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

Logo ECTIVA® 10 Capsules RECALLED October 2010
ECTIVA® 15 Capsules RECALLED October 2010

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

ECTIVA® 10 Capsules RECALLED October 2010
ECTIVA® 15 Capsules RECALLED October 2010

COMPOSITION
Ectiva® 10
Each capsule contains Sibutramine hydrochloride monohydrate 10 mg equivalent to 8,37 mg of
sibutramine free base.
Ectiva® 15
Each capsule contains Sibutramine hydrochloride monohydrate 15 mg equivalent to 12,55 mg of sibutramine free base.

PHARMACOLOGICAL CLASSIFICATION
A 11.3 Anorexigenics

PHARMACOLOGICAL ACTION
Ectiva®
is a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), which exerts its effects in vivo through its secondary and primary amine metabolites. In animal models, sibutramine reduces body weight gain by a dual action to decrease calorie intake through enhancement of post-ingestive satiety responses and to increase energy expenditure by enhancing resting metabolic rate.
Pharmacokinetic properties
Sibutramine is well absorbed and undergoes extensive first-pass metabolism.
Peak plasma levels were achieved 1.2 hours after a single oral dose of 20 mg and half-life of the parent compound is 1.1 hours. The pharmacologically-active metabolites 1 and 2 reach T
max in three hours with elimination half-lives of 14 and 16 hours, respectively. Linear kinetics have been demonstrated over the dose range 10 to 30 mg, with no dose-related change in elimination half-lives and a dose-proportionate increase in plasma concentrations. On repeated dosing, steady-state concentrations of metabolites 1 and 2 are achieved within four days, with an approximately two-fold accumulation.
Pharmacokinetics of sibutramine and its metabolites are similar in obese subjects to those in normal weight subjects and there is no evidence of substantial difference in the pharmacokinetics of males and females.
The pharmacokinetic profile observed in elderly subjects was similar to that seen in young subjects. Sibutramine and its metabolites 1 and 2 are approximately 97%, 94% and 94% plasma protein bound, respectively.
Metabolism is the major route of elimination of sibutramine and its active metabolites 1 and 2. Metabolites are excreted preferentially in urine, with a urine:faeces ratio of 10:1.

INDICATIONS
Ectiva®
is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet. Ectiva® is recommended for obese patients with an initial body mass index of 30 kg/m2 or higher or 27 kg/m2 or higher in the presence of other factors (e.g. hypertension, diabetes, dyslipidaemia).

CONTRA-INDICATIONS
Known hypersensitivity to sibutramine hydrochloride monohydrate or any other component of the product.
Organic causes of obesity.
A history of, or presence of, major eating disorders such as anorexia nervosa or bulimia nervosa.
Psychiatric illness.
Gilles de la Tourettes syndrome.
Known or suspected pregnancy or lactating women.
Concomitant use, or use during the past two weeks, with monoamine oxidase inhibitors (MAOI’s), other CNS active drugs for the treatment of mental disorders (such as anti-depressants, antipsychotics), for sleep disturbances (tryptophan) or other centrally acting weight reducing agents.
Uncontrolled hypertension.
Severe hepatic impairment.
Severe renal impairment.
Presence of, or history of, coronary artery disease, congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or TIA).
Hyperthyroidism.
Benign prostatic hyperplasia with urinary retention.
Phaeochromocytoma.
Narrow angle glaucoma.
History of drug, medication or alcohol abuse.
Children and young adults up to the age of 18 years, owing to insufficient data.

DOSAGE AND DIRECTIONS FOR USE
Adults:
One capsule of Ectiva® 10 taken orally once daily in the morning with or without food.
Elderly patients:
The efficacy and tolerability of Ectiva® has only been assessed in a small number of elderly patients, therefore cautious use of Ectiva® is recommended in the elderly (over 65 years), although the dosage recommendations are unchanged.
Children:
Ectiva®
has not been studied in children (under 18 years of age) therefore Ectiva® is not recommended in this age group.

