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Please note: that prescription orders to RD addresses will incur additional $2.95 due to the recent changes in freight by the courier company.
Classification
Prescription Only medicine - Please View 'Prescription Medicine' under Customer Service before ordering
Dosage
The recommended starting dose of REDUCTIL is one 10mg capsule administered once daily with or without food. If there is inadequate weight loss (ie less than 2kg) after 4 weeks, the dose may be increased to one 15mg capsule once daily provided 10mg was well tolerated. Blood pressure and heart rate changes should be taken into account when deciding to increase the dose. (see Warnings and Precautions ) . Doses above 15mg daily are not recommended.
In most of the clinical trials, REDUCTIL was given in the morning.
Elderly Patients: REDUCTIL is contraindicated for elderly patients over 65 years of age (see Contraindications/Warnings & Precautions ).
Children: REDUCTIL is contraindicated for children under 18 years of age.
Duration of Treatment: Patients who have demonstrated an adequate response to REDUCTIL (ie weight loss of ≥2kg within 4 weeks at a defined dose), usually achieve maximal weight loss (5% -10% of initial body weight) after completing 6 months continuous treatment with REDUCTIL. Current data supports that maximal weight loss is maintained when treatment with REDUCTIL is extended to 1 year. Studies involving more than 1 year administration of REDUCTIL to patients are ongoing.
Treatment must be discontinued in patients who have not responded adequately, i.e whose weight loss stabilizes at less than 5% of their initial bodyweight or whose weight loss within 3 months after starting therapy has been less than 5% of their initial bodyweight. Treatment should not be continued in patients who regain 3kg or more after previously achieved weight loss.
In patients with associated co-morbid conditions, it is recommended that treatment with REDUCTIL should only be continued if it can be shown the weight loss induced is associated with clinical benefits.
Ingredients
Each REDUCTIL capsule contains 10mg of sibutramine hydrochloride. It also contains as inactive ingredients: lactose, cellulose - microcrystalline, silica- colloidal anhydrous and magnesium stearate in a hard-gelatin capsule [which contains gelatin, sodium lauryl sulfate, titanium dioxide, shellac, lecithin, dimethicone, indigo carmine CI73015, iron oxide black CI77499 and quinidine yellow CI47005 (10mg capsules only)]
Purpose/Usage
REDUCTIL (sibutramine hydrochloride ) is the first orally administered serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitor (SNRI) to be used for the management of obesity.
REDUCTIL is indicated for weight loss and maintenance in obese (Body Mass Index 30 or greater) and overweight (Body Mass Index 27 or greater with co-morbid conditions) patients.
REDUCTIL (sibutramine hydrochloride ) is the first orally administered serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitor (SNRI) to be used for the management of obesity.
Sibutramine produces its therapeutic effects predominantly via its active secondary and primary amine metabolites (metabolites 1 and 2 respectively) which are inhibitors of noradrenaline, serotonin (5-hydroxytryptamine; 5-HT) and dopamine reuptake. In human brain tissue, metabolites 1 and 2 are ~3-fold more potent as in vitro inhibitors of noradrenaline and serotonin reuptake than of dopamine. Plasma samples taken from sibutramine-treated volunteers caused significant inhibition of both noradrenaline reuptake (73%) and serotonin reuptake (54%) with no significant inhibition of dopamine reuptake (16%). Sibutramine and its metabolites are neither monoamine-releasing agents nor are they monoamine oxidase inhibitors. They have no affinity with a large number of neurotransmitter receptors, including serotonergic (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), adrenergic (β1, β2, β3,α1, α2), dopaminergic (D1-like, D2-like), muscarinic, histaminergic (H1), benzodiazepine and NMDA receptors.
In animal models, it potently 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. It is postulated that sibutramine decreases food intake by enhancing central noradrenaline and 5-HT function mediated through α-1 and 5-HT2A/2C receptors, respectively, and increases metabolic rate by enhancing peripheral noradrenaline function through α-3 adrenoreceptors. In man dose-dependant reductions in bodyweight are seen following treatment with sibutramine.
