Pharmacological action - inhibiting gastrointestinal lipases.
It acts in the lumen of the stomach and small intestine by forming a covalent bond with the active radical of the serine of the gastric and pancreatic lipases. Inactivated enzymes are not capable of hydrolyzing food fat triglycerides to absorbable free fatty acids and monoglycerides. Undigested fats are not absorbed, creating a calorie deficit that positively affects body weight control. For the manifestation of activity, no systemic absorption of orlistat is required, at a recommended therapeutic dose (120 mg 3 times a day), it inhibits about 30% the intake of fat from the food by approximately 30%.
In several studies of up to 6 weeks, the effect of therapeutic doses of orlistat on gastrointestinal and systemic physiological processes in patients with normal body weight and obesity was studied. According to two studies, the postprandial concentration of cholecystokinin in plasma decreased with multiple admission of orlistat, in two other experiments - did not significantly differ from that in the placebo group. There were no clinically significant changes in gallbladder motility, bile composition or its lithogenicity, proliferation rate of intestinal cells; There was no decrease in the time of gastric emptying and a decrease in gastric acidity. During these studies, orlistat had no effect on plasma triglyceride levels or systemic lipases. In 28 healthy male volunteers who received orlistat 120 mg 3 times a day for 3 weeks, slightly affected the balance of calcium, magnesium, phosphorus, zinc, copper and iron. Based on the results of determining the maximum effect, a dose-response curve was constructed that reflects the relationship between the daily dose of orlistat and the excretion of fats with feces as a representative index of inhibition of gastrointestinal lipase. The "dose-response" curve showed a steep rise area with an increase in the orlistat dose to 400 mg / day and an output on the plateau with a further increase in the dose. In doses exceeding 120 mg 3 times a day, the percentage of increase in the effect was minimal.
To establish the connection between obesity, the degree of development of visceral fat and the risk of developing cardiovascular diseases, type 2 diabetes, certain forms of cancer, gallstones, some disorders of the respiratory system, and increased mortality as a whole, epidemiological studies were undertaken. These studies have shown that achieving and maintaining weight loss improves health outcomes in obese patients who have been at risk of developing co-morbid comorbid conditions. The long-term effects of orlistat on morbidity and mortality associated with obesity have not been investigated.
Influence of orlistat on the reduction, maintenance and repeated weight gain and a number of comorbid parameters (type 2 diabetes, plasma lipids, blood pressure, etc.) was studied in seven long-term (1-2 years) multicenter, double-blind, placebo-controlled clinical trials . During the first year of therapy, weight loss was noted and maintained at the achieved level. In the second year of treatment with orlistat, according to some studies, body weight was maintained at the level achieved during the first year of therapy or continued to decrease; According to other studies, body weight was restored. Studies included 2,800 patients taking orlistat, and 1,400 patients receiving placebo. Most patients had obesity-related risk factors and comorbid conditions. All seven studies compared groups of patients who received only orlistat or placebo, respectively orlistat or placebo, against a background diet. During the period of reduction and maintenance of body weight, all patients were recommended a well-balanced hypocaloric diet (calorie reduction of approximately 20% and 30% reduction in calories from fat). In addition, all patients were offered dietary recommendations. The decrease in body weight was noted 2 weeks after the start of treatment and lasted 6-12 months. According to the generalized data of five clinical trials, after randomization, the average weight loss at the end of 6 months and 1 year of therapy among adherent patients was 5.63 and 6.08 kg in the orlistat group, 2.81 and 2.63 kg in the placebo group, respectively . 57% of patients who received orlistat 120 mg 3 times a day, and 31% of patients in the placebo group at the end of 1 year of treatment, showed a decrease in body weight by at least 5% of the baseline. According to five studies, the proportion of patients whose body weight after 1 year of therapy decreased by 5% or more, was in the orlistat group 35.5-54.8%, in the placebo group - 16.0-27.4%. Loss of body weight equal to or greater than 10% of the baseline was observed in 16.4-24.8% of patients who took orlistat during 1 year and in 3.8-11.9% of patients in the placebo group.
Results of the first year of observations: weight loss, maintenance of body weight, risk factors.
