ZOLOFT
Sertraline hydrochloride 50 mg, 100 mg tablets Registered trademark of Pfizer Inc
Presentation
White film-coated tablets containing sertraline hydrochloride equivalent to 50 mg sertraline, with the Pfizer logo on one side and code ZLT-50 on the other. Approximate tooling dimensions are 1.03cm x 0.42cm x 0.36cm.
White film-coated tablets containing sertraline hydrochloride equivalent to 100 mg sertraline, with the Pfizer logo on one side and code ZLT-100 on the other. Approximate tooling dimensions are 1.31cm x 0.52cm x 0.44cm.
Zoloft tablets include the following inert ingredients: Calcium hydrogen phosphate, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate, white opadry, clear opadry.
Actions
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 noradrenaline and dopamine neuronal reuptake. 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 downregulation of brain noradrenaline receptors as observed with other clinically effective antidepressants and antiobsessional drugs.
Sertraline has not demonstrated potential for abuse. In a placebo-controlled, double blind, randomised 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 -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 to 200 mg. In man, following oral once daily dosing over the range of 50 to 200 mg for 14 days, peak plasma concentrations (Cmax) of sertraline occur at about 4.5 to 8.4 hours 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 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady state concentrations, which are achieved after one 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. The pharmacokinetics of sertraline in paediatric OCD patients have been shown to be comparable with adults (although paediatric patients metabolise sertraline with slightly greater efficiency). However, lower doses may be advisable for paediatric patients given their lower body weights (especially 6-12 years), in order to avoid excessive plasma levels.
Sertraline undergoes extensive first pass hepatic metabolism. The principal metabolite in plasma, N-desmethylsertraline, is substantially less active (about 20 times than sertraline) 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 hours. Sertraline and N-desmethylsertraline are both extensively metabolised in man and the resultant metabolites excreted in faeces 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 tablets.
Indications
ZOLOFT is indicated for the treatment of symptoms of depression, including depression accompanied by symptoms of anxiety, in patients with or without a history of mania. Following satisfactory response, continuation with ZOLOFT therapy is effective in preventing relapse of the initial episode of depression or recurrence of further depressive episodes.
Zoloft is indicated for the treatment of obsessive compulsive disorder (OCD). Following initial response, sertraline has been associated with sustained efficacy, safety and tolerability in up 2 years of treatment of OCD.
Zoloft is indicated for the treatment of paediatric patients with OCD.
Zoloft is indicated for the treatment of panic disorder, with or without agoraphobia.
Dosage and Administration
ZOLOFT should be administered once daily, either in the morning or evening.
ZOLOFT tablets can be administered with or without food.
Initial Treatment
Depression and OCD - Sertraline treatment should be administered at a dose of 50 mg/day.
Panic Disorder - Therapy for panic disorder should be initiated at 25 mg/day. After one 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 and Panic Disorder - Patients not responding to a 50 mg dose may benefit from dose increases. Dose changes should be made at intervals of at least one week, up to a maximum of 200 mg/day.
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.
Use in Children - The safety and efficacy of sertraline has been established in paediatric OCD patients aged 6 to 17. The administration of sertraline to paediatric OCD patients (aged 13 to 17) should commence at 50 mg/day. Therapy for paediatric OCD patients (aged 6 to 12) should commence at 25 mg/day, increasing to 50 mg/day after one week. Subsequent doses may be increased in case of lack of response in 50 mg/day increments, up to 200 mg/day, as needed. In a clinical trial in patients aged 6 to 17 years with depression or OCD, sertraline appeared to have a similar pharmacokinetic profile to that found in adults. However, the generally lower body weights of children compared to those of adults should be taken into consideration in advancing the dose from 50 mg, in order to avoid excessive dosing.
Titration in Children and Adolescents - Sertraline has an elimination half-life of approximately one day; dose changes should not occur at intervals of less than one week.
Use in the 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.
