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

Logo ASPEN SERTRALINE 50 MG (TABLET)
ASPEN SERTRALINE 100 MG (TABLET)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

ASPEN SERTRALINE 50 MG (TABLET)
ASPEN SERTRALINE 100 MG (TABLET)

COMPOSITION:
Each tablet contains:
ASPEN SERTRALINE 50 MG TABLET:
Sertraline Hydrochloride 56 mg equivalent to
Sertraline50 mg base
ASPEN SERTRALINE 100 MG TABLET:
Sertraline Hydrochloride 112 mg equivalent to Sertraline 100 mg base

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 (5HT
1A, 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 to 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 vitrobiochemical 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 radioactively was recovered in the urine and a similar amount in the faeces, including 12-14% unchanged sertraline. The terminal elimation half-life of N-desmethylsertraline is approximately 62to 104 hours. Desmethylsertraline exhibits time related dose dependent increases in AUC, C
max, and Cminwith a 5 to 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 to 500 ng/mL.
Age– Sertraline plasma clearance in elderly patients is approximately 40% lower than in younger (25 to 32 year old) individuals. Steady state, therefore, should be achieved after 2 to 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:
ASPEN SERTRALINE is indicated for the treatment of major depressive disorders such as single episodes and recurrent depression.
ASPEN SERTRALINE is also indicated for the treatment of obsessive-compulsive disorder (OCD)
ASPEN SERTRALINE 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; paraesthesias, (numbness or tingling sensations); chills or hot flushes.
The effectiveness of ASPEN SERTRALINE in long-term use, that is, for more than 12 weeks, has not been systematically evaluated. Therefore, the physician who elects to use ASPEN SERTRALINE 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:
ASPEN SERTRALINE is contra-indicated in patients with known hypersensitivity to sertraline.
The concomitant use of ASPEN SERTRALINE 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”

WARNINGS:
Activation of mania/hypomania
–hypomania or mania may occur in patients treated with ASPEN SERTRALINE. 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 an undesirable result of treatment with ASPEN SERTRALINE for some patients, approximately 0.5 kg – 1.0 kg weight loss.
Seizure–Seizures have been observed occasionally in patients using ASPEN SERTRALINE. ASPEN SERTRALINE should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. ASPEN SERTRALINE 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 ASPEN SERTRALINE should be written for the smallest quantity of tablets consistent with good patient management, in order toreduce the risk of overdose.
Weak uricosuric effect– ASPEN SERTRALINE 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 ASPEN SERTRALINE.
Driving/Use of machinery–ASPEN SERTRALINE 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 ASPEN SERTRALINE in patients with diseases or conditions that could affect metabolism or haemodynamic responses.
ASPEN SERTRALINE 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 ASPEN SERTRALINE. The elimination half-life of ASPEN SERTRALINE is prolonged. The use of ASPEN SERTRALINE in patients with liver disease must be approached with caution. If ASPEN SERTRALINE 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 C
max) are modest, ASPEN SERTRALINE should be used with care in these patients. The dose of ASPEN SERTRALINE may have to be reduced in patients with impaired renal function.
Interference with cognitive and motor performance–ASPEN SERTRALINE does not cause sedation and does not interfere with psychomotor performance.
Safety and efficacy in children under 18 years of age have not been established.
(See contra-indications 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. This risk may persist until significant remission occurs. A casual role, however, for antidepressant medicine in inducing such behaviour has not been established. Patients being treated with ASPEN SERTRALINE should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or atany 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 notbeen established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing ASPEN SERTRALINE, 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, ASPEN SERTRALINE should be tapered (See PRECAUTIONS and DOSAGE AND DIRECTIONS FOR USE)

INTERACTIONS:
Monoamine oxidase inhibitors
–Cases of serious reactions, sometimes fatal, have been reported in patients receiving ASPEN SERTRALINE in combination with 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 ASPEN 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 ASPEN SERTRALINE treatment and starting MAOI.
CNS depressants and alcohol–Concomitant use of ASPEN SERTRALINE and alcohol in depressed patients is not recommended.

Special precautionary monitoring is advised with the following:
Protein bound medicines–ASPEN SERTRALINE is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, ASPEN SERTRALINE 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,ASPEN SERTRALINE has no significant effects on the protein binding of the substrate. (see also Other interactions).
Serotonergic agents–Co-administration of ASPEN SERTRALINE 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 ASPEN SERTRALINE. 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 reuptake inhibitor (SSRI) to another has not been established.
Other interactions–Co-administration of ASPEN SERTRALINE with diazepam or tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters.
Co-administration with cimetidine caused a substantial decrease in ASPEN SERTRALINE clearance. The clinical significance of these changes is unknown.
Warfarin–Co-administration of ASPEN SERTRALINE 200 mg daily and warfarin resulted in a small but statistically significant increase in prothrombin time. Accordingly prothrombin time should be carefully monitored when ASPEN SERTRALINE therapy is initiated or stopped.
No interactions reported with the following:
ASPEN SERTRALINE 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 ASPEN SERTRALINE therapy, so that appropriate adjustments to the lithium dose may be made if necessary. Co-administration 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 ASPEN SERTRALINE with medication 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 ASPEN SERTRALINE 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 ASPEN SERTRALINE 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 ASPEN SERTRALINE 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that ASPEN SERTRALINE is not a clinically relevant inhibitor of CYP 2C9. The apparent lack of clinically significant effects of the chronic administration of ASPEN SERTRALINE 200 mg daily on plasma concentrations of diazepam suggests that ASPEN SERTRALINE is not a clinically relevant inhibitor of CYP 2C19. ASPEN SERTRALINE has little or no potential to inhibit CYP 1A2.