Population with a different degree of severity of risk factors. In a population with an altered lipid profile (LDL ≥ 130 mg / dL, LDL / HDL ≥ 3.5, HDL cholesterol more than 35 mg / dL), randomization after 1 year of treatment with orlistat was more pronounced than in the placebo group of changes in LDL (-7.83% in the orlistat group, + 1.14% in the placebo group), LDL / HDL ratio (-0.64 and 0.46 in orlistat groups and placebo, respectively). The level of HDL in the placebo group increased by 20.1%, in the orlistat group - by 18.8%. Among patients with initially elevated blood pressure (SAD ≥140 mm Hg), saddling parameters for randomisation after 1 year of orlistat therapy were better (-10.89 mm Hg) compared to the placebo group (-5.07 mm Hg ., St.). In patients with a baseline DAD ≥90 mm Hg. Art. When orlistat was taken, the decrease in DAD was 7.9 mm Hg. In case of taking a placebo, 5.5 mm Hg. Art. After 1 year of treatment, the reduction of this index was greater in the orlistat group compared with placebo (-39 pmol / L and 16 pmol / L, respectively) when randomly assigned to patients with an initial fasting insulin level (≥120 pmol / l). A more pronounced decrease in the waist circumference in patients with a baseline value of ≥ 100 cm was also noted in the orlistat group (-7.29 cm vs. 4.53 cm in the placebo group).
Effect on repeated weight gain. The purpose of the three studies was to compare the effect of orlistat and placebo on reducing the weight gain after previous reduction only on the background of a diet (study 14302) or diet followed by orlistat (studies 14119C and 14185). In these studies, a less strict diet was used to maintain body weight, and patients received insignificant dietary recommendations (compared with diet and recommendations in studies to reduce body weight). In studies 14119C and 14185, the primary loss of body weight in patients was the result of taking orlistat in combination with a moderately hypocaloric diet for 1 year. According to the results of the study 14302, the effect of Orlistat intake for 1 year on the repeated weight gain was recorded for patients whose loss was only 8% or more if the diet was maintained during the previous 6 months. In the 14119C study, the repeated increase in body weight in patients receiving placebo was 52% of the pre-lost body weight, in the orlistat group - 26% (p <0.001). According to the data of the study 14185, these figures were 63 and 35%, respectively (p <0.001), in the study 14302 - 53 and 32% (p <0.001).
Results of the second year of follow-up: long-term monitoring of body weight and risk factors
Therapeutic effects of orlistat after 2 years of treatment were studied during four out of five one-year clinical trials (see the results of the first year of observations). By the end of year 1, the patients' diet was revised and, if necessary, changed. The diet prescribed for patients in the 2nd year of treatment was aimed at maintaining the achieved body weight. The results of four large, multicenter, bi-annual, double-blind, placebo-controlled studies showed that orlistat is more effective than placebo for long-term body weight control. According to the generalized data of these tests, weight loss in 40% of patients who received orlistat for 2 mg for 2 years 3 times a day for 2 years and 24% of patients receiving placebo during this period, when randomized, was ≥5%. It was also shown that the relative advantage of weight loss in the orlistat group (120 mg 3 times a day) compared to the placebo group was the same after the 1 st and 2 nd year of treatment, and therefore the pharmacological superiority of orlistat persisted for more than 2 years. In these studies, the percentage of patients whose weight reduction was equal to or exceeded 5 and 10% after two years of treatment with orlistat was 25.0-45.1% and 16.9-24.8%, respectively, in the placebo group - 15, 0-27.9% and 3.5-11.5%.
Changes in risk factors associated with obesity, after two years of therapy, have also been studied in randomizing the population as a whole and in populations with varying degrees of risk factors.
In the population as a whole, the differences in risk factors between orlistat and placebo groups were similar to those after the first year of follow-up in terms of total cholesterol, LDL, LDL, triglycerides, fasting glucose, fasting insulin, DAD, waist circumference, and Thighs. Differences between the groups of patients in terms of HDL and SAD levels in comparison with the results of the first year of treatment were less pronounced.
When randomized in a population with different degrees of risk factors, the differences in patients who received orlistat and placebo were similar to those after the first year of follow-up for LDL, HDL, triglycerides, fasting insulin, DAD, and waist circumference. The difference between LDL / HDL and SAD groups was less than after the first year of therapy.
Studies in patients with type 2 diabetes. Table 2 presents the results of a one-year, double-blind, placebo-controlled study of orlistat in patients with type 2 diabetes (n = 321), whose condition was stabilized with sulfonylurea preparations.
