Anti-obesity agents

Sibutramine

One capsule of Reductil 10 mg contains 10 mg of sibutramine hydrochloride monohydrate (equivalent to 8.37 mg of sibutramine). One capsule of Reductil 15 mg contains 15 mg of sibutramine hydrochloride monohydrate (equivalent to 12.55 mg of sibutramine).

10 mg Hard capsule with a blue cap and yellow body 15 mg Hard capsule with a blue cap and white body

Reductil 10 mg / 15 mg is indicated as adjunctive therapy within a weight management programme for:

- Patients with nutritional obesity and a body mass index (BMI) of 30 kg/m² or higher

- Patients with nutritional excess weight and a BMI of 27 kg/m² or higher, if other obesity-related risk factors such as type 2 diabetes or dyslipidaemia are present.

Note:

Reductil may only be prescribed to patients who have not adequately responded to an appropriate weight-reducing regimen alone, ie patients who have difficulty achieving or maintaining>5% weight loss within 3 months.

Treatment with Reductil 10 mg / 15 mg should only be given as part of a long-term integrated therapeutic approach for weight reduction under the care of a physician experienced in the treatment of obesity. 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 Reductil is stopped. Patients should change their lifestyle while on Reductil so that they are able to maintain their weight once drug treatment has ceased. They should be informed that, if they fail to do so, they may regain weight. Even after cessation of Reductil continued monitoring of the patient by the physician should be encouraged.

Adults: The initial dose is one (1) capsule of Reductil 10 mg swallowed whole, once daily, in the morning, with liquid (eg a glass of water). The capsule can be taken with or without food.

In those patients with an inadequate response to Reductil 10 mg (defined as less than 2 kg weight loss after four (4) weeks treatment), the dose may be increased to one (1) capsule of Reductil 15 mg once daily, provided that Reductil 10 mg was well tolerated.

Treatment must be discontinued in patients who have responded inadequately to Reductil 15 mg (defined as less than 2 kg weight loss after four (4) weeks treatment). Non-responders are at a higher risk of undesirable effects.

Duration of treatment:

Treatment must be discontinued in patients who have not responded adequately, ie whose weight loss stabilises at less than 5% of their initial bodyweight or whose weight loss within three (3) months after starting therapy has been less than 5% of their initial bodyweight. Treatment should not be continued in patients who regain 3 kg or more after previously achieved weight loss.

In patients with associated co-morbid conditions, it is recommended that treatment with Reductil 10 mg / 15 mg should only be continued if it can be shown that the weight loss induced is associated with other clinical benefits, such as improvements in lipid profile in patients with dyslipidaemia or glycaemic control of type 2 diabetes.

Reductil 10 mg / 15 mg should only be given for periods up to one year. Data on use over one year is limited.

Under 18 years, not recommended.

 Known hypersensitivity to sibutramine hydrochloride monohydrate or to any of the excipients

- Organic causes of obesity

- History of major eating disorders

- Psychiatric illness. Sibutramine has shown potential antidepressant activity in animal studies and, therefore it cannot be excluded that sibutramine could induce a manic episode in bipolar patients.

- Gilles de la Tourette's syndrome

- Concomitant use, or use during the past two weeks, of monoamine oxidase inhibitors or of other centrally-acting drugs for the treatment of psychiatric disorders (such as antidepressants, antipsychotics) or for weight reduction, or tryptophan for sleep disturbances.

- History of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or TIA)

- Inadequately controlled hypertension

- Hyperthyroidism

- Severe hepatic impairment

- Severe renal impairment and in patients with end stage renal disease on dialysis

- Benign prostatic hyperplasia with urinary retention

- Phaeochromocytoma

- Narrow angle glaucoma

- History of drug, medication or alcohol abuse

- Pregnancy and lactation

- Children and young adults up to the age of 18 years, owing to insufficient data

- Patients above 65 years of age, owing to insufficient data.

Warnings:

Blood pressure and pulse rate should be monitored in all patients on Reductil 10 mg / 15mg, as sibutramine has caused clinically relevant increases in blood pressure in some patients. In the first three months of treatment, these parameters should be checked every 2 weeks; between month 4 and 6 these parameters should be checked once monthly and regularly thereafter, at maximum intervals of three months. Treatment should be discontinued in patients who have an increase, at two consecutive visits, in resting heart rate of > 10 bpm or systolic/diastolic blood pressure of > 10 mmHg. In previously well-controlled hypertensive patients, if blood pressure exceeds 145/90 mmHg at two consecutive readings, treatment should be discontinued (see section 4.8 “Undesirable effects, cardiovascular system”). In patients with sleep apnoea syndrome particular care should be taken in monitoring blood pressure.

- For use of sibutramine concomitantly with sympathomimetics.

- Although sibutramine has not been associated with primary pulmonary hypertension, it is important, in view of general concerns with anti-obesity drugs, 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.

- Reductil 10 mg / 15 mg should be given with caution to patients with epilepsy.

- Increased plasma levels have been observed in the assessment of sibutramine in patients with mild to moderate hepatic impairment. Although no adverse effects have been reported, Reductil 10 mg / 15 mg should be used with caution in these patients.

- Although only inactive metabolites are excreted by the renal route, Reductil 10 mg / 15 mg should be used with caution in patients with mild to moderate renal impairment.

- Reductil 10 mg / 15 mg should be given with caution to patients who have a family history of motor or verbal tics.

