).

Switching from Selective Serotonin Re-Uptake Inhibitors (SSRIs), Antidepressants or Antiobsessional Drugs: There is limited controlled experience regarding the optimal timing of switching from other antidepressants or antiobsessional drugs to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents eg, fluoxetine. The duration of a washout period for switching from one SSRI to another has not been established.
Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 0.4% 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 antidepressant and antiobsessional drugs.
Seizures: Seizures are a potential risk with antidepressant and antiobsessional drugs. Seizures were reported in approximately 0.08% of patients treated with sertraline in the development program of depression. No seizures were reported in patients treated with sertraline in the development program for panic. During the development program for OCD, 4 out of approximately 1800 patients exposed to sertraline experienced seizures (approximately 0.2%). Three of these patients were adolescents, 2 with seizure disorder and 1 with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. In all these cases, the relationship to sertraline therapy was uncertain. Since sertraline has not been evaluated in patients with a seizure disorder, it should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. The drug should be discontinued in any patients who develops seizures.
Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.
Suicide: Since the possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs, patients should be closely supervised during the early course of therapy.
Because of the well-established co-morbidity between OCD and depression, panic disorder and depression, and PTSD and depression, the same precautions observed when treating patients with depression should be observed when treating patients with OCD, panic disorder or PTSD.
Hepatic Insufficiency: Sertraline is extensively metabolized by the liver. A multiple-dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and approximately 3-fold greater AUC and C_max in comparison to normal subjects. There were no significant differences in plasma protein-binding observed between the 2 groups. The use of sertraline in patients with hepatic disease should be approached with caution. A lower or less frequent dose should be used in patients with hepatic impairment.
Renal Insufficiency: Sertraline is extensively metabolized. Excretion of unchanged drug in 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.
Effects on the Ability to Drive or Operate Machinery: Clinical pharmacology studies have shown that sertraline has no effect on psychomotor performance. However, as psychotropic drugs may impair the mental or physical abilities required for the performance of potentially hazardous tasks eg, driving a car or operating machinery, the patient should be cautioned accordingly.
Use in Pregnancy & Lactation: Reproduction studies have been performed in rats and rabbits at doses up to approximately 20 and 10 times the maximum daily human mg/kg dose, respectively. There was no evidence of teratogenicity at any dose level. At the dose level corresponding to approximately 2.5-10 times the maximum daily human mg/kg dose, however, sertraline was associated with delayed ossification in fetuses, probably secondary to effects on the dams.
There was decreased neonatal survival following maternal administration of sertraline at doses approximately 5 times the maximum human mg/kg dose. Similar effects on neonatal survival have been described for other antidepressant drugs. The clinical significance of these effects is unknown.
There are no adequate and well-controlled studies in pregnant woman. Because animal reproduction studies are not always predictive of human response, sertraline should be used during pregnancy only if the perceived benefits outweigh the risks. Women of childbearing potential should employ an adequate method of contraception if taking sertraline.
Limited data concerning sertraline levels in breast milk are available. Isolated studies in very small numbers of nursing mothers and their infants indicated negligible or undetectable levels of sertraline in infant serum, although levels in breast milk were more concentrated than in maternal serum. Use in nursing mothers is not recommended unless, in the judgment of the physician, the benefit outweighs the risk.
If sertraline is used during pregnancy and/or lactation, the physician should be aware that symptoms, including those compatible with withdrawal reactions, have been reported in some neonates whose mothers had been on SSRI antidepressants, including sertraline.

