Xenical

Orlistat.

Pharmacology: Pharmacodynamics: Mechanism of Action: Xenical is a potent, specific and reversible long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the serine residue of the active sites of gastric and pancreatic lipases. The inactivated enzyme is thus unable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on the weight control.
Based on fecal fat measurements, the effect of Xenical is seen as soon as 24-48 hrs after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pre-treatment levels, within 48-72 hrs.
Efficacy/Clinical Studies: Obese Adults: Clinical trials have demonstrated that orlistat promotes weight loss, exceeding that achieved with diet alone. Weight loss was apparent within 2 weeks of initiation of treatment and continued for a duration of 6-12 months, even in individuals who failed to respond to dieting alone. Over 2 years, statistically significant improvements in metabolic risk factors associated with obesity were observed. Furthermore, significant improvements in body fat were observed in comparison to placebo. Orlistat was also effective in prevention of weight regain, with approximately half of the patients regaining no >25% of lost weight and about half of these regaining no weight or even continuing to lose weight.
Obese Patients with Type 2 Diabetes: Clinical trials conducted over a period of 6 months to 1 year showed that overweight or obese patients with type 2 diabetes had greater weight loss compared to dieting alone. It was also demonstrated that the weight loss was primarily due to decreased body fat. Additionally, despite receiving antidiabetic medication, the average patient had poor glycemic control prior to study entry, but showed statistically significant and clinically meaningful improvements in glycemic control following treatment with orlistat. Furthermore, antidiabetic medication usage decreased, insulin levels were lower and decreased insulin resistance was apparent. The weight loss in these patients was accompanied by a decrease in HbA1c, fasting blood glucose and postprandial blood glucose levels (see table). It has not been demonstrated that the effect on HbA1c is independent from weight reduction.

Click on icon to see table/diagram/image

Delay in Onset of Type 2 Diabetes in Obese Patients: A clinical trial conducted over a 4-year period showed that orlistat significantly reduced the risk of onset of type 2 diabetes, with the risk decreased by approximately 37%, compared to the placebo group. The decrease in risk for patients with impaired glucose tolerance at baseline was even more marked at approximately 45%. Additionally, weight loss was significantly greater in the orlistat group than in the placebo group, and was maintained throughout the 4-year study period. Furthermore, orlistat-treated patients showed significant reductions in metabolic risk factors compared to placebo.
Obese Adolescents: A clinical trial conducted over 1 year, showed that obese adolescents treated with orlistat had a decreased BMI, compared to those in the placebo group who had an increased BMI. Furthermore, those in the orlistat group had significantly decreased fat mass and waist and hip circumference compared to those in the placebo group. Diastolic blood pressure was also significantly reduced in the orlistat group compared to placebo.
Pharmacokinetics: Absorption: In normal weight and obese volunteers, the systemic exposure to orlistat was minimal. Plasma concentrations of intact orlistat were nearly nonmeasurable (<5 ng/mL) following a single oral administration of orlistat 360 mg.
In general, after long-term treatment at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 micromol), without evidence of accumulation, showing consistency with negligible absorption.
Distribution: The volume of distribution cannot be determined because the drug is minimally absorbed. In vitro, orlistat is >99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.
Metabolism: Based on animal data, it is likely that the metabolism of orlistat occurs mainly presystemically. Two major metabolites (M1 and M3) accounted for approximately 42% of the total radioactivity in plasma resulting from the minute fraction of the dose that was absorbed systemically in obese patients.
The 2 major metabolites have very weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/mL and 108 ng/mL, respectively), these metabolites are pharmacologically inconsequential.
Elimination: Studies in normal weight and obese subjects have shown that fecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of the administered dose was excreted in feces and 83% of that as unchanged orlistat.
The cumulative renal excretion of total orlistat-related materials was <2% of the given dose. The time to reach complete excretion (fecal plus urinary) was 3-5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.
Special Populations: Plasma concentrations of orlistat and its metabolites, M1 and M3, were similar in pediatric patients compared to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat and placebo treatment groups, respectively.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Teratogenicity: In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogenic effect in animals, no malformative effects is expected in man.

In conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) ≥30 kg/m², or overweight patients (BMI ≥28 kg/m²) with associated risk factors eg, type II diabetes, hyperlipidemia and hypertension. Treatment with orlistat should be discontinued after 12 weeks if patients have been unable to loose at least 5% of their body weight as measured at the start of drug therapy.

Standard Dosage: Recommended Dose: 1 cap which should be taken immediately before, during or up to 1 hr after each main meal. If a meal is missed or contains no fat, the dose of orlistat should be omitted.
The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30% of calories from fat. It is recommended that the diet should be rich in fruit and vegetables. The daily intake of fat, carbohydrate and protein should be distributed over 3 main meals.
Doses of orlistat >120 mg 3 times daily have not been shown to provide additional benefit. The effect of orlistat results in an increase in fecal fat as early as 24-48 hrs after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pre-treatment levels, within 48-72 hrs.
Special Populations: The effect of orlistat in patients with hepatic and/or renal impairment has not been studied. Orlistat is not intended to be used in children.

Single doses of Xenical 800 mg and multiple doses of up to 400 mg 3 times daily for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg 3 times daily have been administered to obese patients for 6 months without significant increase of adverse findings.
Orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with recommended dose.
Should a significant overdose of Xenical occur, it is recommended that the patient be observed for 24 hrs. Based on human and animal studies, any systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.