At randomization, a decrease in body weight of 5% or more was noted in 30% of patients in the orlistat group (120 mg 3 times daily in combination with diet) and 13% in the placebo group in combination with diet (p <0.001).
Glucose tolerance in obese patients was studied in biennial trials using the oral glucose tolerance test (PGTT), in obese patients with previously untreated Type 2 diabetes mellitus and patients receiving treatment for this disease, in whom the results of the initial PGTT for Randomizations were normal, borderline, or characteristic of diabetes mellitus. Changes in the results of normal to disturbed or characteristic diabetes for 2 years after orbital treatment in the orlistat group (n = 251) were 7.2% and 0.0%, in the placebo group (n = 201) 12.6% and 1, 9% respectively. Among the patients with initially disrupted PGTT were those in whom the results of ADT were normalized or became characteristic of diabetes during the 1 st and 2 nd year of follow-up. After the first year of therapy in the orlistat group, the proportion of patients with normalized BTT was 73% (in the placebo group - 45.8%), with a deterioration in the results of OGTT - 2.6% (in the placebo group - 10.4%). At the end of the second year of treatment in the orlistat group, the indices of parathyroid hormone normalized in 71.7% of patients (in the placebo group - in 50%) or became characteristic of diabetes mellitus in 1.7% (7.5% in the placebo group).
Because orlistat absorption is minimal, studies in special patient groups (elderly people, children, patients of different races, patients with impaired liver and kidney function) were not conducted. Clinical trials of orlistat did not include a sufficient number of patients 65 years of age or older to determine whether there are differences in response to therapy between elderly and younger patients. The safety and efficacy of orlistat when taken for more than 2 years have not been investigated at this time.
The systemic exposure of orlistat is minimal. After ingestion of 360 mg of radiolabeled 14C-orlistat, the peak of radioactivity in the plasma was reached after about 8 hours; The concentration of unchanged orlistat was close to the detection limit (less than 5 ng / ml). In therapeutic studies involving monitoring of plasma samples of patients, unchanged orlistat was detected sporadically in plasma and its concentrations were low (less than 10 ng / ml), with no evidence of accumulation, consistent with minimal absorption of the drug. The absolute bioavailability of unchanged orlistat was studied in male rats who received it at doses of 150 and 1000 mg / kg / day, and in male dogs receiving 100 and 1000 mg / kg / day Orlistat orally, and amounted to 0.12%, 0 , 59% in rats and 0.7%, 1.9% in dogs, respectively. In vitro orlistat more than 99% binds to plasma proteins, mainly with lipoproteins and albumin. Orlistat minimally penetrates into the red blood cells. According to studies in animals, the metabolism of orlistat is probably carried out mainly in the wall of the stomach and small intestine. In a study in obese patients who ingested 14C orlistat, two metabolites-M1 (hydrolyzed 4-membered lactone ring) and M3 (M1 with the cleaved N-formylleucine residue) accounted for about 42% of the total radioactivity of the plasma. M1 and M3 have an open beta-lactone ring and show extremely weak inhibitory activity against lipases (compared with orlistat weaker 1000 and 2500 times, respectively). Considering the low activity and low concentration of metabolites in plasma (about 26 ng / ml and 108 ng / ml for M1 and M3, respectively 2-4 hours after taking orlistat at therapeutic doses), these metabolites are considered pharmacologically insignificant. The main metabolite M1 has a short T1 / 2 (about 3 hours), the second metabolite is displayed more slowly (T1 / 2 - 13.5 hours). In obese patients, the equilibrium concentration of metabolite M1 (but not M3) increases in proportion to the dose of orlistat.
After a single oral intake of 360 mg of 14C-orlistat by patients with normal body weight and obese, excretion of unsweetened orlistat through the intestine was the main route of excretion. Orlistat and its metabolites M1 and M3 also undergo excretion with bile. About 97% of the radiolabeled substance introduced was excreted with faeces, incl. 83% - unchanged. The total renal excretion of total radioactivity when taking 360 mg of 14C-orlistat was less than 2%. The time of complete elimination with feces and urine is 3-5 days. The excretion of orlistat was similar in patients with normal body weight and with obesity. Based on limited data, T1 / 2 of absorbed orlistat fluctuates within 1-2 hours.