Duration of treatment
Treatment should only be continued beyond 3 months in patients who have responded to treatment as indicated by a weight loss greater than or equal to 5% of the initial weight, within 3 months of the start of treatment.
In those patients with an inadequate response on Ectiva® (suggested as less than 2 kg weight loss in four weeks) providing Ectiva® 10 is well tolerated, the dose may be increased to Ectiva® 15 once daily.
Unless weight loss in maintained, treatment should not be continued.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Treatment with Ectiva® should only be given as part of an integrated therapeutic approach for weight reduction under the care of physicians experienced in the treatment of obesity.
Ectiva® should only be prescribed to patients who have not adequately responded to an appropriate weight-reducing regimen alone, i.e. patients whose weight loss was less than 5 kg within 3 months.
An appropriate approach to obesity management should include dietary and behavioural modification as well as increased physical activity. This integrated approach is essential for a lasting change in eating habits and behaviour which is fundamental to the long-term maintenance of the reduced weight level once therapy is complete. The duration of treatment with Ectiva® should not exceed one year.
Patients should change their lifestyle in terms of weight management while on Ectiva® so that they are able to maintain the weight loss once the medication has ceased. They should be informed that, if they fail to do so, they may regain weight, and that even after cessation of therapy they should continue to be monitored by the attending physician.
Secondary organic causes of obesity must be excluded by diagnosis before prescribing this agent.
The management of obesity should be undertaken using a global approach, and should include dietary, medical and psychotherapeutic methods.
It is recommended that blood pressure and pulse rate should be monitored in all patients on Ectiva®. In the first two months of treatment, these parameters should be checked at least every two weeks, thereafter, once a month. In hypertensive patients whose blood pressure is properly controlled (= 145/90 mmHg) these checks must be carried out with utmost care and, if necessary, at shorter intervals. Patients whose blood pressure levels exceed 145/90 mmHg at two consecutive readings are to be withdrawn from therapy. Patients experiencing sustained, clinically significant increases should be discontinued from treatment.
Ectiva® should be given with caution to those patients with controlled hypertension.
Special care is recommended when agents which prolong the QTc interval are administered concomitantly. These agents include astemizole, mexiletine, propafenone, sotalol, cisapride, sertinole and tricyclic antidepressants.
Special care is also recommended in patients with conditions liable to induce QT prolongation (potassium depletion, magnesium depletion).
Although Ectiva® has not been associated with primary pulmonary hypertension, it is important to be on the look out for symptoms such as progressive dyspnoea, chest pain and ankle oedema in the course of routine check-ups. The patient should be advised to consult a doctor immediately if these symptoms occur.
Although only inactive material is excreted by the renal route, Ectiva® should be used with caution in patients with mild to moderate renal impairment.
Ectiva® should be given with caution to patients who have a family history of motor or verbal tics.
Ectiva® has been assessed in patients with mild to moderate hepatic impairment resulting in an increased bio-availability of 24%, with no adverse clinical effects. Ectiva® should, however, be used with caution in patients with mild to moderate hepatic impairment.
Ectiva® should be given with caution to patients with epilepsy.
Women of child-bearing potential should employ adequate contraception whilst taking Ectiva®.
Adverse events
The majority of adverse events occurred early on treatment (first 4 weeks) and decreased in intensity and frequency over time. In general they were not serious, did not lead to cessation of treatment and were reversible.
In placebo-controlled studies in obese patients the adverse events that occurred on Ectiva® treatment at a statistically significantly greater incidence than placebo are listed by body system (frequent > 10%, occasional 1 –10%; rare < 1%).
General occurrences Rare Chills
Cardiovascular system Occasional Tachycardia
Palpitations
Raised blood pressure/hypertension
Vasodilation (hot flushes)
Gastrointestinal system Frequent

Occasional
Loss of appetite
Constipation
Nausea
Rectal disorder (worsening of haemorrhoids)
Central nervous system Frequent

Occasional
Dry mouth
Insomnia
Dizziness
Paraesthesia
Headache
Anxiety
Skin Occasional Sweating
Sensory functions Occasional Taste perversion
Rare adverse events which occurred on sibutramine treatment and considered to be clinically important are:
One case of acute interstitial nephritis.
One case of mesangio-capillary glomerulonephritis.
One case of Henoch-Schönlein purpura, thought to be related to concomitant administration of intravenous flucloxacillin.
Convulsions were reported in three obese patients (< 0,1%).
Reversible increases in liver enzymes without clinical sequela were reported in 1,1% of sibutramine treated patients in placebo-controlled trials compared to 0,5% on placebo.
Three (< 0,1%) cases of thrombocytopenia.
There has been one report of a post-treatment acute psychotic eposide in a patient with a likely pre-treatment schizo-affective disorder.
Adverse events which led to discontinuation of obese patients in placebo-controlled clinical trials at an incidence of = 0,5% than on placebo were : hypertension (0,8%), insomnia (0,8%), depression (0,7%) and dizziness (0,6%).
Withdrawal symptoms such as headache and increased appetite have rarely been observed. There is no evidence of a withdrawal or abstinence syndrome or mood swings on cessation of treatment.

Cardiovascular changes
Mean increases in resting systolic and diastolic blood pressure have been observed in the range 1 –3 mmHg, and increases in mean pulse rate of 3–5 bpm have been observed.
Relative to placebo, a small increased incidence of patients experienced sustained increases in resting blood pressure and pulse defined as two consecutive increases of 10 mmHg/10 bpm or greater. In placebo controlled studies clinically significant adverse events which could potentially be associated with increase in blood pressure and pulse have been rare on Ectiva® treatment and occurred at similar incidences to those seen on placebo.
Sustained increases should be detected by routine medical monitoring.
For patients who experience sustained increases in blood pressure or pulse on Ectiva®, discontinuation should be considered. The majority of potentially clinically significant increases in blood pressure and pulse rate observed in Ectiva® clinical trials tend to occur early on treatment.

