INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ZYLIN (Tablets)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

ZYLIN (Tablets)

COMPOSITION:
Each film-coated ZYLIN tablet contains sertraline hydrochloride equivalent to 50 mg
sertraline.

PHARMACOLOGICAL CLASSIFICATION:
A 1.2 Psychoanaleptics (Antidepressants)

PHARMACOLOGICAL ACTION:
The mechanism of action of sertraline is presumed to be linked to the inhibition of central nervous system neuronal uptake of serotonin (5HT). Sertraline blocks the uptake of serotonin into human platelets. Sertraline is a specific inhibitor of neuronal serotonin re-uptake and has only very weak effects on the norepinephrine and dopamine neuronal re-uptake.
It is devoid of stimulant, sedative or anticholinergic activity or cardiotoxicity in animals. Sertraline does not enhance catecholaminergic activity and it has no affinity for cholinergic, serotonergic (5HT1A, 5HT1B, 5HT2), dopaminergic, adrenergic (alpha1, alpha2, beta) histaminergic, GABA or benzodiazepine receptors.
Pharmacokinetics:
The chronic administration of sertraline in animals was associated with downregulation of brain norepinephrine receptors as observed with other clinically effective antidepressants.
Sertraline exhibits dose proportional pharmacokinetics over the range 50 mg –200 mg. After oral administration over the range of 50 –200 mg once daily for 14 days, mean peak blood levels are reached at 4,5 –8,4 hours post dose. The average terminal plasma half-life is about 26 hours.
Steady-state plasma levels are reached after approximately one week of once daily dosing. Approximately 98% of the circulating drug is bound to plasma proteins. Consistent with the terminal elimination half-life, there is approximately two-fold accumulation with repeated dosing as compared to a single dose.
Sertraline undergoes extensive first pass hepatic metabolism. Both in vitro biochemical and in vivo pharmacological testing have shown the principal metabolite, N-desmethylsertraline, to have significantly less clinical activity. Both sertraline and N-desmethylsertraline are extensively metabolised with only a small amount (<0,2%) of unchanged sertraline excreted in the urine.
About 40 –45% of the dose administered radioactivity was recovered in the urine and a similar amount in the faeces, including 12 –14% unchanged sertraline. The terminal elimination half-life of N-desmethylsertraline is approximately 62 –104 hours. Desmethylsertraline exhibits time related dose dependent increases in AUC, Cmax and Cmin with a 5 –9 fold increase in their parameters between day 1 and day 14.
Protein binding –Sertraline is highly bound to serum proteins (98%) in the range of 20 –500 ng/mL.
Age –Sertraline plasma clearance in elderly patients is approximately 40% lower than in younger (25 –32 year old) individuals.
Steady state, therefore, should be achieved after 2 –3 weeks in older patients. There is a decreased clearance of desmethylsertraline in older males, but not in older females.
Liver disease –The administration of sertraline is delayed in patients with impaired liver function. Dosages should be reduced (see “Warnings”).

INDICATIONS:
ZYLIN is indicated for the treatment of major depressive disorders such as single episodes and recurrent depression.
ZYLIN is also indicated for the treatment of obsessive-compulsive disorder (OCD).
ZYLIN is also indicated for the treatment of panic disorder, with or without agoraphobia.
Panic disorder:
Panic disorder is characterised by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behaviour related to the attacks. Panic disorder is characterised by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, light-headed, or faint; derealisation (feelings of unreality) or depersonalisation (being detached from oneself); fear of loosing control; fear of dying; paresthesias (numbness or tingling sensations); chills or hot flushes.
The effectiveness of ZYLIN in long-term use, that is, for more than 12 weeks, has not been systematically evaluated. Therefore, the physician who elects to use ZYLIN for extended periods should periodically re-evaluate the long-term usefulness of the medicine for the individual patient (see “Dosage and Directions for Use”).

CONTRA-INDICATIONS:
ZYLIN is contra-indicated in patients with known hypersensitivity to sertraline.
The concomitant use of ZYLIN with a monoamine oxidase inhibitor (MAOI) is contra-indicated (see “Warnings”).
Use in hepatic or renal insufficiency –see “Warnings –Use in patients with concomitant illness”.
Children under the age of 18 years (see “Warnings”and “Side Effects and Special Precautions”).