Pharmacodynamics/Clinical Studies
Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.
The long-term effects of REDUCTIL on the morbidity and mortality associated with obesity have not been established. Sibutramine's effect on weight loss was examined in double-blind, placebo-controlled obesity trials with study durations of 8 weeks to 18 months and doses ranging from 1 to 30mg once daily. A total of 8052 patients were included in these studies; 5335 patients being treated with REDUCTIL and 2717 patients with placebo. The patients involved in these studies either had uncomplicated obesity with Body Mass Index (BMI) ranging from 27 to 40 kg/m2 or were obese with comorbid condition(s) and BMI ≥ 27kg/m2. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5mg to 30mg once daily. In two 12-month studies (one of these studies only involved obese patients who had lost at least 6 kg on a 4-week very low calorie diet), maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of weight loss achieved with REDUCTIL was consistent across studies.
Data from two 12-month studies in uncomplicated obese patients and obese patients with type 2 diabetes mellitus indicate that patients who lose at least 2 kg in the first 4 weeks with a given dose of Reductil are most likely to achieve long-term weight loss on that dose of Reductil. Approximately 75% of such patients went on to achieve a weight loss of ≥5% of their initial bodyweight at month 12. Conversely, uncomplicated obese and obese type 2 diabetic patients, who did not lose ≥2 kg after 4 weeks treatment with Reductil did not lose at least 5% of their initial bodyweight by month 12 (see Dosage and Administration ).
Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months treatment with REDUCTIL in placebo-controlled clinical trials. These data were consistent with more objective measurements of abdominal visceral adiposity such as computed tomography (CT) scans; CT scans on obese patients in a 2-year study provide evidence of a significant decrease in abdominal visceral fat of 24% and in subcutaneous fat of 17% after Reductil 10 mg, compared to baseline. These changes were associated with significant reductions from baseline in mean weight, waist circumference and fasting blood glucose, insulin, C-peptide and triglycerides.
Double-blind, placebo-controlled obesity trials with study durations of 12 weeks to 18 months have provided evidence that the weight loss resulting from treatment with REDUCTIL was associated with improvements in patients' glycaemic control, serum lipid profiles (similar to those seen with non-pharmacological mediated weight loss), and serum uric acid. Treatment with REDUCTIL (5 to 20mg once daily) is associated with mean increases in blood pressure of 1 to 3mmHg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings, which were not associated with any clinically significant outcomes, are similar in normotensives and in patients with hypertension controlled with medication. With the latter patients, control of blood pressure was not adversely affected. Those patients who lose significant ( ≥5% weight loss) amounts of weight on REDUCTIL tend to have smaller increases in blood pressure and pulse rate (see Warnings and Precautions ).
Studies in healthy volunteers indicate that REDUCTIL does not affect the sympathoadrenal system, the hypothalamic-pituitary-end organ axes and other endocrine parameters including testosterone and postprandial cholecystokinin.
Echocardiographic Data: Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with cardiac valve dysfunction. The possible occurrence of cardiac valve disease with REDUCTIL was specifically investigated in two studies using echocardiography. In the first study 209 patients (mean age, 54 years) received REDUCTIL 15mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In a second study, 104 patients received either sibutramine 10 mg or sibutramine 20 mg and 52 patients received placebo daily for 6 months. Echocardiography was performed at baseline and at month 6. In patients with normal valves at baseline, no sibutramine-treated patient compared to one placebo-treated patient (moderate mitral regurgitation) had valvular heart disease at month 6.
Pharmacokinetics
The pharmacokinetics of sibutramine and its pharmacologically active metabolites are similar in obese subjects to those in normal weight subjects, and there is no evidence of any clinically significant difference in the pharmacokinetics of males and females. The pharmacokinetic profile observed in elderly healthy subjects (mean age 70 years) is similar to that seen in young healthy subjects. Nevertheless, REDUCTIL is not intended for use in the elderly over 65 years of age as safety and efficacy in this population has not been established. Based on steady-state trough plasma concentrations of the active metabolites of sibutramine, there was no evidence of any clinically significant pharmacokinetic difference seen between Afro-Americans and Caucasians.