- Women of child-bearing potential should employ adequate contraception whilst taking Reductil 10 mg / 15 mg.

- There is the possibility of drug abuse with CNS-active drugs. However, available clinical data have shown no evidence of drug abuse with sibutramine.

- There are general concerns that certain anti-obesity drugs are associated with an increased risk of cardiac valvulopathy. However, clinical data show no evidence of an increased incidence with sibutramine.

- Patients with a history of major eating disorders, such as anorexia nervosa and bulimia nervosa, are contraindicated. No data are available for sibutramine in the treatment of patients with binge (compulsive) eating disorder.

- Sibutramine should be given with caution to patients with open angle glaucoma and those who are at risk of raised intraocular pressure, e.g. family history.

- In common with other agents that inhibit serotonin reuptake, there is a potential for an increased risk of bleeding (including gynaecological, gastrointestinal and other cutaneous or mucous bleeding) in patients taking sibutramine. Sibutramine should, therefore, be used with caution in patients predisposed to bleeding events and those taking concomitant medications known to affect haemostasis or platelet function.

- Cases of depression, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. Special attention is therefore required in patients with a history of depression. If signs or symptoms of depression occur during the treatment with sibutramine, the discontinuation of sibutramine and commencement of an appropriate treatment should be considered.

- Reductil 10 mg / 15 mg contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Sibutramine and its active metabolites are eliminated by hepatic metabolism; the main enzyme involved is CYP3A4, and CYP2C9 and CYP1A2 can also contribute.Caution should be exercised on concomitant administration of Reductil 10 mg / 15 mg with drugs which affect CYP3A4 enzyme activity. CYP3A4 inhibitors include ketoconazole, itraconazole, erythromycin, clarithromycin, troleandomycin and cyclosporin. Co-administration of ketoconazole or erythromycin with sibutramine increased plasma concentrations (AUC) of sibutramine active metabolites (23% or 10% respectively) in an interaction study. Mean heart rate increased by up to 2.5 beats per minute more than on sibutramine alone.

Rifampicin, phenytoin, carbamazepine, phenobarbital and dexamethasone are CYP3A4 enzyme inducers and may accelerate sibutramine metabolism, although this has not been studied experimentally.

The simultaneous use of several drugs, each of which increases levels of serotonin in the brain, 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 antimigraine 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 SSRIs.

As sibutramine inhibits serotonin reuptake (among other effects), Reductil 10 mg / 15mg should not be used concomitantly with other drugs which also raise serotonin levels in the brain.

Concomitant use of Reductil 10 mg / 15 mg with other drugs which may raise the blood pressure or heart rate (e.g. sympathomimetics) has not been systematically evaluated. Drugs of this type include certain cough, cold and allergy medications (eg ephedrine, pseudoephedrine), and certain decongestants (eg xylometazoline). Caution should be used when prescribing Reductil 10 mg / 15 mg to patients who use these medicines.

Reductil 10 mg / 15 mg does not impair the efficacy of oral contraceptives.

At single doses, there was no additional impairment of cognitive or psychomotor performance when sibutramine was administered concomitantly with alcohol. However, the consumption of alcohol is not compatible with the recommended dietary measures as a general rule.

No data on the concomitant use of Reductil 10 mg / 15 mg with orlistat are available.

Two weeks should elapse between stopping sibutramine and starting monoamine oxidase inhibitors.

Most side effects reported with sibutramine occurred at the start of treatment (during the first 4 weeks). Their severity and frequency diminished over time. They were generally not serious, did not entail discontinuation of treatment, and were reversible.

The side effects observed in phase II/III clinical trials are listed below by body system (very common >1/10, common <1/10 and >1/100):

Cardiovascular system

A mean increase in resting systolic and diastolic blood pressure of 2-3 mmHg, and a mean increase in heart rate of 3-7 beats per minute have been observed. Higher increases in blood pressure and heart rate cannot be excluded in isolated cases.

Any clinically significant increase in blood pressure and pulse rate tends to occur early on in treatment (first 4-12 weeks). Therapy should be discontinued in such cases.

For use of Reductil 10 mg / 15 mg in patients with hypertension.

Clinically significant adverse events seen in clinical studies and during postmarketing surveillance are listed below by body system:

Blood and lymphatic system disorders:

Thrombocytopenia, Henoch-Schonlein purpura

Cardiovascular disorders:

Atrial fibrillation, paroxysmal supraventricular tachycardia

Immune system disorders:

Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported

Psychiatric disorders:

Agitation

Depression in patients both with and without a prior history of depression.

Nervous system disorders:

Seizures

Serotonin syndrome in combination with other agents affecting serotonin release.

Transient short-term memory disturbance

Eye disorders:

Blurred vision

Gastrointestinal disorders:

Diarrhoea, vomiting, gastrointestinal haemorrhage

Skin and subcutaneous tissue disorders:

Alopecia, rash, urticaria, cutaneous bleeding reactions (ecchmosis, petechiae)

Renal and urinary disorders:

Acute interstitial nephritis, mesangiocapillary glomerulonephritis, urinary retention

Reproductive system and breast disorders:

Abnormal ejaculation/orgasm, impotence, menstrual cycle disorders, metrorrhagia

Investigations:

Reversible increases in liver enzymes

Other:

Withdrawal symptoms such as headache and increased appetite have rarely been observed.

Abbott Laboratories Limited

(POM)

22 June 2009