WARNINGS:
Activation of mania/hypomania
–hypomania or mania may occur in patients treated with ZYLIN.
Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants and antiobsessional agents.
Weight loss –Significant weight loss may be undesirable result of treatment with ZYLIN for some patients, approximately 0,5 kg –1,0 kg weight loss.
Seizure – Seizures have been observed occasionally in patients using ZYLIN. ZYLIN should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. ZYLIN should be discontinued in any patient who develops seizures.
Suicide –The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for ZYLIN 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 –ZYLIN is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.
Electroconvulsive therapy –There are no clinical studies establishing the risks or benefits of combined use of ECT and ZYLIN.
Driving/Use of machinery –ZYLIN has no effect on psychomotor performance. However patients should be cautioned accordingly when driving a car or operating machinery.
Use in patients with concomitant illness –Caution is advisable in using ZYLIN in patients with disease or conditions that could affect metabolism or hemodynamic responses.
ZYLIN has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.
Liver impairment – As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of ZYLIN. The elimination half-life of ZYLIN is prolonged. The use of ZYLIN in patients with liver disease must be approached with caution. If ZYLIN is administered to patients with liver disease, a lower or less frequent dose should be considered.
Renal impairment –In patients with mild to moderate renal impairment (creatinine clearance 20 –60 mL/min) or severe renal impairment (creatinine clearance <30 mL/min), multiple dose pharmacokinetic parameters (AUC or Cmax) are modest, ZYLIN should be used with care in these patients. The dose of ZYLIN may have to be reduced in patients with impaired renal function.
Interference with cognitive and motor performance –ZYLIN does not cause sedation and did not interfere with psychomotor performance.
Safety and efficacy in children under 18 years of age have not been established (see “Contraindications”and “Side Effects and Special Precautions”).
Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. The risk may persist until significant remission occurs. A causal role, however, for antidepressant medicine in inducing such behaviour has not been established. Patients being treated with ZYLIN should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders.
The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Although a casual link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing ZYLIN, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision is made to discontinue treatment, ZYLIN should be tapered (see “Side Effects and Special Precautions”and “Dosage and Directions for Use”).

INTERACTIONS:
Monoamine oxidase inhibitors
– Cases of serious reactions, sometimes fatal, have been reported in patients receiving ZYLIN in combination with a MAOI, including the selective MAOI, selegiline, and the reversible MAOI, moclobemide. Some cases presented with features resembling neuroleptic malignant syndrome. Similar cases, sometimes fatal, have been reported with other antidepressants during combined treatment with a MAOI and in patients who have recently discontinued an antidepressant or antiobsessional drug and have been started on a MAOI. Symptoms of a drug interaction between a SSRI and a MAOI 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 ZYLIN 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 ZYLIN treatment and starting a MAOI.
CNS depressants and alcohol –Concomitant use of ZYLIN and alcohol in depressed patients is not recommended.
Protein bound medicines –ZYLIN is highly bound to serum proteins (98%) in the range of 20 –500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, ZYLIN does not alter the plasma protein binding of two other highly protein bound medicines, viz. warfarin and propranolol.
However, in interaction with diazepam, tolbutamide and warfarin respectively, ZYLIN has no significant effects on the protein binding of the substrate (see also “Other Interactions”).
Serotonergic agents –Co-administration of ZYLIN with other agents, which enhance serotonergic neurotransmission, such as tryptophan or fenfluramine, should be avoided due to the potential for pharmacodynamic interaction.
Switching from other antidepressants or antiobsessional agents – There is limited controlled experience regarding the optimal timing of switching from other antidepressants or antiobsessional agents to ZYLIN. Care and prudent medical judgement 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 selective serotonin re-uptake inhibitor (SSRI) to another has not been established.
Other interactions – Co-administration of ZYLIN with diazepam or tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters. Co-administration with cimetidine caused a substantial decrease in ZYLIN clearance. The clinical significance of these changes is unknown.
Warfarin –Co-administration of ZYLIN 200 mg daily with warfarin resulted in a small but statistically significant increase in prothrombin time. Accordingly prothrombin time should be carefully monitored when ZYLIN therapy is initiated or stopped.

