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Zorest

Reals Pharmaceuticals Limited
Plot 1 Junaid Dosunmu Street,Central Business District, Alausa, P.0. Box 3560 Ikeja, Lagos, Nigeria.
Email: reals@realsgroup.com
Tel: + 234-1-774-1205
Fax: +234-1-263-0919
Website: http://realsgroup.com

Brand Name

Zorest

Manufacturer

Medibios Laboratories Pvt. Ltd. J/176, M.I.D.C., Tarapur, Thane- 401 506, India.

Therapeutic Class

Antidepressants and mood stabilisers

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Tablet(NRN:A4·9022 ): Each film-coated tablet contains: Sertraline Hydrochloride E P. equivalent to Sertraline 25 mg, Sertraline Hydrochloride EP. equivalent to Sertraline 50 mg, Sertraline Hydrochloride E.P. equivalent to Sertraline 100 mg;

Pack size: ZOREST 25, 50, 100 Tablets: Tablets are packed in blister strips. Carton containing 30 tablets.

Pharmacology

PHARMACOLOGICAL ACTION

Mechanism of action

Sertraline, a naphthaleneamine derivative, is a selective serotonin reuptake inhibitor (SSRI). Sertraline has only weak effects on neuronal reuptake of norepinephrine and dopamine. Chronic administration of sertraline in animals has resulted in downregulation of post-synaptic beta-adrenergic receptors.

Sertraline's inhibition of serotonin reuptake enhances serotonergic transmission, which results in subsequent inhibition of adrenergic activity in the locus ceruleus. Sertraline has no specific affinity for adrenergic (alpha 1, alpha 2, or beta) receptors, muscarinic cholinergic receptors, gamma-aminobutyric acid receptors, dopaminergic receptors, histaminergic receptors, serotonergic (5HT1A, 5HT1B, 5HT2) or benzodiazepine receptors. Sertraline does not inhibit monoamine oxidase.

Pharmacokinetics

After oral administration, sertraline is slowly absorbed. It undergoes rapid first pass metabolism. The Cmax and the AUC are proportional to the dose over the range of 50-200 mg of sertraline, demonstrating linear pharmacokinetics. Sertraline undergoes extensive first pass metabolism in the liver. After once-daily dosing of sertraline, steady state plasma concentrations are reached In about 7 days in adult subjects and after 2-3 weeks in older patients.

The primary initial pathway of sertraline metabolism is N-demethylation to form N-desmethylsertraline, which is substantially less active than the parent compound, exhibiting only about 1/8 in of its activity. Both sertraline and desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation.

The elimination half-lives of sertraline and desmethylsertraline are 24-26 and 62-104 hours respectively. Both sertraline and its metabolite, desmethylsertraline are extensively distributed into the tissues, the volume of distribution for the parent compound being about 76 L/kg. The plasma protein binding is greater than 98%. About 40-45% of an administered radioactive dose was recovered in the urine within 9 days with less than 0.2% recovered unchanged; faecal recovery is 40-45%, including 12-14% unchanged sertraline.

The clearance of sertraline is about 38 ± 14 mL/min/kg in healthy, young subjects which is decreased by about 40% in older individuals. Clearance of desmethylsertraline is also decreased in older men but not in older women.

The pharmacokinetics of sertraline have not been studied in patients with significant renal Impairment.
Since sertraline is extensively metabolised in the liver. Its metabolism may be altered in hepatic function impairment. Therefore caution is advised when sertraline is administered to such patients; a lower dose or less frequent dosing should be considered.

Indications

ZOREST is indicated for the treatment of symptoms of major depressive illness such as single episodes and recurrence of further depressive episodes. Sertraline is also indicated for the treatment of obsessive compulsive disorder (OCD).

Contra-indications

ZOREST is contra-indicated in patients who have shown hypersensitivity to any components of the product. Concomitant use of ZOREST in patents taking monoamine oxidase inhibitor (MAOls) is contra-Indicated (see Warnings). Pregnancy and lactation as safety has not been established.