Reproduction studies have been performed in rats and rabbits at doses up to approximately 20 and 10 times the maximum daily human mg/kg dose, respectively. There was no evidence of teratogenicity at any dose level. At the dose level corresponding to approximately 2.5-10 times the maximum daily human mg/kg dose, however, sertraline was associated with delayed ossification in fetuses, probably secondary to effects on the dams.
There was decreased neonatal survival following maternal administration of sertraline at doses approximately 5 times the maximum human mg/kg dose. Similar effects on neonatal survival have been described for other antidepressant drugs. The clinical significance of these effects is unknown.
There are no adequate and well-controlled studies in pregnant woman. Because animal reproduction studies are not always predictive of human response, sertraline should be used during pregnancy only if the perceived benefits outweigh the risks. Women of childbearing potential should employ an adequate method of contraception if taking sertraline.
Limited data concerning sertraline levels in breast milk are available. Isolated studies in very small numbers of nursing mothers and their infants indicated negligible or undetectable levels of sertraline in infant serum, although levels in breast milk were more concentrated than in maternal serum. Use in nursing mothers is not recommended unless, in the judgment of the physician, the benefit outweighs the risk.
If sertraline is used during pregnancy and/or lactation, the physician should be aware that symptoms, including those compatible with withdrawal reactions, have been reported in some neonates whose mothers had been on SSRI antidepressants, including sertraline.

Clinical Trial Data: Side effects that occurred significantly more frequently with sertraline than with placebo in multiple-dose studies for depression were: Autonomic Nervous System: Dry mouth and increased sweating.
Central and Peripheral Nervous System: Dizziness and tremor.
Gastrointestinal: Diarrhea/loose stools, dyspepsia and nausea.
Psychiatric: Anorexia, insomnia and somnolence.
Reproductive: Sexual dysfunction (principally ejaculatory delay in males).
The side effect profile commonly observed in double-blind, placebo-controlled studies in patients with OCD, panic disorder and PTSD was similar to that observed in clinical trials in patients with depression.
Post-Marketing Data: Voluntary reports of adverse events in patients receiving sertraline since market introduction have been received.
They include the following: Autonomic Nervous System: Mydriasis and priapism.
Body as a Whole: Allergic reaction, allergy, anaphylactoid reaction, asthenia, fatigue, fever, hot flushes, malaise, decreased and increased weight.
Cardiovascular: Chest pain, edema peripheral, hypertension, palpitations, periorbital edema, syncope and tachycardia.
Central and Peripheral Nervous System: Coma, convulsions, headache, migraine, movement disorders (including extrapyramidal symptoms eg, hyperkinesia, hypertonia, teeth grinding or gait abnormalities), involuntary muscle contractions, paresthesia and hypoesthesia. Also reported were signs and symptoms associated with serotonin syndrome: In some cases associated with concomitant use of serotonergic drugs, that included agitation, confusion, diaphoresis, diarrhea, fever, hypertension, rigidity and tachycardia.
Endocrinological: Galactorrhea, gynecomastia, hyperprolactinemia, hypothyroidism and syndrome of inappropriate ADH secretion (SIADH).
Gastrointestinal: Abdominal pain, increased appetite, constipation, pancreatitis, vomiting and microscopic colitis.
Hearing/Vestibular: Tinnitus.
Hematopoietic: Altered platelet function, abnormal bleeding (eg, epistaxis, gastrointestinal bleeding or hematuria), leucopenia, purpura and thrombocytopenia.
Laboratory Changes: Abnormal clinical laboratory results.
Liver/Biliary: Serious liver events (including hepatitis, jaundice and liver failure) and asymptomatic elevations in serum transaminases (SGOT and SGPT).
Metabolic/Nutritional: Hyponatremia and increased serum cholesterol.
Musculoskeletal: Arthralgia.
Psychiatric: Agitation, aggressive reaction, anxiety, depressive symptoms, euphoria, hallucination, decreased libido in male and female, paroniria, psychosis and yawning.
Reproductive: Menstrual irregularities.
Respiratory: Bronchospasm.
Skin: Alopecia, angioedema, photosensitivity skin reaction, pruritus, rash (including rare reports of serious exfoliative skin disorders eg, Stevens-Johnson syndrome and epidermal necrolysis) and urticaria.
Urinary: Face edema, urinary incontinence and urinary retention.
Vision: Abnormal vision.
Others: Symptoms following the discontinuation of sertraline have been reported and included agitation, anxiety, dizziness, headache, nausea and paresthesia.