Pharmacokinetics in children
Plasma concentrations of orlistat and its metabolites (M1 and M3) in children do not differ from those in adults when comparing identical doses of the drug. Daily excretion of fat with feces accounted for 27% of food in orlistat and 7% - with placebo.
Carcinogenicity, mutagenicity, effects on fertility
In studies on rats and mice receiving orlistat at doses up to 1000 and 1500 mg / kg / day, respectively (exceeding the daily dose for humans in the calculation for AUC - in 46 and 38 times), there were no carcinogenic properties. Orlistat showed no mutagenic and genotoxic activity in the Ames test, the V79 / HPRT test, in in vitro clastogenesis studies on human peripheral lymphocyte culture, in an unscheduled DNA synthesis test on rat hepatocyte culture, in an in vivo micronucleus test in mice. In rats receiving 400 mg / kg / day orlistat (12 times the daily dose for humans, calculated as body surface area, in mg / m2), there were no signs of its effect on fertility and reproduction.
In studies on rats and rabbits that received up to 800 mg / kg / day of orlistat (exceeding the daily dose for humans in terms of body surface area, in mg / m2, 23 and 47 times for rats and rabbits, respectively), teratogenic Or embryotoxic properties. The increase in cases of cerebral ventricular expansion was noted in teratological studies in rats receiving orlistat in medium and high doses, exceeding the daily dose for humans in terms of body surface area, in mg / m2, 6 and 23 times, respectively. These findings were not reproduced in two additional teratological studies on rats receiving orlistat in similar doses.
Application of Orlistat
According to the Physician Desk Reference (2009), orlistat is indicated for the treatment of obesity, incl. Reduction and maintenance of body weight, in combination with a hypocaloric diet. Orlistat is also indicated to reduce the risk of repeated weight gain after its initial decline. Orlistat is indicated for obese patients with a body mass index (BMI, its calculation - see "Specific guidance") ≥30 kg / m2 or ≥27 kg / m2 in the presence of other risk factors (diabetes, hypertension, dyslipidemia).
Hypersensitivity, chronic malabsorption syndrome, cholestasis.
Restrictions on the use
Children's age (safety and efficacy not established), hyperoxaluria in history, nephrolithiasis (calcium oxalate stones).
Application in pregnancy and lactation
Adequate well-controlled studies of orlistat in pregnant women have not been conducted. Since animal test data may not always predetermine the response in humans, orlistat is not recommended for use during pregnancy.
The action category for fetus by FDA is X.
It is not known whether orlistat is secreted into breast milk, nor should it be used in nursing women.
Side effects of Orlistat
According to seven double-blind, placebo-controlled clinical trials, patients who took orlistat 120 mg 3 times daily against a diet during the first and second year of observation most often (with a frequency of ≥5%) and at least 2 Times more often than in the placebo group (against the background of the diet), there were side effects from the gastrointestinal tract, which reflected the mechanism of action of the drug.
These and other frequently observed adverse reactions were mostly of medium severity and transient, their frequency decreased in the second year of treatment. In general, the first episode of side effects occurred within 3 months of the start of therapy. The duration of 50% of all gastrointestinal side effects associated with treatment with orlistat was less than 1 week, in most cases - no more than 4 weeks. However, side effects from the gastrointestinal tract in some patients can develop for 6 months or more of therapy.
In controlled clinical trials, 8.8% of patients taking orlistat had to stop treatment due to side effects, compared to 5% in the placebo group. In the orlistat group, treatment was most often interrupted due to side effects from the gastrointestinal tract.
Table 4 shows the side effects observed in seven multicenter, double-blind, placebo-controlled trials in patients taking orlistat 120 mg 3 times daily in combination with a diet for 2 years at a rate of ≥2% and exceeding that In the placebo group in combination with a diet ("-" means no reported frequency of the sign ≥2% and exceeded placebo).
Other clinical studies and post-marketing experience
There are rare reports of hypersensitivity reactions to orlistat including itching, rash, hives, angioedema, bronchospasm and anaphylaxis.
We described very rare cases of bullous rash, an increase in the activity of transaminases and APF, as well as isolated, possibly serious, cases of hepatitis.
In the postmarketing period, cases of pancreatitis have been documented (cause-and-effect relationship with orlistat reception or pathophysiological development mechanisms not established).
