Indications for use:
Long-term therapy in obese or overweight patients, including those with obesity-associated risk factors, in combination with a moderately hypocaloric diet.
In combination with hypoglycemic products (metformin, sulfonylurea products and / or insulin) or a moderately hypocaloric diet in overweight or obese patients with type 2 diabetes.
Suppression of gastrointestinal lipases. The presence of lipases in the gastrointestinal tract is necessary for the manifestation of the Xenical effect. Since the secretion of lipases is stimulated by the presence of food in the gastrointestinal tract, Xenical should be taken with meals. Several studies have shown that the pharmacological activity of Xenical does not change if it is taken within 1 hour after a meal. In addition, after the abolition of Xenical, the absorption of dietary fats quickly normalizes, and adverse effects from the gastrointestinal tract caused by the pharmacological effect of the product quickly disappear.
Tolerability related to the mechanism of action of the product. The tolerability of Xenical is related to its mechanism of action. A number of studies have found that the content of fat in food is directly related to the frequency and severity of adverse events from the gastrointestinal tract with each dose of Xenical. With an increase in the fat content in food, the total amount of fat excreted in the feces increases. However, the amount of fat in the feces as a percentage of dietary fat does not change and is within 30%.
Hypolipidemic effect of Xenical. In addition to the reduction in blood lipids that can be expected from weight loss per se, Xenical has its own, additional positive effect on hyperlipidemia. Cholesterol is poorly soluble in bile salt solutions. Its solubility increases in direct proportion to the amount of free fatty acids and monoglycerides present there. By suppressing gastrointestinal lipases, Xenical reduces the amount of free fatty acids and monoglycerides in the intestinal lumen and thereby reduces the solubility and subsequent absorption of cholesterol. In addition, the appointment of Xenical leads to the creation of a non-physiological suspension of unabsorbed fats in the intestinal lumen. As a result, the absorption of non-polar lipids such as cholesterol is reduced.
Lack of increased proliferation of colon cells. Since Xenical partially inhibits the hydrolysis and absorption of fats in the intestine, the amount of fat that the colonic mucosa comes into contact with increases. The role of high fat intake in the development of colon cancer is controversial and has recently been disputed. One of the many proposed mechanisms is an increase in the concentration of bile acids, which can have a toxic effect on the colonic mucosa. That is why the action of Xenical on colon cell proliferation has been studied. The administration of therapeutic doses (120 mg 3 times a day) of Xenical to obese patients did not affect cell proliferation in colon biopsies, despite the fact that the amount of fat and free fatty acids in the feces increased. Furthermore, the content of bile acids significantly decreased. There was no correlation between changes in the composition of feces and the colon cell proliferation index, nor was there an increase in this index.
If Xenical were to be systemically absorbed, one would expect it to inhibit systemic lipoprotein and hepatic lipases, due to their structural similarity to gastrointestinal lipases. Therefore, an assessment of the degree of its absorption and systemic activity is important for confirming the safety of Xenical.
Plasma concentrations. Plasma concentrations of unchanged Xenical were radioisotope monitored in healthy volunteers and overweight or obese volunteers. In studies with a single dose of the product (at doses up to 800 mg), plasma concentrations of the active substance in healthy volunteers remained below 5 ng / ml. With repeated administration of the product, cumulation did not occur, and plasma concentrations of unchanged Xenical were less than 1% of total radioactivity.
In clinical studies where plasma samples were analyzed after 1 and 2 years of Xenical use, the unchanged product after taking therapeutic doses (120 mg 3 times a day) was found in plasma only sporadically, and its plasma concentrations were extremely low (less than 10 ng / ml). There were no signs of product accumulation, which also corresponds to negligible absorption.
No effect on the activity of systemic lipases. At therapeutic doses, Xenical did not affect the activity of systemic hepatic lipases or lipoprotein lipase in healthy volunteers. The maximum plasma concentrations following therapeutic doses of Xenical are much lower than the 50% inhibitory concentrations in vitro, which for pancreatic, hepatic or lipoprotein lipases are 120 mg / ml. The absence of systemic absorption and action on the activity of systemic lipases minimizes the possibility of systemic side effects, even with long-term use of the product.
The volume of distribution of Xenical cannot be determined, since the product is absorbed minimally and has no definite systemic pharmacokinetics.
Most likely, Xenical is metabolized mainly in the wall of the gastrointestinal tract. In plasma at minimal concentrations, two of its metabolites, M1 and M3, were detected, which account for within 42% of the product absorbed into the bloodstream. M1 and M3 have extremely weak antilipase activity, which is 1000 and 2500 times lower, respectively, than that of Xenical. They are considered pharmacologically inactive.