Use in 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 in patients with hepatic impairment (see WARNINGS AND PRECAUTIONS).
Use in Renal Insufficiency - Sertraline is extensively metabolised. 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 WARNINGS AND PRECAUTIONS).
Use in Children
More than 250 paediatric OCD patients have been exposed to sertraline in completed and ongoing studies. The safety profile of sertraline in these paediatric studies is comparable to that observed in adult OCD studies. The efficacy of sertraline in paediatric patients with depression or panic has not been demonstrated in controlled trials. Safety and effectiveness in paediatric patients below the age of 6 have not been established.
Contraindications
ZOLOFT is contraindicated in patients with a known hypersensitivity to sertraline.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see Warnings and Precautions ).
Warnings and Precautions
Monoamine Oxidase Inhibitors
Cases of serious reactions, sometimes fatal, have been reported in patients receiving sertraline in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI, selegiline and the reversible MAOI, moclobemide. Some cases presented with features resembling serotonin syndrome the symptoms of which include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. Therefore, sertraline should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should elapse after discontinuing sertraline treatment before starting an MAOI (see Contraindications ).
Other Serotonergic Drugs
Coadministration of sertraline with other drugs which enhance the effects of serotonergic neurotransmission, such as tryptophan or fenfluramine or 5-HT agonists, should be undertaken with caution and avoided whenever possible due to the potential for pharmacodynamic interaction (see Interactions ).
Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), Antidepressants or Antiobsessional Drugs
There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or antiobsessional drugs to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents such as fluoxetine. The duration of washout period which should intervene before 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 for depression. No seizures were reported in patients treated with sertraline in the development program for panic. During the development program for OCD, four out of approximately 1,800 patients exposed to sertraline experienced seizures (approximately 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. 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. Sertraline should be discontinued in any patient who develops seizures.
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.
Withdrawal
Withdrawal effects may occur and dosage may need to be tapered when discontinuing treatment, particularly for those on higher doses.
Use in Hepatic Insufficiency
Sertraline is extensively metabolised by the liver. A multiple dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and approximately three-fold greater AUC and Cmax in comparison to normal subjects. There were no significant differences in plasma protein binding observed between the two 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.
Use in Renal Insufficiency
Sertraline is extensively metabolised. Excretion of unchanged drug in urine is a minor route of elimination. In studies of 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 (AUC0-24 or Cmax) 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.
Driving/Use of Machinery
Clinical pharmacology studies have shown that sertraline has no effect on psychomotor performance. However, as psychotropic drugs may impair the mental or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery, the patient should be cautioned accordingly.
Use in Pregnancy and 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 to 10 times the maximum daily human mg/kg dose, however, sertraline was associated with delayed ossification processes in foetuses, probably secondary to effects on the dams.
There was decreased neonatal survival following maternal administration of sertraline at doses of 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 women. 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.
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.
Women of childbearing potential should employ an adequate method of contraception if taking sertraline.
Adverse Effects
Clinical Trial Data
Side effects that occurred significantly more frequently with sertraline than with placebo in multiple dose studies for depression and OCD were:
- Autonomic Nervous System - Dry mouth and increased sweating.
- Central and Peripheral Nervous System - Dizziness and tremor.
- Gastrointestinal - Diarrhoea/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 and panic disorder was similar to that observed in clinical trials in patients with depression.
Unlike tricyclic antidepressants, no weight gain is observed in controlled clinical trials with sertraline treatment for depression or OCD; some patients may experience
a reduction in body weight with sertraline.
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, asthenia, fatigue, fever and hot flushes.
- Cardiovascular - Chest pain, hypertension, palpitations, periorbital oedema, syncope and tachycardia.
- Central and Peripheral Nervous System: Coma, convulsions, headache, migraine, movement disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, teeth grinding or gait abnormalities), 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, diarrhoea, fever, hypertension, rigidity and tachycardia.
- Endocrinological - Galactorrhea, hyperprolactinemia and hypothyroidism.