Absorption
Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 hours) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.
The effect of food on steady-state kinetics of sibutramine and its two active metabolites, during long-term treatment with REDUCTIL, will not be significant. Administration of sibutramine with food in a single dose study resulted in reduced Cmax for each of the two active metabolites and delayed Tmax whilst the AUCs were not significantly altered.
Distribution: In vitro, sibutramine and its metabolites 1 and 2 are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses. Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. Tissue distribution was unaffected by pregnancy, with relatively low transfer to the foetus.
Metabolism: Sibutramine is metabolised in the liver principally by the cytochrome P450 isoenzyme CYP3A4 to, principally, two demethylated active metabolites which are secondary and primary amines. These active metabolites are further metabolised to pharmacologically inactive conjugated hydroxy-metabolites. Based on in-vitro studies there was no indication of sibutramine's affinity for the CYP2D6 isoenzyme - a low capacity enzyme involved in pharmacokinetic interactions of 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 (ie ketaconazole or erythromycin) with REDUCTIL increased plasma concentrations of the active metabolites and this was accompanied by recorded modest increase in heart rate.
The high capacity of the CYP3A4 and the low therapeutic dose of sibutramine suggest a relatively low potential for sibutramine to affect the metabolism of other drugs metabolised by this isoenzyme. However, caution should be exercised on concomitant administration of REDUCTIL with drugs that affect CYP3A4 isoenzyme activity (see Interactions).
The plasma concentrations of the active metabolites reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of the secondary- and primary amine metabolites (14 and 16 hours, respectively) were unchanged following repeated dosing.
Elimination: Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and faeces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were two inactive conjugated hydroxy-metabolites; unchanged sibutramine, and the active secondary and primary amine metabolites were not detected. The primary route of excretion for the active metabolites is hepatic metabolism and for the inactive hydroxy-metabolites is renal excretion. The plasma levels of the two active metabolites (ie the secondary and primary amine metabolites) peaked in 3 hours (Tmax) with elimination t1/2 of 14 hours and 16 hours respectively. Linear kinetics have been demonstrated over the dose range 10mg to 30mg. Steady-state for the two active metabolites was achieved within 4 days with an approximate two-fold accumulation.
Renal Insufficiency: The effect of renal disease has not been studied. However, since sibutramine and its two active metabolites are eliminated by hepatic metabolism, renal disease is unlikely to have a significant effect on their disposition. Elimination of the inactive hydroxy-metabolites, which are renally excreted, may be affected in this population. REDUCTIL should not be used in patients with severe renal impairment
Hepatic Insufficiency: In a study, with patients with moderate hepatic impairment receiving a single 15mg oral dose of sibutramine, the combined AUCs of the two active metabolites were increased by 24% compared to healthy subjects while plasma concentrations of the two inactive hydroxy-metabolites were unchanged. The observed differences in concentrations of the active metabolites do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. REDUCTIL should not be used in patients with severe hepatic dysfunction.
Indications: REDUCTIL 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. REDUCTIL is recommended for obese patients with an initial body mass index ≥30kg/m2, or ≥ 27kg/m2 in the presence of other obesity-related risk factors (e.g., diabetes, dyslipidaemia, hypertension).
Reductil may only be prescribed to patients who have not adequately responded to an appropriate weight-reducing regimen alone (hypocaloric diet and/or exercise) i.e patients who have difficulty achieving or maintaining >5% weight loss within 3 months.
BMI is calculated by taking the patient's weight, in kg, and dividing by the patient's height, in meters, squared.
REDUCTIL is not intended for use in obese children under 18 years as safety and efficacy in this population has not been established.
REDUCTIL is not intended for use in elderly patients over 65 years of age as safety and efficacy in this population has not been established.
