Product Overview
pharmachologic effect
Pharmacodynamics.
Orlistat is a potent, specific and reversible inhibitor of gastrointestinal lipases with a long-lasting effect. Its therapeutic effect is carried out in the lumen of the stomach and small intestine and consists in the formation of a covalent bond with the active serine site of gastric and pancreatic lipases.
At the same time, the inactivated enzyme loses its ability to break down food fats, which come in the form of triglycerides, into absorbed free fatty acids and monoglycerides.
Since the undigested triglycerides are not absorbed, the resulting decrease in caloric intake in the body leads to a decrease in body weight.
Thus, the therapeutic effect of the drug is carried out without absorption into the systemic circulation. Judging by the results of the fat content in the feces, the effect of orlistat begins 24-48 hours after ingestion. After discontinuation of orlistat, the fat content in the feces after 48-72 hours usually returns to the level that had occurred before the start of therapy.
Clinical efficacy. In patients taking orlistat, there is a greater loss of body weight compared to patients on diet therapy.
Weight loss begins within the first 2 weeks after the start of treatment and lasts from 6 to 12 months even in patients with a negative response to diet therapy. For 2 years, there has been a statistically significant improvement in the profile of metabolic risk factors associated with obesity.
In addition, there was a significant decrease in body fat compared to taking a placebo. Orlistat is effective in preventing re-weight gain.
Re-gaining body weight, no more than 25% of the lost weight, is observed in about half of the patients, and in half of these patients, re-gaining body weight is not observed or even its further decrease is observed.
In patients with overweight or obesity and type 2 diabetes, taking orlistat for 6 months to 1 year, there is a greater loss of body weight compared to patients receiving diet therapy alone.
Weight loss occurs mainly due to a decrease in the amount of body fat. With orlistat therapy, statistically and clinically significant improvement in glycemic control is observed. In addition, against the background of therapy with orlistat, a decrease in the dose of hypoglycemic agents, insulin concentration, as well as a decrease in insulin resistance is observed.
When using orlistat for 4 years, the risk of developing type 2 diabetes mellitus is significantly reduced (by about 37% compared with placebo). The degree of risk reduction is even more significant in patients with an underlying impaired glucose tolerance (approximately 45%).
Maintaining body weight at a new level is observed throughout the entire period of drug use. When using orlistat for 1 year in obese adolescents, there is a decrease in BMI, a decrease in fat mass, as well as waist and hip circumference compared with the placebo group.
Also, in patients receiving therapy with orlistat, there is a significant decrease in diastolic blood pressure compared with the placebo group.
Orlistat is a potent, specific and reversible inhibitor of gastrointestinal lipases with a long-lasting effect. Its therapeutic effect is carried out in the lumen of the stomach and small intestine and consists in the formation of a covalent bond with the active serine site of gastric and pancreatic lipases.
At the same time, the inactivated enzyme loses its ability to break down food fats, which come in the form of triglycerides, into absorbed free fatty acids and monoglycerides.
Since the undigested triglycerides are not absorbed, the resulting decrease in caloric intake in the body leads to a decrease in body weight.
Thus, the therapeutic effect of the drug is carried out without absorption into the systemic circulation. Judging by the results of the fat content in the feces, the effect of orlistat begins 24-48 hours after ingestion. After discontinuation of orlistat, the fat content in the feces after 48-72 hours usually returns to the level that had occurred before the start of therapy.
Clinical efficacy. In patients taking orlistat, there is a greater loss of body weight compared to patients on diet therapy.
Weight loss begins within the first 2 weeks after the start of treatment and lasts from 6 to 12 months even in patients with a negative response to diet therapy. For 2 years, there has been a statistically significant improvement in the profile of metabolic risk factors associated with obesity.
In addition, there was a significant decrease in body fat compared to taking a placebo. Orlistat is effective in preventing re-weight gain.
Re-gaining body weight, no more than 25% of the lost weight, is observed in about half of the patients, and in half of these patients, re-gaining body weight is not observed or even its further decrease is observed.
In patients with overweight or obesity and type 2 diabetes, taking orlistat for 6 months to 1 year, there is a greater loss of body weight compared to patients receiving diet therapy alone.