Interactions with other medications and other forms of interaction
In vitro hepatic microsome studies indicated that CYP3A4 is the major cytochrome P450 isoenzyme responsible for Ectiva® metabolism. There was no indication of an affinity for CYP2D6, a low capacity enzyme involved in pharmacokinetic interactions on numerous drugs. Further in vitro studies revealed that sibutramine had no significant effect on the activity of the major P450 isoenzymes, including CYP3A4.
In vivo, co-administration of CYP3A4 inhibitors ketoconazole or erythromycin with Ectiva® increased plasma concentrations by 23% and 10% respectively, and modest increases in heart rate were reported.
Co-administration of cimetidine with Ectiva® produced no significant change in plasma concentration.
Caution should therefore be exercised on concomitant administration of Ectiva® with drugs which affect CYP3A4 enzyme activity. CYP3A4 inhibitors include ketoconazole, erythromycin, troleandomycin and cyclosporin; inducers include rifampicin, macrolide antibiotics, phenytoin, carbamazepine, phenobarbitone and dexamethasone.
The simultaneous use of several drugs each of which increases levels of serotonin in the blood may give rise to serious interactions. This phenomenon is called serotonin syndrome and may occur in rare cases in connection with the simultaneous use of a selective serotonin reuptake inhibitor (SSRI) together with certain anti migraine drugs (such as sumatriptan, dihydroergotamine), or along with certain opioids (such as pentazocine, pethidine, fentanyl, dextromethorphan), or in the case of simultaneous use of two SSRI’s.
As Ectiva® inhibits serotonin reuptake (among other effects), it should not be used concomitantly with other drugs which raise serotonin levels.
Concomitant use of Ectiva® with other drugs which may raise the blood pressure or heart rate has not been systematically evaluated. Drugs of this type include certain cough, cold and allergy medications, and certain decongestants.
Caution should be used when prescribing Ectiva® to patients who use these medications.
The use of Ectiva® in combination with other CNS active drugs has not been systematically evaluated and is therefore not recommended.
Ectiva® does not affect the efficacy of the oral contraceptive pill.
At single doses, there was no impairment of cognitive or psychomotor performance when Ectiva® was administered concomitantly with alcohol.
However, the concomitant use of Ectiva® with excess alcohol is not recommended.
Pregnancy and lactation
Whilst reproduction studies in animals have shown that Ectiva® is not teratogenic, the safety of Ectiva® in human pregnancy has not been established and Ectiva® is therefore contraindicated in human pregnancy.
Use in lactation
It is not known whether Ectiva® is excreted in breast milk and therefore administration during lactation is contra-indicated.
Women of child-bearing potential should employ an adequate method of contraception whilst taking Ectiva®.
Effects on ability to drive and use of machines
Although Ectiva® did not affect psychomotor or cognitive performance in healthy volunteers, any CNS active drug may impair judgement, thinking or motor skills. Therefore patients should be cautioned that their ability to drive a vehicle or operate hazardous machinery when taking Ectiva® may be impaired.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There is limited experience of overdose with Ectiva®. No specific therapy is recommended and there is no specific antidote. Treatment should consist of general measures employed in the management of overdose such as airway establishment, cardiac and vital sign monitoring and general symptomatic and supportive measures. Early administration of activated charcoal may delay the absorption of Ectiva®; gastric lavage may be of benefit.
Cautious use of beta-blockers may be indicated in patients with elevated blood pressure or tachycardia.

IDENTIFICATION
Ectiva® 10
A hard gelatine capsule with a blue opaque cap printed and a yellow opaque body printed “10” in grey, containing a white to off-white free-flowing powder.
Ectiva® 15
A hard gelatine capsule with a blue opaque cap and a white opaque body printed “15” in grey, containing a white to off-white free-flowing powder.

PRESENTATION
Ectiva® 10        Blister packs of 30.
Ectiva® 15 Blister packs of 30.

STORAGE INSTRUCTIONS
Store in a dry place, below 25ºC.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
Ectiva® 10        33/11.3/0027
Ectiva® 15 33/11.3/0028

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Abbott Laboratories S.A. (Pty) Limited
Abbott Place
219 Golf Club Terrace
CONSTANTIA KLOOF
1709

DATE OF PUBLICATION OF THIS PACKAGE INSERT
26 January 1999

MARKETED AND DISTRIBUTED BY
Aspen Pharmacare

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Source: Pharmaceutical Industry

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