PREGNANCY AND LACTATION
The safety of ASPEN SERTRALINE during pregnancy and lactation has not been established. Women of child-bearing potential should employ an adequate method of contraception if taking ASPEN SERTRALINE.

DOSAGE AND DIRECTIONS FOR USE:
ASPEN SERTRALINE should be given as a single daily dose with or without food.
Depression
The starting does 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 ASPEN SERTRALINE 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.
Usein the elderly–No special precautions are required. The usual adult dosage is recommended.
Use in children–The use of ASPEN SERTRALINE 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 ASPEN SERTRALINE therapy has to be discontinued, ASPEN SERTRALINE should to be tapered, (see PRECAUTIONS and DOSAGE AND DIRECTIONS FOR USE).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Gastro-intestinal disorders
:
Frequent:
•        Anorexia
•        Nausea
•        Diarrhoea/loose stools
•        Dyspepsia
•        Abdominal pain
•        Dry mouth
•        Flatulence
Less frequent:
•        Constipation
•        Vomiting
•        Increased appetite
Has been reported but frequency unknown:
•        Taste perversion
Central nervous system disorders:
Frequent:
•        Tremor
•        Dizziness
•        Insomnia
•        Somnolence
•        Fatigue
•        Sexual dysfunction (primarily ejaculatory delay in males)
•        Headache
Less frequent:
•        Agitation
•        Nervousness
•        Anxiety
•        Yawning
Have been reported but frequency unknown:
•        Paraesthesia
•        Hypoesthesia
•        Twitching
•        Hypertonia
•        Female sexual dysfunction
•        Impaired concentration
•        Psychosis
•        Tinnitus
•        Convulsions
•        Movementdisorder (such as gait abnormalities)
Cardiac disorders:
Less frequent:
•        Palpitations
Skin and subcutaneous tissue disorders:
Less frequent:
•        Rash
•        Hot flushes
Has been reported but frequency unknown:
•        Erythema multiforme
Metabolic and nutritional disorders:
Has been reported but frequency unknown:
•        Thirst
Eye disorders:
Less frequent:
•        Vision abnormal
Respiratory disorders:
Have been reported but frequency unknown:
•        Rhinitis
•        Pharyngitis
Renal and urinary disorders:
Have been reported but frequency unknown:
•        Micturition frequency
•        Micturition disorder
Musculo-skeletal disorders:
Has been reported but frequency unknown:
•        Myalgia
Hepatobiliary disorders:
Have been reported but frequency unknown:
•        Pancreatitis
•        Serious liver events (including hepatitis, jaundice and liver failure)
Reproductive system and breast disorders:
Less frequent:
•        Galactorrhoea
Have been reported but frequency unknown:
•        Hyperprolactinaemia
•        Menstrual symptoms
General disorders:
Frequent:
•        Increased sweating
Less frequent:
•        Fever
Has been reported but frequency unknown:
•        Back pain
There have been reports of extrapyramidal symptoms associated with the use of ASPEN SERTRALINE and of aggravation of Parkinson’s disease in patients taking ASPEN SERTRALINE. Caution should be exercised when prescribing ASPEN SERTRALINE to patients with extrapyramidal disorders and patients should be carefully monitored.
Abrupt discontinuation of ASPEN SERTRALINE may lead to withdrawal symptoms which include dizziness, sweating, nausea, insomnia, tremor, confusion, sensory disturbances, agitation and anxiety.
The following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: paresthesia, hypoesthesia, depressive symptoms, hallucinations, aggressive reaction, agitation, anxiety and psychosis.
Laboratory abnormalities:
Asymptomatic elevations of serum transaminases (SGOT and SGPT) have been reported infrequently (approximately 0,8%) in association with ASPEN SERTRALINE therapy. The abnormalities usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
There have been rare reports of altered platelet function and/or abnormal clinical laboratory results in patients taking ASPEN SERTRALINE. While there have been reports of abnormal bleeding or purpura in several patients taking ASPEN SERTRALINE it is unclear whether ASPEN SERTRALINE has a causative role.
Hyponatraemia has been reported and appeared to be reversible when ASPEN SERTRALINE was discontinued. Some cases were possibly due to inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients takingdiuretics or other medications.
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 in Major Depressive Disorder, there were increased reports of hostility and suicide – related adverse events such as suicidal ideation and self-harm. (See CONTRA-INDICATIONS)
Abrupt discontinuation of ASPEN SERTRALINE can lead to discontinuation effects.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
On the evidence available, ASPEN SERTRALINE has a wide margin of safety in overdose. Serious sequelae have not been reported following overdoses of ASPEN SERTRALINE alone of up to 6 g. Although there have been no deaths reported when ASPEN SERTRALINE was taken alone, deaths involving overdoses of ASPEN SERTRALINE 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 ASPEN SERTRALINE. 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 ASPEN SERTRALINE, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

IDENTIFICATION:
ASPEN SERTRALINE 50 MG TABLETS:
White to off-white, film-coated, capsule shaped tablet with “ST”over score line “50”on one side.
ASPEN SERTRALINE 100 MG TABLETS:
White to off-white, film-coated, capsule shaped tablet with “ST”over score line “100”on one side.

PRESENTATION:
Blister strips of 10 tablets with clear, colourless, blister forming foil on the bottom and silver aluminum foil printed with black ink on the top. Blisters strips are cartoned in packs of 30 tablets each.

STORAGE INSTRUCTIONS:
Store in a dry place below 25°C.
Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
ASPEN SERTRALINE 50 MG TABLETS: A38/1.2/0482
ASPEN SERTRALINE 100 MG TABLETS: A38/1.2/0483

NAME AND BUSINESS ADDRESS OF APPLICANT:
PHARMACARE LIMITED
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
4 October 2005

574998/060214

UNIPRINT - POS

New addition to this site: November 2006
Source: Pharmaceutical Industry

SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2006