Chronic malabsorption syndrome; cholestasis; known hypersensitivity to orlistat or any of the components contained in the medicinal product.

The majority of patients in long-term studies of up to 4 years of treatment had vitamins A, D, E and K and β-carotene levels with normal range. In order to ensure adequate nutrition, the use of a multivitamin supplement could be considered.
Patients should be advised to adhere to the dietary guidelines (see Dosage & Administration). The possibility of experiencing gastrointestinal events (see Adverse Reactions) may increase when Xenical is taken with a diet high in fat (eg, in a 2000-kcal/day diet, >30% of calories from fat equates to >67 g of fat). The daily intake of fat should be distributed over 3 main meals. If Xenical is taken with any 1 meal very high in fat, the possibility of gastrointestinal effects may increase. Weight loss induced by Xenical is accompanied by improved metabolic control in type 2 diabetics which might allow or require reduction in the dose of hypoglycemic medication eg, sulfonylureas.
A reduction in cyclosporin plasma levels has been observed when Xenical is co-administered. Therefore, it is recommended to monitor more frequently than usual the cyclosporin plasma levels when Xenical is co-administered (see Interactions).
In a PK study, oral administration of amiodarone during orlistat treatment demonstrated a 25-30% reduction in the systemic exposure to amiodarone and desethylamiodarone. Due to the complex pharmacokinetics of amiodarone, the clinical effect of this is unclear. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. A reduced therapeutic effect of amiodarone is possible.
Laboratory Tests: Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants.
Renal and Hepatic Impairment: Clinical investigations in patients with renal and/or hepatic impairment have not been undertaken.
Use in pregnancy: In animal reproductive studies, no embryotoxic or teratogenic effects were observed with orlistat. In absence of teratogenic effect in animals, no malformative effect is expected in human beings. However, Xenical is not recommended for use during pregnancy in the absence of clinical data.
Use in lactation: The secretion of orlistat in human breast milk has not been investigated. Xenical should not be taken during breastfeeding.
Use in children: Clinical investigations in children <12 years have not been undertaken.

Use in pregnancy: In animal reproductive studies, no embryotoxic or teratogenic effects were observed with orlistat. In absence of teratogenic effect in animals, no malformative effect is expected in human beings. However, Xenical is not recommended for use during pregnancy in the absence of clinical data.
Use in lactation: The secretion of orlistat in human breast milk has not been investigated. Xenical should not be taken during breastfeeding.

Clinical Trials: Adverse reactions to Xenical are largely gastrointestinal in nature and related to the pharmacologic effect of the drug on preventing the absorption of ingested fat. Commonly observed events were oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. The incidence of these increases the higher the fat content of the diet. Patients should be counseled as to the possibility of gastrointestinal effects occurring and how best to handle them eg, reinforcing the diet, particularly the percentage of fat it contains. Consumption of a diet low in fat will decrease the likelihood of experiencing adverse gastrointestinal events and this may help patients to monitor and regulate their fat intake.
These adverse gastrointestinal reactions are generally mild and transient. They occurred early in the treatment (within 3 months) and most patients experienced only one episode.
Treatment-emergent GI-adverse events that occurred commonly among patients treated with Xenical were the following: Abdominal pain/discomfort, flatulence, liquid stools, soft stools, rectal pain/discomfort, tooth disorder, gingival disorder.
Other events observed were the following: Upper respiratory infection, lower respiratory infection, influenza, headache, menstrual irregularity, anxiety, fatigue, urinary tract infection.
Unique treatment adverse events observed in obese type 2 diabetic patients were hypoglycemia (very common) and abdominal distension (common). Weight loss induced by Xenical is accompanied by improved metabolic control in type 2 diabetics which might allow or require reduction in the dose of hypoglycemic medication (see Precautions).
In a 4-year clinical trial, the general pattern of adverse event distribution was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal related adverse events occurring in year 1 decreasing year on year over the 4-year period.
Post-Marketing: Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption, increase in transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported during the post-marketing. No causal relationship or physiopathological mechanism between hepatitis and orlistat therapy has been established. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants during post-marketing.
Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs (see Interactions).

No interactions based on specific drug-drug interaction studies with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine gastrointestinal therapeutic system (GITS), nifedipine slow release, sibutramine or alcohol have been observed.
However, when warfarin or other oral anticoagulants are given in combination with orlistat, international normalised ratio (INR) values should be monitored.
Decreases in the absorption of vitamins D and E, and β-carotene have been observed when co-administered with Xenical. If a multivitamin supplement is recommended, it should be taken at least 2 hrs after the administration of Xenical or at bedtime.
A reduction in cyclosporin plasma levels has been observed when Xenical is co-administered (see Precautions). Therefore, it is recommended to monitor more frequently than usual the cyclosporin plasma levels when Xenical is co-administered (see Precautions).
In a PK study, oral administration of amiodarone during orlistat treatment demonstrated a 25-30% reduction (see Precautions) in the systemic exposure to amiodarone and desethylamiodarone. Due to the complex pharmacokinetics of amiodarone, the clinical effect of this is unclear. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. A reduced therapeutic effect of amiodarone is possible.
Convulsions have been reported in patients treated concomitantly with Xenical and antiepileptic drugs. A causal relationship has not been established, however, patients should be monitored for possible changes in the frequency and/or severity of convulsions.
Incompatibilities: Not applicable.

Do not store above 25°C. Store in original package in order to protect from moisture.

Anti-Obesity Agents

A08AB01 - orlistat ; Belongs to the class of peripherally acting antiobesity products.

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