Precautions
REDUCTIL is contraindicated in patients:
With known hypersensitivity to sibutramine hydrochloride or any of the inactive ingredients of REDUCTIL
With organic causes of obesity
Who have history of major eating disorders such as anorexia nervosa or bulimia nervosa
With 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
With Gilles de la Tourette's syndrome
Using, or have used during the past two weeks monoamine oxidase inhibitors, other centrally-acting drugs for the treatment of either psychiatric disorders (such as antidepressants, antipsychotics) or weight reduction, or tryptophan for sleep disturbances. (see Interactions )
With a history of coronary artery disease, congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrythmia or cerebrovascular disease (stroke or TIA)
With inadequately controlled hypertension (>145/90 mmHg) (see WARNINGS and PRECAUTIONS)
With hyperthyroidism
With severe liver impairment
With severe renal impairment
With benign prostatic hyperplasia with urinary retention
With phaeochromocytoma
With narrow angle glaucoma
With a history of drug, medication or alcohol abuse
Who are pregnant or breastfeeding
Children and young adults up to the age of 18 years, owing to insufficient data
Patients above 65 years, owing to insufficient data
Warnings and Precautions
Cardiovascular Parameters: Blood pressure and pulse rate should be monitored in all patients on REDUCTIL 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 at least every 2 weeks, thereafter, regularly 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 mm Hg. In previously well-controlled hypertensive patients, if blood pressure exceed 145/90 mmHg at two consecutive readings, treatment should be discontinued.
In the obese patient, blood pressure should be determined using an appropriate cuff size based on arm circumference, measurement in the seated position and taking measurements in both arms (at least initially).
Concurrent Cardiovascular Disease: See Contraindications.
Hepatic Impairment
: Although patients with mild to moderate hepatic impairment showed a 24% increase in bioavailability of sibutramine with no adverse clinical effects, REDUCTIL should , however, be used with caution in these patients (see Contraindications ).
Impaired Renal Function: Although only inactive metabolites are excreted by the renal route, REDUCTIL should be used with caution in patients with mild to moderate renal impairment (see Contraindications ).
Seizures: Seizures were reported in <0.1% of patients treated with REDUCTIL in controlled studies. REDUCTIL should be given with caution to patients with a history of seizures.
Motor or Verbal Tics
: Reductil should be given with caution to patients who have a family history of motor or verbal tics.
Gallstones: Weight loss can precipitate or exacerbate gallstone formation.
Primary Pulmonary Hypertension:
There were no cases of primary pulmonary hypertension reported in clinical studies conducted with REDUCTIL, this being consistent with REDUCTIL not causing the release of serotonin from nerve terminals. This is in contrast to certain other central-acting weight loss medications which cause the release of serotonin from nerve terminals and have been associated with pulmonary hypertension, a rare but lethal disease. Although sibutramine has not been associated with primary pulmonary hypertension, it is important, in view of general concerns with anti-obesity drugs, to check for symptoms such as progressive dyspnoea, chest pain and ankle oedema in the course of routine monitoring of patients. The patient should be advised to consult a doctor immediately if these symptoms occur.
Use in Pregnancy:
Whilst reproduction studies in animals have shown that REDUCTIL is not teratogenic, the safety of REDUCTIL in pregnant women has not been established.
Therefore the use of REDUCTIL during pregnancy is contraindicated. Women of child-bearing potential should employ adequate contraception while taking REDUCTIL. Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during treatment with REDUCTIL.
Use During Lactation: It is not known whether sibutramine or its metabolites are excreted in human breast milk and therefore administration of Reductil is contraindicated during lactation.
Use in Children: The safety and effectiveness of REDUCTIL in children and young adults up to the age of 18 years is contraindicated , owing to insufficient data.
Use in Elderly: Use in patients above 65 years of age is contraindicated, owing to insufficient data.
Effects on Ability to Drive and Use Machines: REDUCTIL was shown not to affect psychomotor or cognitive performance in studies involving healthy volunteers. As centrally-active medication may have the potential to impair judgement , thinking and motor skills, patients should be cautioned that their ability to drive a vehicle or operate hazardous machinery may be impaired when taking REDUCTIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity: There was no evidence of carcinogenicity in mice (up to 20 mg/kg/day for 2 years) or in female rats (up to 9 mg/kg/day for 2 years). In male rats there was a higher incidence of benign tumours of the testicular interstitial cells; such tumours are commonly seen in rats and are hormonally mediated. The relevance of these tumours to humans is not known.