No interaction found with the following
ZYLIN has no effect on the beta-adrenergic blocking ability of atenolol.
No interaction of sertraline 200 mg daily was observed with glibenclamide or digoxin.
Lithium –It is recommended that plasma lithium levels be monitored following initiation of ZYLIN therapy, so that appropriate adjustments to the lithium dose may be made if necessary. Coadministration with lithium may lead to a higher incidence of 5HT-associated side effects, resulting in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction.
Therefore, caution is recommended when co-administering ZYLIN with medications such as lithium, which may act via serotonergic mechanisms.
Medicines metabolised by cytochrome P450 (CYP) 2D6 –There is variability among antidepressants in the extent of clinically important inhibition of the drug metabolising isoenzyme CYP 2D6 and, in formal interaction studies, chronic dosing with ZYLIN 50 mg daily showed minimal elevation of steady state desipramine plasma levels (a marker of CYP 2D6 isoenzyme activity).
Medicines metabolised by other CYP enzymes –Chronic administration of ZYLIN 200 mg daily does not inhibit the CYP 3A3/4 mediated 6-ß hydroxylation of endogenous cortisol or the metabolism of carbamazepine or terfenadine.
The apparent lack of clinically significant effects of the chronic administration of ZYLIN 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that ZYLIN is not a clinically relevant inhibitor of CYP 2C9. The apparent lack of clinically significant effects of the chronic administration of ZYLIN 200 mg daily on plasma concentrations of diazepam suggests that ZYLIN is not a clinically relevant inhibitor of CYP 2C19. ZYLIN has little or no potential to inhibit CYP 1A2.

PREGNANCY AND LACTATION:
The safety of ZYLIN during pregnancy and lactation has not been established. Women of childbearing potential should employ an adequate method of contraception if taking ZYLIN.

DOSAGE AND DIRECTIONS FOR USE:
ZYLIN should be given as a single daily dose with or without food.
Depression
The starting dose is 50 mg daily and the usual therapeutic dose in depression is 50 mg daily. In difficult to treat patients, the dose may be titrated up in 50 mg increments at 2 weekly intervals, to 150 mg –200 mg.
Obsessive-Compulsive Disorder
The minimum effective dose in OCD is also 50 mg daily and increases above 100 mg daily did not have any additional benefit. Full activity is usually seen after 2 –4 weeks and even longer in OCD. Effect may however be seen within 7 days.
Panic Disorder
For panic disorder, the minimum recommended effective dose of ZYLIN is 50 mg/day. However, therapy for panic disorder should commence at 25 mg/day, increasing to 50 mg/day after one week. This dosage regimen has been demonstrated to reduce the frequency of early treatment emergent side effects characteristic of panic disorder.
Use in the elderly –No special precautions are required. The usual adult dosage is recommended.
Use in children –The use of ZYLIN in children is not recommended, as safety and efficacy have not been established.
Use in hepatic and renal impairment –see “Warnings –Use in patients with concomitant illness”. If ZYLIN therapy has to be discontinued, ZYLIN should be tapered (see “Side Effects and Special Precautions”and “Dosage and Directions for Use”).