In clinical studies in patients with type 2 diabetes mellitus, the nature and incidence of adverse events were comparable to those in people without diabetes mellitus with excessive body weight and obesity.
Orlistat does not affect the pharmacokinetics of pravastatin, alcohol, digoxin (prescribed in a single dose) and phenytoin (prescribed in a single dose of 300 mg), on the bioavailability of nifedipine (sustained-release tablets), and ovulatory-suppressive activity of oral contraceptives. Alcohol did not affect pharmacodynamics (excretion of fats with feces) and systemic exposure of orlistat.
According to preliminary data, with simultaneous application of orlistat and cyclosporin, the plasma level in the plasma decreases (orlistat and cyclosporine should not be taken at the same time, to reduce the likelihood of drug interaction, cyclosporine should be taken 2 hours before or 2 hours after taking orlistat).
Orlistat reduces the absorption of beta-carotene contained in food additives by 30% and inhibits the absorption of vitamin E (in the form of tocopherol acetate) by approximately 60%. The influence of orlistat on the absorption of vitamins D, A, contained in additives, is unknown to date.
Although the level of carboxylated osteocalcin, a marker of intake with vitamin K food, did not change when orlistat was taken, the tendency of the people taking orlistat to decrease the content of vitamin K.
Studies in 12 volunteers with normal body weight showed that orlistat (120 mg 3 times daily for 16 days) did not affect the pharmacokinetics (both R- and S-enantiomers) and pharmacodynamics (PV and level VII of the factor) of warfarin . However, in the postmarketing period, cases of a decrease in the level of prothrombin and an increase in the INR index were recorded with the simultaneous use of orlistat and anticoagulants. In this regard, patients who are on long-term warfarin therapy, with simultaneous treatment with orlistat, carefully monitor coagulation parameters.
With the simultaneous administration of orlistat and levothyroxine sodium hypothyroidism is possible (in the postmarketing period, there have been cases of hypothyroidism in patients taking orlistat and levothyroxine sodium). In such cases it is necessary to monitor the function of the thyroid gland, the interval between taking these drugs should be at least 4 hours.
A single dose of 800 mg of orlistat or its repeated administration in a dose of up to 400 mg 3 times a day for 15 days by people with normal body weight and with obesity was not accompanied by significant side effects.
If a significant overdose of orlistat is found, the patient should be monitored for 24 hours. According to animal and human studies, systemic effects associated with the lipaspptive properties of orlistat should be rapidly reversible.
Routes of administration
Precautions for the substance Orlistat
Before the appointment of orlistat should be deleted organic cause of obesity, for example hypothyroidism.
At the time of treatment, a balanced low-calorie diet is recommended, in which fats provide no more than 30% of calories. The likelihood of side effects from the gastrointestinal tract increases with a high content of fat in the diet (more than 30% of daily calories). Daily intake of fats, carbohydrates and proteins should be distributed among the three main meals. Since orlistat reduces the absorption of some fat-soluble vitamins, patients must take multivitamin preparations containing fat-soluble vitamins to ensure their adequate intake. In addition, the content of vitamin D and beta-carotene in obese patients may be lower than in people who are not obese. Multivitamins should be taken 2 hours before or 2 hours after taking orlistat, for example, before going to bed. The intake of orlistat at doses exceeding 120 mg 3 times a day does not provide an additional effect. In patients taking orlistat and cyclosporine simultaneously, more frequent monitoring of the plasma cyclosporin content is required.
In patients who did not receive prophylactic vitamin supplements, with two or more consecutive visits to the doctor during the first and second years of treatment with orlistat, a decrease in the level of vitamins in the plasma was recorded in the following percentage of cases (in brackets the data in the placebo group are indicated): vitamin A 2, 2% (1%), vitamin D 12.0% (6.6%), vitamin E 5.8% (1%), beta-carotene 6.1% (1.7%).
In some patients, the content of oxalate in urine may increase with orlistat.
As with other medications to reduce body weight, in some groups of patients (for example, with anorexia nervosa or bulimia), there is a possibility of abuse of orlistat.
Orlistat's induction of weight loss may be combined with an improvement in the metabolic control of diabetes mellitus, which will require a reduction in the doses of oral hypoglycemic agents (sulfanylurea, metformin, etc.) or insulin.
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