Precautions/Warnings

WARNINGS:

Severe adverse reactions including the serotonin syndrome may occur if ZOREST is administered with a monoamine oxidase inhibitor (MAOI). Although no clinical data are available demonstrating the effects of the combined use of ZOREST and monoamine oxidase inhibitors (MAOI), it is prudent to avoid their combined use until specific data are available, as experience suggests that the combination may produce a potentially lethal serotonin syndrome. A wash-out period of at least 14 days should elapse between discontinuation of one medication and initiation of the other.

ZOREST should be used with caution in patients with epilepsy or a history of similar disorders and should be avoided if epilepsy is poorly controlled. Renal excretion is a minor route of elimination of sertraline.

However, sertraline pharmacokinetics have not been studied in patients with renal impairment and the safety of ZOREST in patients with severe renal impairment and the dose adjustments required, if any have not been established.

Caution should be exercised when ZOREST is administered to such patients. Sertraline is extensively metabolised in the liver. A lower or less frequent dose may be required in patients with significant liver function impairment.

While switching from other antidepressant or anti-obsessional medicines to ZOREST, care and prudent medical judgement should be exercised since there is limited controlled experience. No data are available on the concomitant use of ZOREST with serotonergic medicines such as sumatriptan, tryptophan or fenfluramine.

Therefore, these medicines should not be used concomitantly. The possibility of a suicide attempt is inherent in patients with depressive illness. Close supervision of high risk patients should accompany the administration of ZOREST. There are no clinical studies establishing the risks of benefits of the combined use of electroconvulsive therapy (ECT) and sertraline. Clinical studies with sertraline have clearly shown a lack of any adverse effect on the psychomotor performance.

However, since antidepressant or anti-obsessional medicines may impair the abilities required to perform potentially hazardous tasks such as driving a car or operating machinery, the patient should be cautioned accordingly. There have been reports of activation of mania/hypomania.

Significant weight loss, although less frequently reported with the use of sertraline, may be undesirable in some patients. Mean decreases of approximately 7% in the serum uric acid have been reported with sertraline use. However, the clinical significance of this finding is not known and there have been no reports of acute renal failure with sertraline.

Sertraline has not been shown to cause sedation or alter psychomotor performance. Electrocardiographic studies have shown that sertraline does not cause any significant ECG abnormalities. However, sertraline has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. The concomitant use of ZOREST and alcohol in depressed patients is not recommended.

Special Precautions

Extrapyramidal symptoms and an aggravation of Parkinson's disease have been observed with SSRls. Caution should be exercised when ZOREST is administered to such patients and careful monitoring should be done. Withdrawal symptoms may occur if ZOREST is discontinued abruptly. These include dizziness, sweating, nausea, insomnia, tremor, confusion, sensory disturbances, agitation and anxiety.

Caution in concurrent use of highly protein bound medicines with ZOREST is recommended because of possible displacement of either medication from protein binding sites, leading to Increased plasma concentrations of the free medicine and increased risk of adverse effects.

Paediatrics: Safety and efficacy of ZOREST in paediatric patients have not been established.

Geriatrics: No geriatrics-specific problems have been documented to date with the use of ZOREST.

KNOWN SYMPTOMS OF OVER DOSAGE AND PARTICULARS OF ITS TREATMENT

Sertraline has a wide margin of safety. No serious sequelae have been reported following sertraline overdose as high as 6 g. Although there have been no reports of death due to sertraline-only overdose, fatalities have occurred in combination with other medicines and/or alcohol. No specific therapy is recommended and there is no specific antidote to ZOREST.

Treatment is essentially symptomatic and supportive, possibly including:

  • Establishing and monitoring airway
  • Ensuring adequate oxygenation and ventilation
  • Monitoring cardiac function and vital signs

Administering activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or gastric lavage Dialysis, forced diuresis, haemoperfusion and exchange transfusions are unlikely to be of benefit due to ZOREST’s large volume of distribution and high degree of protein binding.

Interactions

ZOREST has not been shown to alter alcohol metabolism and does not appear to potentiate cognitive and psychomotor effects of alcohol, or carbamazepine or haloperidol or phenytoin in normal subjects. Concomitant use of ZOREST and alcohol is not recommended. Small but statistically significant changes in some pharmacokinetic parameters of diazepam and tolbutamide have been observed when these medicines were co-administered with ZOREST.