Weight loss occurs mainly due to a decrease in the amount of body fat. With orlistat therapy, statistically and clinically significant improvement in glycemic control is observed. In addition, against the background of therapy with orlistat, a decrease in the dose of hypoglycemic agents, insulin concentration, as well as a decrease in insulin resistance is observed.
When using orlistat for 4 years, the risk of developing type 2 diabetes mellitus is significantly reduced (by about 37% compared with placebo). The degree of risk reduction is even more significant in patients with an underlying impaired glucose tolerance (approximately 45%).
Maintaining body weight at a new level is observed throughout the entire period of drug use. When using orlistat for 1 year in obese adolescents, there is a decrease in BMI, a decrease in fat mass, as well as waist and hip circumference compared with the placebo group.
Also, in patients receiving therapy with orlistat, there is a significant decrease in diastolic blood pressure compared with the placebo group.
Indications
Long-term therapy of obese patients with a BMI of at least 30 kg / m2 or overweight patients with a BMI of at least 28 kg / m2, incl. having risk factors associated with obesity, in combination with a moderately hypocaloric diet; in combination with hypoglycemic drugs (metformin, sulfonylurea derivatives and / or insulin) and / or a moderately hypocaloric diet in patients with type 2 diabetes mellitus who are overweight or obese.
Contraindications
Hypersensitivity sensitivity to orlistat or any other components of the drug; chronic malabsorption syndrome; cholestasis; pregnancy, breastfeeding period; children under 12 years of age.
Side effects
Clinical trial data.
Side effects of the drug are classified in relation to each of the organ systems, depending on the frequency of occurrence, using the following classification: very often (more than 1/10); often (more than 1/100, less than 1/10); infrequently (more than 1/1000, less than 1/100); rarely (more than 1/10 000, less than 1/1000); very rarely, including single messages (less than 1/10 000).
Adverse reactions during the use of orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological effect of orlistat, which prevents the absorption of food fats.
Very often, such phenomena as oily discharge from the rectum, gas with some discharge, urgency to defecate, steatorrhea, increased frequency of bowel movements, loose stools, flatulence, pain or discomfort in the abdomen were noted.
Their frequency increases with increasing fat content in food. Patients should be informed about the possibility of adverse reactions from the gastrointestinal tract and taught how to eliminate them by following the diet, especially with regard to the amount of fat contained in it.
Eating a low fat diet reduces the likelihood of gastrointestinal side effects and thereby helps patients control and regulate fat intake. These side effects are usually mild and transient.
They occur in the early stages of treatment (in the first 3 months), and most patients had no more than one episode of such reactions. When treating with orlistat, the following adverse events from the gastrointestinal tract often occur: "soft" stools, pain or discomfort in the rectum, fecal incontinence, abdominal distension, tooth damage, and gum disease.
There were also very common - headache, upper respiratory tract infections, flu; often - lower respiratory tract infections, urinary tract infections, dysmenorrhea, anxiety, weakness. In patients with type 2 diabetes mellitus, the nature and frequency of adverse events were comparable to those in persons without diabetes mellitus, overweight and obesity.
The only new side effects in patients with type 2 diabetes mellitus were hypoglycemic conditions, occurring with a frequency of more than 2% and an incidence of at least 1% compared with placebo (which could result from improved compensation for carbohydrate metabolism), and often bloating.
In a 4-year clinical study, the overall safety profile did not differ from that obtained in 1- and 2-year studies. At the same time, the overall incidence of adverse events from the gastrointestinal tract decreased annually over the 4-year period of taking the drug.
Post-marketing surveillance. Rare cases of allergic reactions are described, the main clinical manifestations of which were skin rash, itching, urticaria, angioedema, bronchospasm and anaphylaxis.
Very rare cases of bullous rash, increased activity of transaminases and alkaline phosphatase, as well as individual, possibly serious, cases of the development of hepatitis have been described (a causal relationship with taking orlistat or pathophysiological mechanisms of development have not been established).
With the simultaneous use of orlistat with indirect anticoagulants, cases of a decrease in prothrombin, an increase in the international normalized ratio (INR) and unbalanced therapy with anticoagulants, which led to a change in hemostatic parameters, were recorded.
Cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis, and oxalate nephropathy have been reported (incidence not known). With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures (see the section "Interaction with other drugs").
Side effects of the drug are classified in relation to each of the organ systems, depending on the frequency of occurrence, using the following classification: very often (more than 1/10); often (more than 1/100, less than 1/10); infrequently (more than 1/1000, less than 1/100); rarely (more than 1/10 000, less than 1/1000); very rarely, including single messages (less than 1/10 000).
Adverse reactions during the use of orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological effect of orlistat, which prevents the absorption of food fats.
Very often, such phenomena as oily discharge from the rectum, gas with some discharge, urgency to defecate, steatorrhea, increased frequency of bowel movements, loose stools, flatulence, pain or discomfort in the abdomen were noted.
Their frequency increases with increasing fat content in food. Patients should be informed about the possibility of adverse reactions from the gastrointestinal tract and taught how to eliminate them by following the diet, especially with regard to the amount of fat contained in it.
Eating a low fat diet reduces the likelihood of gastrointestinal side effects and thereby helps patients control and regulate fat intake. These side effects are usually mild and transient.
They occur in the early stages of treatment (in the first 3 months), and most patients had no more than one episode of such reactions. When treating with orlistat, the following adverse events from the gastrointestinal tract often occur: "soft" stools, pain or discomfort in the rectum, fecal incontinence, abdominal distension, tooth damage, and gum disease.
There were also very common - headache, upper respiratory tract infections, flu; often - lower respiratory tract infections, urinary tract infections, dysmenorrhea, anxiety, weakness. In patients with type 2 diabetes mellitus, the nature and frequency of adverse events were comparable to those in persons without diabetes mellitus, overweight and obesity.
The only new side effects in patients with type 2 diabetes mellitus were hypoglycemic conditions, occurring with a frequency of more than 2% and an incidence of at least 1% compared with placebo (which could result from improved compensation for carbohydrate metabolism), and often bloating.
In a 4-year clinical study, the overall safety profile did not differ from that obtained in 1- and 2-year studies. At the same time, the overall incidence of adverse events from the gastrointestinal tract decreased annually over the 4-year period of taking the drug.
Post-marketing surveillance. Rare cases of allergic reactions are described, the main clinical manifestations of which were skin rash, itching, urticaria, angioedema, bronchospasm and anaphylaxis.
Very rare cases of bullous rash, increased activity of transaminases and alkaline phosphatase, as well as individual, possibly serious, cases of the development of hepatitis have been described (a causal relationship with taking orlistat or pathophysiological mechanisms of development have not been established).
With the simultaneous use of orlistat with indirect anticoagulants, cases of a decrease in prothrombin, an increase in the international normalized ratio (INR) and unbalanced therapy with anticoagulants, which led to a change in hemostatic parameters, were recorded.
Cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis, and oxalate nephropathy have been reported (incidence not known). With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures (see the section "Interaction with other drugs").
Interaction
No interaction of orlistat with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine GITS (gastrointestinal and nifedipine based on drug interactions studies).
However, it is necessary to monitor the INR indicators while treating with warfarin or other indirect anticoagulants. When taken simultaneously with orlistat, a decrease in the absorption of vitamins D, E and beta-carotene was noted.
If multivitamins are recommended, they should be taken at least 2 hours after taking orlistat or before bed. With the simultaneous administration of orlistat and cyclosporine, a decrease in the concentration of cyclosporine in the blood plasma was noted, therefore, more frequent determination of the concentration of cyclosporine in the blood plasma is recommended while taking cyclosporine and orlistat.
When taking amiodarone orally during therapy with orlistat, there was a decrease in the systemic exposure of amiodarone and desethylamiodarone (by 25-30%), however, due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear.
The addition of orlistat to long-term therapy with amiodarone may lead to a decrease in the therapeutic effect of amiodarone (no studies have been carried out). Simultaneous administration of orlistat and acarbose should be avoided, due to the lack of pharmacokinetic data.
With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures.
A causal relationship between the development of seizures and orlistat therapy has not been established. However, patients should be monitored for possible changes in the frequency and / or severity of seizures.