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Side effects:
Cardiac disorders:
Less frequent: Palpitations.
Nervous system disorders:
Frequent: Headache, tremor, dizziness, insomnia, somnolence, dry mouth.
Less frequent: Agitation, nervousness, anxiety, depressive symptoms, hallucinations, aggressive reaction.
The following have been reported but the frequencies are unknown:
Paraesthesia, hypoesthesia, twitching, hypertonia, impaired concentration, extrapyramidal symptoms, aggravation of Parkinson’s disease, convulsions.
Skin and subcutaneous tissue disorders:
Frequent: Rash.
The following has been reported but the frequency is unknown: Erythema multiforme.
Endocrine disorders:
The following has been reported but the frequency is unknown: Pancreatitis.
Hepato-biliary disorders:
The following has been reported but the frequency is unknown: Serious liver events (including hepatitis, jaundice and liver failure).
Gastro-intestinal disorders:
Frequent: Gastrointestinal complaints (including nausea, diarrhoea/loose stools and dyspepsia), flatulence, abdominal pain.
Less frequent: Constipation, vomiting, increased appetite.
General disorders:
Frequent: Fatigue, fever, increased sweating.
Less frequent: Hot flushes, yawning.
The following has been reported but the frequency is unknown: Taste perversion.
Metabolism and nutrition disorders:
Frequent: Anorexia.
Less frequent: Appetite increase.
The following has been reported but the frequency is unknown: Thirst.
Musculoskeletal, connective tissue and bone disorders:
The following has been reported but the frequencies are unknown: Myalgia, back pain, movement disorders (such as gait abnormalities).
Psychiatric disorders:
The following have been reported but the frequencies are unknown: Psychosis.
Reproductive system and breast disorders:
Frequent: Male sexual dysfunction (primarily ejaculatory delay in males), female sexual dysfunction.
The following has been reported but the frequency is unknown: Menstrual symptoms, hyperprolactinemia, galactorrhoea.
Respiratory, thoracic and mediastinal disorders:
The following have been reported but the frequencies are unknown: Rhinitis, pharyngitis.
Eye disorders:
Less frequent: Abnormal vision.
Ear disorders:
The following has been reported but the frequency is unknown: Tinnitus.
Renal and urinary disorders:
The following have been reported but the frequencies are unknown: Micturition frequency, micturition disorder.
Investigations:
Less frequent: Asymptomatic elevations of serum transaminases (SGOT and SGPT), altered platelet function and/or abnormal clinical laboratory results.
The abnormalities usually occurred within the first 1 –9 weeks of drug treatment and promptly diminished upon drug discontinuation. While there have been reports of abnormal bleeding or purpura in several patients taking ZYLIN it is unclear whether ZYLIN had a causative role.
Caution should be exercised when prescribing ZYLIN to patients with extrapyramidal disorders and patients should be carefully monitored.

In children, reports of hostility, suicidal ideation and self-harm.

Safety and efficacy in children under 18 years of age have not been established. In clinical trials of Major Depressive Disorder, there were increased reports of hostility and suicide-related adverse events such assuicidal ideation and self-harm (see “Contra-indications”).

Abrupt discontinuation of ZYLIN can lead to discontinuation effects:
Abnormal dreams, agitation, anxiety, dizziness, gait instability, headache, increased sweating, insomnia, nausea, confusion, sensory disturbances including electric shock sensations and paresthesias, tremor, unusual tiredness, vertigo, vomiting.
Hyponatraemia has been reported and appeared to be reversible when ZYLIN was discontinued.
Some cases were possibly due to inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients taking diuretics or other medications.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
On the evidence available, ZYLIN has a wide margin of safety in overdose. Serious sequelae have not been reported following overdoses of ZYLIN alone of up to 6 g. Although there have been no deaths reported when ZYLIN was taken alone, deaths involving overdose of ZYLIN in combination with other medicines and/or alcohol have been reported. Therefore, any overdosage should be treated aggressively.
No specific therapy is recommended and there are no specific antidotes to ZYLIN. Establish and maintain an airway, ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, a cathartic, may be as, or more, effective than emesis or lavage, and should be considered in treating overdosage. Monitoring of cardiac and vital signs is recommended, along with general symptomatic and supportive measures. Due to the large volume of distribution of ZYLIN, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

IDENTIFICATION:
ZYLIN is a light blue, round, biconvex, film coated tablet with break line on one side and plain on the other side.

PRESENTATION:
ZYLIN tablets are available in 100, 500 and 1000 tablets packed in white HDPE bottles with white child resistant caps and 30 or 100 tablets packed in Aluminium/PVC/PVdC blister strips. Ten tablets are packed in a blister strip. Three or 10 blister strips are packed in an outer carton.
ZYLIN are also available in bulk pail of 10 kg tablets packed into a 35 litre HMHDPE blue container with black lid and metal locking ring.

STORAGE INSTRUCTIONS:
Store in a cool (below 25ºC), dry place.
Do not remove the blisters from the carton until required for use.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
A39/1.2/0596

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Zydus Healthcare S.A. (Pty) Ltd.
Adrina Building, 32-34 Klinkenberg Road, Potchefstroom 2531

DATE OF PUBLICATION OF THE PACKAGE INSERT:
13 April 2007

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New addition to this site: January 2008
Source: Pharmaceutical Industry

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