The clearance of ZOREST is significantly decreased by cimetidine. However, its clinical significance is unknown. Prothrombin time should be monitored in patients receiving ZOREST and warfarin concomitantly, since a statistically significant increase in prothrombin time has been observed in such patients. Studies have shown no interaction of sertraline with digoxin or glibenclamide. The SSRls have been reported to interact with medicines metabolised by cytochrome P450.

There is considerable variability in the extent to which these medicines inhibit isozyme P450 2D6. In this regard, no significant interactions of sertraline have been reported. Sertraline has shown minimal elevation of desipramine plasma concentration (a marker of isozyme P450 2D6 activity). The carbamazepine plasma concentration (a marker of isozyme P450 3A4 activity) were not altered following concomitant administration with sertraline.

The beta adrenergic blocking activity of atenolol is not affected by ZOREST. The pharmacokinetics of lithium are not altered by ZOREST. However, a careful monitoring of plasma lithium concentration is recommended for making adjustments in lithium doses, if required. Caution is advised when sertraline is admmistered with medicines such as lithium which may act via serotonergic mechanisms since a higher incidence of serotonin associated side-effects may occur.

PREGNANCY AND LACTATION

Pregnancy: Adequate and well-controlled studies in pregnant women have not been performed. Animal reproduction studies have not shown any evidence of teratogenicity or embryotoxicity with sertraline. However, since animal reproduction studies are not always predictive of human response, ZOREST should be used during pregnancy only if the potential benefits outweigh the risks. Women of childbearing potential who are on ZOREST should be employ an adequate method of contraception.

Lactation: Limited data concerning sertraline levels in breast milk are available, hence use of ZOREST in breast feeding mothers is not recommended.

Adverse Effects

Side-effects

The side-effects that have been reported with the use of sertraline include:

Gastro-intestinal: Nausea, diarrhoea, dyspepsia.

Central nervous system: Dizziness, insomnia, somnolence

Body as a whole: Tremor, increased sweating, dry mouth.

Others: Male sexual dysfunction (primary ejaculation delay).

Other adverse effects that have been observed in patients treated with sertraline with a frequency equal to or greater than that with placebo include:

Cardiovascular: Palpitation.

Nervous system: Headache, paresthesia, hypoesthesia, twitching, hypertonia,

Skin: Rash.

Gastro-intestinal: Constipation, vomiting, flatulence, anorexia, abdominal pain, increased appetite.

Body as a whole: Fatigue, fever, hot flushes, back pain, thirst, myalgia.

Psychiatric: Agitation, nervousness, anxiety, yawning, female sexual dysfunction, impaired concentration

Genito-urinary: Micturition frequency, micturition disorder, menstrual disorder.

Respiratory: Rhinitis, pharyngitis.

Special senses: Abnormal vision, tinnitus, taste perversion.

Laboratory abnormalities such as elevation in serum levels of transaminases (AST, ALT) (diminishing upon drug discontinuation) and reversible hyponatraemia have been reported with sertraline use.

Most of the reports of hyponatraemia were associated with elderly patients and those taking diuretics of other medicines concomitantly.

Dosage & Administration

ZOREST tablets should be given as a single daily dose with or without food.

Adults:

Depression: The starting dose is 50 mg daily and the usual antidepressant dose is 50 mg daily. In patients with incomplete response but good toleration at lower doses, dosage adjustments should be made in 50 mg increments over a period of 2 weeks to a maximum of 200 mg dally.

Obsessive Compulsive Disorder: The minimum effective dose is 50 mg daily and doses above 100 mg did not have any additional benefit. The onset of therapeutic effect may be seen within 7 days, although 2-4 weeks (and even longer in OCD) are usually necessary for full activity

Use in patients with renal or hepatic impairment: ZOREST should be used with caution in patients with renal and hepatic impairment. 

Use in children
The safety and efficacy of ZOREST have not been established in children.

Use In the elderly
No special precautions are required. The usual adult dose is recommended.

Storage/Handling Recommendations

Keep in a cool & dry place. Protect from light

KEEP All MEDICINES OUT OF THE REACH OF CHILDREN

Review Date

2016-03-18 08:31:13