However, it is necessary to monitor the INR indicators while treating with warfarin or other indirect anticoagulants. When taken simultaneously with orlistat, a decrease in the absorption of vitamins D, E and beta-carotene was noted.
If multivitamins are recommended, they should be taken at least 2 hours after taking orlistat or before bed. With the simultaneous administration of orlistat and cyclosporine, a decrease in the concentration of cyclosporine in the blood plasma was noted, therefore, more frequent determination of the concentration of cyclosporine in the blood plasma is recommended while taking cyclosporine and orlistat.
When taking amiodarone orally during therapy with orlistat, there was a decrease in the systemic exposure of amiodarone and desethylamiodarone (by 25-30%), however, due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear.
The addition of orlistat to long-term therapy with amiodarone may lead to a decrease in the therapeutic effect of amiodarone (no studies have been carried out). Simultaneous administration of orlistat and acarbose should be avoided, due to the lack of pharmacokinetic data.
With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures.
A causal relationship between the development of seizures and orlistat therapy has not been established. However, patients should be monitored for possible changes in the frequency and / or severity of seizures.
How to take, course of administration and dosage
Inside with water.
Treatment of obese patients with a BMI of at least 30 kg / m2 or overweight patients with a BMI of at least 28 kg / m2, incl. have risk factors associated with obesity, in combination with a moderately low-calorie diet.
Adults and children over 12 years old.
The recommended dose of Listata is 1 tab. (120 mg) with each main meal (with meals or no later than 1 hour after meals). In combination with hypoglycemic drugs (metformin, sulfonylurea derivatives and / or insulin) and / or a moderately hypocaloric diet in patients with type 2 diabetes mellitus with overweight or obesity.
Adults.
The recommended dose of Listata is 1 tab. (120 mg) with each main meal (with meals or no later than 1 hour after meals). If a meal is skipped or if the meal does not contain fat, then Listat can also be skipped.
Listata should be taken in conjunction with a balanced, moderately hypocaloric diet containing no more than 30% of calories as fat. The daily intake of fats, carbohydrates and proteins should be split between the 3 main meals.
An increase in the dose of Listata over the recommended dose (120 mg 3 times / day) does not lead to an increase in its therapeutic effect. The efficacy and safety of Listata in patients with impaired liver and / or kidney function, as well as in elderly patients and children under 12 years of age have not been studied.
Treatment of obese patients with a BMI of at least 30 kg / m2 or overweight patients with a BMI of at least 28 kg / m2, incl. have risk factors associated with obesity, in combination with a moderately low-calorie diet.
Adults and children over 12 years old.
The recommended dose of Listata is 1 tab. (120 mg) with each main meal (with meals or no later than 1 hour after meals). In combination with hypoglycemic drugs (metformin, sulfonylurea derivatives and / or insulin) and / or a moderately hypocaloric diet in patients with type 2 diabetes mellitus with overweight or obesity.
Adults.
The recommended dose of Listata is 1 tab. (120 mg) with each main meal (with meals or no later than 1 hour after meals). If a meal is skipped or if the meal does not contain fat, then Listat can also be skipped.
Listata should be taken in conjunction with a balanced, moderately hypocaloric diet containing no more than 30% of calories as fat. The daily intake of fats, carbohydrates and proteins should be split between the 3 main meals.
An increase in the dose of Listata over the recommended dose (120 mg 3 times / day) does not lead to an increase in its therapeutic effect. The efficacy and safety of Listata in patients with impaired liver and / or kidney function, as well as in elderly patients and children under 12 years of age have not been studied.
Overdose
In persons with normal body weight and obese patients, taking single doses of 800 mg or repeated administration of 400 mg orlistat 3 times / day for 15 days was not accompanied by the appearance of significant adverse events.
In addition, obese patients have experience with the use of orlistat 240 mg 3 times / day for 6 months, which was not accompanied by a significant increase in the frequency of adverse events.
In cases of overdose of orlistat, either the absence of adverse events was reported, or the adverse events did not differ from those observed when taking orlistat in therapeutic doses. In case of severe overdose of orlistat, it is recommended to observe the patient for 24 hours.
According to human and animal studies, any systemic effects that could be associated with the lipase-inhibiting properties of orlistat should be quickly reversible.