- Gastrointestinal - Abdominal pain, pancreatitis and vomiting.
- Haematopoietic - Altered platelet function, abnormal bleeding (such as epistaxis, gastrointestinal bleeding or hematuria), leucopoenia, purpura and hrombocytopenia.
- 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.
- Psychiatric - Agitation, aggressive reaction, anxiety, depressive symptoms, hallucination and psychosis.
- Reproductive - Menstrual irregularities.
- Respiratory - Bronchospasm.
- Skin - Alopecia, angiooedema and rash (including rare reports of serious exfoliative skin disorders).
- Urinary - Face oedema and urinary retention.
- Other - Symptoms following the discontinuation of sertraline have been reported and included agitation, anxiety, dizziness, headache, nausea and paresthesia.
Interactions
Monoamine Oxidase Inhibitors
See Contraindications and Warnings and Precautions.
CNS Depressants and Alcohol
The co-administration of sertraline 200mg 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, such as lithium, which may act via serotonergic mechanisms, 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 Warnings and Precautions).
Serotonergic Drugs
(see Warnings and Precautions )
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 three 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 subsections Warfarin, CNS Active Drugs and Hypoglycaemic Drugs ).
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 ( see subsection CYP 2C9 ).
Cimetidine
Co-administration of sertraline with cimetidine caused a substantial decrease in sertraline clearance. The clinical significance of this change is unknown.
CNS active drugs
Co-administration of sertraline 200mg daily with diazepam resulted in small, statistically significant changes in some pharmacokinetic parameters. The clinical significance of these changes is unknown.
Hypoglycaemic drugs
Co-administration of sertraline 200mg daily with tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters. The clinical significance of these changes is unknown.
Sertraline 200mg daily did not affect the pharmacokinetics of glibenclamide.
Patients receiving biguanides should monitor their blood glucose carefully when sertraline is introduced.
Atenolol
Sertraline had no effect on the beta-adrenergic blocking ability of atenolol.
Digoxin
Sertraline 200mg daily did not change serum digoxin levels or digoxin renal clearance.
Electroconvulsive Therapy (ECT)
There are no clinical studies establishing the risks or benefits of the combined use of ECT and sertraline.
Drugs Metabolised by Cytochrome P450 (CYP) 2D6
There is variability among antidepressants in the extent to which they inhibit the activity of isozyme cytochrome CYP 2D6 The clinical significance of this depends on the extent of the inhibition and the therapeutic index of the co-administered drug. CYP 2D6 substrates with a narrow therapeutic index include TCAs and class 1C antiarrhythmics such as propafenone and flecainide. In formal interaction studies, chronic dosing with sertraline 50mg daily showed minimal elevation (mean 23-37%) of steady state desipramine plasma levels (a marker of CYP 2D6 isoenzyme activity).
Drugs Metabolised by Other CYP Enzymes (CYP 3A3/4, CYP 2C9, CYP 2C19, CYP 1A2)
CYP 3A3/4 - In vivo interaction studies have demonstrated that chronic administration of sertraline 200 mg daily does not inhibit the CYP 3A3/4 mediated 6-b 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 CYP 3A3/4 mediated metabolism of alprazolam. The results of these studies suggest that sertraline is not a clinically relevant inhibitor of CYP 3A/34.
CYP 2C9 - 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 CYP 2C9.
CYP 2C19 - 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.
CYP 1A2 - In vitro studies indicate that sertraline has little or no potential to inhibit CYP 1A2.
Overdosage
On the evidence available, sertraline has a wide margin of safety in overdose. An overdose of sertraline alone of up to 13.5g has been reported. Deaths have been reported involving overdoses of sertraline, primarily in combination with other drugs and/or alcohol. Therefore, any overdosage should be treated aggressively. Symptoms of overdose include serotonin-mediated side effects such as somnolence, gastrointestinal disturbances (such as 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 and 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 sign 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.
Pharmaceutical Precautions
Store below 30°C
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