Mutagenicity: In vitro and in vivo assays found sibutramine to be non-mutagenic. Its two major active metabolites were found to have equivocal bacterial mutagenic activity in the Ames test. However, both metabolites gave consistently negative results in other in vitro and in vivo assays.
Impairment of Fertility: In rats, there were no effects on fertility at doses generating combined plasma AUCs of the two major active metabolites up to 43 times those following the maximum human dose (20 mg). At 13 times the human combined AUC, there was maternal toxicity, and the dams' nest-building behaviour was impaired, leading to a higher incidence of perinatal mortality; there was no such effect at approximately 4 times the human combined AUC.
Adverse Effects
Most adverse effects 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 are listed below by body system.
Cardiovascular system: INCIDENCE: (cf. 'cardiovascular changes') Occasional: UNDESIRABLE EFFECTS: Tachycardia, Palpitations, Raised blood pressure/hypertension, Vasodilation (hot flush)
Gastrointestinal system: INCIDENCE: Frequent: UNDESIRABLE EFFECTS: Loss of appetite, Constipation, INCIDENCE: Occasional : UNDESIRABLE EFFECTS: Nausea, Haemorrhoid aggravation
Central nervous system: INCIDENCE: Frequent : UNDESIRABLE EFFECTS: Dry mouth, Insomnia: INCIDENCE: Occasional: UNDESIRABLE EFFECTS: Light-headedness, Paraesthesia, Headache
Anxiety,
Skin: INCIDENCE: Occasional : UNDESIRABLE EFFECTS: Sweating
Sensory functions: INCIDENCE: Occasional: UNDESIRABLE EFFECTS: Taste perversion
Incidence: 'frequent' > 10%; 'occasional' = 1-10%
The following clinically significant adverse events occurred in individual cases under treatment with sibutramine:
Acute interstitial nephritis
Mesangiocapillary glomerulonephritis
Henoch-Sch?in purpura
Seizures
Thrombocytopenia
Reversible increases in liver enzymes
Acute psychotic attack after treatment in one patient with schizo-affective disorder which presumably existed prior to treatment
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.
Occasional cases of blurred vision have been reported from post-marketing surveillance.
Cardiovascular changes: A mean increase in resting systolic and diastolic blood pressure of 1-3 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 have been observed in isolated cases.
Clinically significant increases in blood pressure and pulse rate tend to occur early in treatment (first 4-12 weeks). Therapy should be discontinued in such cases (see Warnings and Precautions ). For use in patients with hypertension, see Contraindications & Warnings and Precautions.
Laboratory Test Findings: The incidence of abnormal liver function tests (LFTs) in placebo-controlled studies was low (sibutramine 0.5%; placebo 0.2%), transient and without clinical sequelae.
Interactions: CNS Active Drugs: The use of REDUCTIL in combination with other CNS-active drugs, particularly serotonergic agents (eg antidepressants, appetite suppressants), has not been systematically evaluated. Consequently, concomitant administration of REDUCTIL with other centrally-acting drugs is not recommended (see Contraindications ).
In patients receiving monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions known as 'serotonin syndrome'. Because REDUCTIL inhibits serotonin reuptake, REDUCTIL should not be used concomitantly with a MAOI (see Contraindications ). At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with REDUCTIL. Similarly, at least 2 weeks should elapse between discontinuation of REDUCTIL and initiation of treatment with a MAOI.
The rare, but serious, constellation of symptoms termed 'serotonin syndrome' has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy (eg sumatriptan succinate and dihydroergotamine), certain opioids, (eg dextromethorphan, pethidine, pentazocine and fentanyl), lithium, or tryptophan. 'Serotonin syndrome' has also been reported with the concomitant use of two serotonin reuptake inhibitors.