In addition, obese patients have experience with the use of orlistat 240 mg 3 times / day for 6 months, which was not accompanied by a significant increase in the frequency of adverse events.
In cases of overdose of orlistat, either the absence of adverse events was reported, or the adverse events did not differ from those observed when taking orlistat in therapeutic doses. In case of severe overdose of orlistat, it is recommended to observe the patient for 24 hours.
According to human and animal studies, any systemic effects that could be associated with the lipase-inhibiting properties of orlistat should be quickly reversible.
Special instructions
Listat is effective for long-term control of body weight (weight loss and maintenance, prevention of re-weight gain).
Treatment with Listata leads to an improvement in the profile of risk factors and diseases associated with obesity, including hypercholesterolemia, type 2 diabetes mellitus, impaired glucose tolerance, hyperinsulinemia, arterial hypertension, and a decrease in the amount of visceral fat.
When used in combination with hypoglycemic drugs such as metformin, sulfonylurea derivatives and / or insulin in overweight patients with type 2 diabetes mellitus (BMI at least 28 kg / m2) or obese (BMI at least 30 kg / m2), Listat's drug in combination with a moderately hypocaloric diet further improves the compensation of carbohydrate metabolism.
In clinical studies, in most patients, the concentrations of vitamins A, D, E, K and beta-carotene remained within the normal range during 4 years of therapy with orlistat. Multivitamins can be used to ensure an adequate intake of all minerals.
The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories as fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, carbohydrates and proteins must be divided into three main doses.
The likelihood of adverse reactions from the gastrointestinal tract may increase if the drug Listat is taken with a diet rich in fats (for example, 2000 kcal / day, of which more than 30% is in the form of fats, which equals about 67 g of fat).
If Listat is taken with food that is very rich in fat, the likelihood of gastrointestinal reactions increases. In patients with type 2 diabetes mellitus, a decrease in body weight during treatment with Listat is accompanied by an improvement in the compensation of carbohydrate metabolism, which may allow or require a reduction in the dose of hypoglycemic drugs (for example, sulfonylurea derivatives).
Influence on the ability to drive vehicles and mechanisms.
Listat's drug does not affect the ability to drive vehicles and mechanisms. Patients with type 2 diabetes mellitus using Listat in combination with hypoglycemic drugs should be careful when driving vehicles and mechanisms due to the possible development of hypoglycemia, accompanied by dizziness, visual impairment.
Treatment with Listata leads to an improvement in the profile of risk factors and diseases associated with obesity, including hypercholesterolemia, type 2 diabetes mellitus, impaired glucose tolerance, hyperinsulinemia, arterial hypertension, and a decrease in the amount of visceral fat.
When used in combination with hypoglycemic drugs such as metformin, sulfonylurea derivatives and / or insulin in overweight patients with type 2 diabetes mellitus (BMI at least 28 kg / m2) or obese (BMI at least 30 kg / m2), Listat's drug in combination with a moderately hypocaloric diet further improves the compensation of carbohydrate metabolism.
In clinical studies, in most patients, the concentrations of vitamins A, D, E, K and beta-carotene remained within the normal range during 4 years of therapy with orlistat. Multivitamins can be used to ensure an adequate intake of all minerals.
The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories as fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, carbohydrates and proteins must be divided into three main doses.
The likelihood of adverse reactions from the gastrointestinal tract may increase if the drug Listat is taken with a diet rich in fats (for example, 2000 kcal / day, of which more than 30% is in the form of fats, which equals about 67 g of fat).
If Listat is taken with food that is very rich in fat, the likelihood of gastrointestinal reactions increases. In patients with type 2 diabetes mellitus, a decrease in body weight during treatment with Listat is accompanied by an improvement in the compensation of carbohydrate metabolism, which may allow or require a reduction in the dose of hypoglycemic drugs (for example, sulfonylurea derivatives).
Influence on the ability to drive vehicles and mechanisms.
Listat's drug does not affect the ability to drive vehicles and mechanisms. Patients with type 2 diabetes mellitus using Listat in combination with hypoglycemic drugs should be careful when driving vehicles and mechanisms due to the possible development of hypoglycemia, accompanied by dizziness, visual impairment.
