Xenical

Orlistat.

Pharmacology: Xenical is a potent, specific and 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 active serine site of the 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 weight control. Systemic absorption of the drug is therefore not needed for activity.
Efficacy in Patients with Type 2 Diabetes: Pooled data from four 1-year studies and three 6-month studies in type 2 diabetic patients showed that the percentage of responders (≥10% of body weight loss) was 11.3% with orlistat as compared to 4.5% with placebo. The mean difference in weight loss with the drug compared to placebo was 2.47 kg in these patients.
The pooled data from the four 1-year studies and three 6-month studies of Xenical as an adjunct to antidiabetic medications are summarized in the following table: See table.

Click on icon to see table/diagram/image
Pharmacokinetics: Absorption: Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were nonmeasurable (<5 ng/mL) 8 hrs following oral administration of orlistat.
In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 micromole), without evidence of accumulation, and consistent with negligible absorption.
Distribution: The volume of distribution cannot be determined because the drug is minimally absorbed and has no defined systemic pharmacokinetics. 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 within the gastrointestinal wall. Based on a study in obese patients, of the minute fraction of the dose that was absorbed systemically, 2 major metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1, with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasma concentration.
M1 and M3 have an open β-lactone ring and extremely 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 and 108 ng/mL, respectively), these metabolites are considered to be 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.

Long-term treatment of obese and overweight patients, including patients with risk factors associated with obesity, in conjunction with a mildly hypocaloric diet. Xenical is effective in long-term weight control (weight loss, weight maintenance and prevention of weight regain). Treatment with Xenical results in an improvement of risk factors and comorbidities associated with obesity, including hypercholesterolemia, non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, hypertension and in a reduction of visceral fat.
In type 2 diabetic patients who are overweight [body mass index (BMI) 28 kg/m²] or obese (BMI 30 kg/m²), Xenical in conjunction with a mildly hypocaloric diet, provides additional glycemic control when used in combination with antidiabetic agents eg, metformin, sulfonylurea and/or insulin.

Adults: Recommended Dose: 1 cap with each main meal (during or up to 1 hr after the meal). If a meal is missed or contains no fat, the dose of Xenical may be omitted. The therapeutic benefits of Xenical (including weight control and improvement of risk factors) are continued with long-term administration.
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 fruits and vegetables. The daily intake of fat, carbohydrate and protein should be distributed over 3 main meals.
Doses >120 mg 3 times daily have not been shown to provide additional benefit.
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.
Elderly: No dose adjustment is necessary for the geriatric patient.
Hepatic and/or Renal Impairment: Dose adjustment is not required.

Overdose of Xenical has not been reported. Single doses of 800 mg Xenical and multiple doses of up to 400 mg thrice daily for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg thrice daily have been administered to obese patients for 6 months without significant increase of adverse findings. 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.

Patients with chronic malabsorption syndrome, cholestasis, and in patients with known hypersensitivity to orlistat or any of the other components contained in Xenical.

The majority of patients in up to 2 full years of treatment had vitamin A, D, E and K and β-carotene levels stayed within normal range. In order to ensure adequate nutrition, the use of a multivitamin supplement could be considered.
Patients should be advised to adhere to 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-calorie/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 oral 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.)
Use in pregnancy & lactation: In animal reproductive studies, no embryotoxic or teratogenic effects were observed with orlistat. In absence of a 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.
The secretion of orlistat in human breast milk has not been investigated. Xenical should not be taken during breastfeeding.
Use in children: The safety and efficacy of Xenical in children <18 years have not been established.

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 are 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 counselled 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 monitor and regulate their fat intake.
These adverse gastrointestinal reactions are generally mild and transient. They occurred early in treatment (within 3 months) and most patients experienced only 1 episode.
Treatment-emergent GI adverse events that occurred commonly among patients treated with Xenical were: Abdominal pain/discomfort, flatulence, liquid stools, soft stools, rectal pain/discomfort, tooth disorder and gingival disorder.
Other events observed rarely were: Upper and lower respiratory infections; influenza; headache; menstrual irregularity; anxiety; fatigue; urinary tract infection.
In type 2 diabetic patients, adverse event reporting was comparable to that reported in overweight and obese patients. The only unique treatment adverse events that occurred at a frequency of >2% and with an incidence ≥1% above placebo were hypoglycemia (which may occur as a result of improved glycaemic control) and abdominal distention.
Post-Marketing Experience: Rare cases of hypersensitivity have been reported. Main clinical symptoms are pruritus, rash, urticaria, angioedema and anaphylaxis.

During pharmacokinetic studies, no interactions with alcohol, digoxin, metformin, nifedipine, oral contraceptives, phenytoin, statins or warfarin have been observed.
Decreases in the absorption of vitamin D, 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. Therefore, it is recommended to monitor more frequently than usual the cyclosporin plasma levels when Xenical is co-administered. (See Precautions.)

Do not store above 25°C.

Anti-Obesity Agents / Antidiabetic Agents

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

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