The oral dose of Xenical is almost completely (within 97%) excreted in the feces, with 83% being eliminated as unchanged product.
Xenical (Xenical) method of administration and doses:
The recommended dose of orlistat is one 120 mg capsule with each main meal (during meals or no later than one hour after meals). If a meal is skipped or if the food does not contain fat, then Xenical can also be skipped.
The patient should receive a balanced, moderately low-calorie diet containing no more than 30% of calories in the form of fat. The daily intake of fats, carbohydrates and proteins must be divided into three main meals.
An increase in the dose of orlistat above the recommended one (120 mg 3 times a day) does not lead to an increase in its therapeutic effect.
The effect of orlistat in patients with liver or kidney damage and in children has not been studied.
Xenical side effects:
In clinical studies, adverse reactions to orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological action of the product that prevents the absorption of dietary fat. Often there were such phenomena as oily discharge from the rectum, gas with some discharge, imperative urge to defecate, steatorrhea, increased defecation and fecal incontinence. As a rule, these side reactions are mild and transient. They occurred in the early stages of treatment (in the first 3 months), and most patients had no more than one episode of such reactions.
Patients should be informed about the possibility of adverse reactions from the gastrointestinal tract and taught how to eliminate them by better dietary compliance, especially in relation to the amount of fat contained in it. The use of a low-fat diet reduces the likelihood of side effects from the gastrointestinal tract.
In addition, the following adverse events may occur from the gastrointestinal tract: pain or discomfort in the abdomen, flatulence, loose stools, soft stools, pain or discomfort in the rectum, damage to the teeth, damage to the gums.
Rare cases of hypersensitivity have been described, consisting of itching, rash, urticaria, angioedema, and anaphylaxis.
Rarely, infections of the upper or lower respiratory tract, influenza, headaches, dysmenorrhea, anxiety, weakness, urinary tract infections were noted while taking orlistat, but they were regarded as not related to the use of the product.
No teratogenic or embryotoxic effects of the product have been observed in animal reproduction studies. In the absence of a teratogenic effect in animals, such an effect should not be expected. However, due to the lack of clinical data, Xenical should not be given to pregnant women. The excretion of orlistat in breast milk has not been studied, so it should not be taken during breastfeeding.
No cases of orlistat overdose have been described. In clinical studies in normal weight and obese individuals, single doses of 800 mg or multiple doses of 400 mg 3 times a day for 15 days were not accompanied by significant adverse events. In addition, obese patients have experience with orlistat 240 mg 3 times a day for 6 months.
In case of a severe overdose of orlistat, it is recommended to observe the patient for 24 hours. According to studies in humans and animals, any systemic effect that could be associated with the lipase-inhibiting properties of orlistat should be rapidly reversible.
Use with other medicinal products:
Interactions with digoxin, metformin, phenytoin, warfarin, oral contraceptives, nifedipine, statins and alcohol were not observed.
It is necessary to keep in mind the possibility of reducing the absorption of vitamins A, D, E, K and beta-carotene.
Weight loss during treatment with Xenical may improve metabolic compensation in patients with diabetes mellitus and require a reduction in the dose of oral hypoglycemic products.
Xenical is effective in terms of long-term weight control (weight loss and maintenance at a new level, prevention of re-gain of body weight).
Treatment with Xenical leads to an improvement in the profile of risk factors and diseases that contribute to obesity, including hypercholesterolemia, type 2 diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, arterial hypertension, and to a decrease in visceral fat.
When used in combination with glucose-lowering products such as metformin, sulfonylurea products, and/or insulin in type 2 diabetics who are overweight (BMI ≥ 28 kg/m2) or obese (BMI ≥ 30 kg/m2) Xenical, in combination with a moderately hypocaloric diet, gives an additional improvement in the compensation of carbohydrate metabolism.
In clinical studies, the majority of patients with vitamin A, D, E, K and beta-carotene concentrations remained within the normal range during two to two full years of orlistat therapy. A multivitamin may be prescribed to ensure adequate intake of all nutrients.
The patient should receive a balanced, moderately low-calorie diet containing no more than 30% of calories in the form of fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, carbohydrates and proteins must be divided into three main meals.
The likelihood of adverse reactions from the gastrointestinal tract may increase if Xenical is taken on the background of a diet rich in fats (for example, 2000 kcal / day, of which more than 30% are in the form of fat, which equals approximately 67 g of fat). Daily fat intake should be divided into three main meals. If Xenical is taken with a meal that is very rich in fat, the likelihood of gastrointestinal reactions is increased.
In patients with type 2 diabetes, weight loss during treatment with Xenical is accompanied by an improvement in carbohydrate metabolism compensation, which may allow or require a reduction in the dose of hypoglycemic products.