As REDUCTIL inhibits serotonin reuptake, it should not be administered with other serotonergic agents such as those listed above.
Drugs That May Raise Blood Pressure and/or Heart Rate: : Concomitant use of REDUCTIL and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as phenylpropanolamine, ephedrine, or pseudoephedrine and certain anti-inflammatory agents (eg NSAIDs). Caution should be used when prescribing REDUCTIL to patients who use these medications.
Drugs That Affect Cytochrome P450(CYP3A4 Isoenzyme) Metabolism: The data indicate that there is a potential for drug interactions to occur between drugs which affect the CYP3A4 isoenzyme of cytochrome P450 (see Pharmacokinetics; Metabolism ), however, the magnitude appears to be small. Caution should therefore be exercised on concomitant administration of REDUCTIL with drugs which either inhibit (eg ketoconazole, erythromycin, troleandomycin and cyclosporin) or induce (eg rifampicin, macrolide antibiotics, phenytoin, carbamazepine, phenobarbitone and dexamethasone) CYP3A4 isoenzyme activity.
Co-administration of ketoconazole or erythromycin with sibutramine increased plasma concentrations (AUC) of sibutramine 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.
Cimetidine: Studies in healthy volunteers indicated that the concomitant administration of REDUCTIL (15mg once daily) and cimetidine (400mg twice daily) caused a marginal clinically insignificant increase in Cmax and AUC of the active metabolites of sibutramine.
Alcohol: At single doses, there was no impairment of cognitive or psychomotor performance when REDUCTIL was administered concomitantly with alcohol. However, the consumption of alcohol is not compatible with the recommended dietary measures as a rule. The concomitant use of REDUCTIL with excess alcohol is not recommended.
Oral Contraceptives: The suppression of ovulation by oral contraceptives was not inhibited by REDUCTIL . No clinically significant systemic interaction was observed; therefore, no requirement for alternative contraceptive precautions are needed when patients taking oral contraceptives are concurrently prescribed sibutramine.
Drugs Highly Bound to Plasma Proteins: Although sibutramine and its two active metabolites are extensively bound to plasma proteins ((94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted.
Orlistat: No data on the concomitant use of REDUCTIL and orlistat are available.
Overdosage
There is very limited experience of overdosing with sibutramine. No specific therapeutic measures are recommended and there is no specific antidote. Treatment should consist of general measures employed in the management of overdosage: an airway should be established;cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of β-blockers may be indicated to control elevated blood pressure or tachycardia. The benefits of forced diuresis and haemodialysis are unknown.
There are a number of reports of overdose in humans (including accidental ingestion by children as young as 18 months) where doses of up to 500 mg sibutramine hydrochloride monohydrate were ingested. A heart rate of 160 beats per minute was observed in one patient who took 500 mg sibutramine hydrochloride monohydrate. Except in one case of multiple drug intoxication with alcohol (where the patient died, possibly due to inhalation of vomit), there were no complications and the individuals made a full recovery.
Pharmaceutical Precautions
Shelf life: 3 years. Store below 25?C.
Chemically, sibutramine hydrochloride monohydrate is a racemic mixture of the (+) and (-) enantiomers of N -{1-[1-(4-chlorophenyl) cyclobutyl]-3-methylbutyl}- N, N -dimethylamine hydrochloride, monohydrate, and has an empirical formula of C17H29Cl2NO. Its molecular weight is 334.33. CAS Number: 125494-59-9. The INN for the free base is 'sibutramine'. The CAS Number for sibutramine free base is CAS 106650-56-0.
Sibutramine hydrochloride is a white to cream crystalline powder with a solubility of 2.9 mg/mL in pH 5.2 water. Its octanol:water partition coefficient is 30.9 at pH 5.0.
Name and Address
Knoll Australia Pty Ltd
Locked Bag 2015
Lane Cove NSW 2066
AUSTRALIA
PO Box 33-1486
Takapuna
AUCKLAND 1332
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Reductil precriptions info from Abbott
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