Monoamine Oxidase Inhibitors: Cases of serious reactions, sometimes fatal, have been reported in patients receiving sertraline in combination with a MAOI, including the selective MAOI, selegiline, and the reversible MAOI, moclobemide. Some cases presented with features resembling the serotonin syndrome, these symptoms 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 a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing sertraline treatment before starting on MAOI.
Other Serotonergic Drugs: Co-administration of sertraline with other drugs which enhance serotonergic neurotransmission eg, tryptophan or fenfluramine, should be undertaken with caution and avoided whenever possible due to the potential for pharmacodynamic interaction.
CNS Depressants and Alcohol: The co-administration of sertraline 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of sertraline and alcohol is not recommended.
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 eg, lithium, which may act via serotonergic mechanism, patients should be appropriately monitored.
Phenytoin: A placebo-controlled trial in normal volunteers suggests that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline therapy, with appropriate adjustments to the phenytoin dose.
Sumatriptan: There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety and agitation following the use of sertraline and sumatriptan. If concomitant treatment with sertraline and sumatriptan is clinically warranted, appropriate observation of the patient is advised (see Other Serotonergic Drugs as previously mentioned).
Protein-Bound Drugs: Since sertraline is bound to plasma proteins, the potential of sertraline to interact with other plasma protein-bound drugs should be borne in mind. However, in 3 formal interaction studies with diazepam, tolbutamide and warfarin, respectively, sertraline was not shown to have significant effects on the protein-binding of the substrate (see Warfarin and Other Drug Interactions as follows).
Warfarin: Co-administration of sertraline 200 mg daily with warfarin resulted in a small but statistically significant increase in prothrombin time, the clinical significance of which is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.
Other Drug Interactions: Formal drug interaction studies have been performed with sertraline. Co-administration of sertraline 200 mg daily with diazepam or tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters. Co-administration with cimetidine caused a substantial decrease in sertraline clearance. The clinical significance of these changes is unknown. Sertraline had no effect on the β-adrenergic-blocking ability of atenolol. No interaction of sertraline 200 mg daily was observed with glibenclamide or digoxin.
Drugs Metabolized by Cytochrome P-450 (CYP) 2D6: There is variability among antidepressants in the extent to which they inhibit the activity of isozyme CYP2D6. The clinical significance of this depends on the extent of the inhibition and the therapeutic index of the co-administered drug. CYP2D6 substrates with a narrow therapeutic index include TCAs and class 1C antiarrhythmics eg, propafenone and flecainide. In formal interaction studies, chronic dosing with sertraline 50 mg daily showed minimal elevation (mean 23-37%) of steady-state desipramine plasma levels (a marker of CYP2D6 isoenzyme activity).
Drugs Metabolized by Other CYP Enzymes (CYP3A¾, CYP2C9, CYP2C19, CYP1A2): CYP3A¾: In vivo interaction studies have demonstrated that chronic administration of sertraline 200 mg daily does not inhibit the CYP3A¾ mediated 6-β hydroxylation of endogenous cortisol or the metabolism of carbamazepine or terfenadine. In addition, the chronic administration of sertraline 50 mg daily does not inhibit the CYP3A¾-mediated metabolism of alprazolam. The results of these studies suggest that sertraline is not a clinically relevant inhibitor of CYP3A/34.
CYP2C9: The apparent lack of clinically significant effects of the chronic administration of sertraline 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that sertraline is not a clinically relevant inhibitor of CYP2C9 (see Other Drug Interactions, Phenytoin and Warfarin as previously mentioned).
CYP2C19: The apparent lack of clinically significant effects of the chronic administration of sertraline 200 mg daily on plasma concentrations of diazepam suggests that sertraline is not a clinically relevant inhibitor of CYP 2C19 (see Other Drug Interactions as previously mentioned).
CYP1A2: In vitro studies indicate that sertraline has little or no potential to inhibit CYP1A2.
Electroconvulsive Therapy (ECT): There are no clinical studies establishing the risks or benefits of the combined use of ECT and sertraline.
Tablet: Pimozide: Increased pimozide levels have been demonstrated in a study of a single low dose of pimozide (2mg) with sertraline co-administration. These increased levels were not associated with any changes in ECG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant use of pimozide and sertraline is contraindicated.

Incompatibilities: None.

APO-SERTRALINE should be stored below 25°C.

Antidepressants

N06AB06 - sertraline ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

POM