Alli

long-term therapy of obese or overweight patients, including those with obesity-associated risk factors, in combination with a moderately hypocaloric diet,

in combination with hypoglycemic drugs (metformin, sulfonylurea derivatives and / or insulin) or a moderately hypocaloric diet in patients with type 2 diabetes mellitus who are overweight or obese.

long-term therapy of obese patients (BMI ≥30 kg / m²²), having obesity-associated risk factors, in combination with a moderately hypocaloric diet,

in combination with hypoglycemic drugs (metformin, sulfonylureas and/or insulin) and / or a moderately hypocaloric diet in patients with type 2 diabetes mellitus who are overweight or obese.

Inside, adults — 1 capsule (120 mg) with each main meal (during, or no later than 1 hour after a meal). If the meal is skipped or the food does not contain fat, then the drug can also be skipped.

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.

Dose adjustments in patients elderly people not required.

Dose adjustments with impaired liver or kidney function not required.

Safety and effectiveness of Allia in children under 18 years of age not installed.

Inside.

Long-term therapy of obese or overweight patients with obesity-associated risk factors, in combination with a moderately hypocaloric diet. In adults and children over 12 years of age, the recommended dose of orlistat is 1 capsule. 120 mg with each main meal (immediately before, during, or no later than 1 hour after a meal).

In combination with hypoglycemic drugs (metformin, sulfonylureas and/or insulin) and / or a moderately hypocaloric diet in patients with type 2 diabetes mellitus who are overweight or obese. In adults, the recommended dose of orlistat is 1 capsule. 120 mg with each main meal (immediately before, during, or no later than 1 hour after a meal).

If the meal is skipped or the food does not contain fat, then take the drug Alli^® you can also skip it.

Alli drug^® it should be taken in combination with a balanced, moderately hypocaloric diet containing no more than 30% of calories in the form of fat. The daily intake of fats, carbohydrates and proteins should be divided into 3 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.

Efficacy and safety of orlistat in patients with impaired liver and/or kidney function, as well as in elderly and children (under 12 years of age) not investigated.

hypersensitivity to the drug or any other components contained in the capsule,

chronic malabsorption syndrome,

cholestasis.

hypersensitivity to the drug or any other components contained in the capsule,

chronic malabsorption syndrome,

cholestasis,

pregnancy,

breastfeeding period,

children under 12 years of age.

With caution: concomitant therapy with cyclosporine, concomitant therapy with warfarin or other oral anticoagulants (see "Interaction").

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), and very rare (<1/10000), including individual cases.

Adverse reactions to orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological effect of the drug, which prevents the absorption of food fats. Very often, there were such phenomena as oily discharge from the rectum, the release of gases with a certain amount of discharge, imperative urge to defecate, steatorrhea, increased defecation, loose stools, flatulence, abdominal pain or discomfort.

Their frequency increases with an increase in the fat content of food. Patients should be informed about the possibility of adverse reactions from the gastrointestinal tract and taught how to eliminate them by better following the diet, especially with regard 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 and thus helps patients to control and regulate their fat intake.

As a rule, these adverse 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.

When treating Alliom, the following adverse events from the gastrointestinal tract often occur: "soft" stools, pain or discomfort in the rectum, fecal incontinence, bloating, tooth damage, gum damage.

There were also very often — headaches, upper respiratory tract infections, influenza, often-lower respiratory tract infections, urinary tract infections, dysmenorrhea, anxiety, weakness.

Rare cases of allergic reactions have been described, the main clinical symptoms of which were itching, rash, urticaria, angioedema, bronchospasm and anaphylaxis.

Very rare cases of bullous rash, increased activity of transaminases and ALP, as well as individual, possibly serious, cases of hepatitis development have been described (a causal relationship with the use of Allia or pathophysiological mechanisms of development have not been established).

With the simultaneous administration of Allia and anticoagulants, cases of a decrease in prothrombin and an increase in INR have been reported.

Cases of rectal bleeding, diverticulitis, pancreatitis and cholelithiasis have been reported (the frequency of occurrence is unknown).

In patients with type 2 diabetes, the nature and frequency of adverse events were comparable to those in individuals without diabetes with overweight and obesity. The only new side effects that occurred with a frequency of >2% and ≥1% compared to placebo were hypoglycemic conditions (which could occur as a result of improved carbohydrate compensation) and bloating.

Classification of the frequency of side effects recommended by WHO: very often - ≥1/10, often-from ≥1/100 to <1/10, infrequently-from ≥1/1000 to <1/100, rarely-from ≥1/10000 to <1/1000, very rarely - <1/10000, frequency unknown-cannot be estimated based on available data.

Clinical trial data

Adverse reactions to orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological effect of the drug, which prevents the absorption of food fats. The frequency of adverse events decreased with prolonged use of orlistat.

The following adverse events occurred with a frequency of >2% and an incidence of ≥1% compared to placebo.

Infectious and parasitic diseases: very often — the flu.

From the side of metabolism: very often — hypoglycemia*.

Mental disorders: often-anxiety.

From the nervous system: very often — a headache.

From the respiratory system, chest and mediastinal organs: very often — upper respiratory tract infections, often-lower respiratory tract infections.

From the gastrointestinal tract: very often-pain or discomfort in the abdomen, oily discharge from the rectum, the release of gases with a certain amount of discharge, imperative urge to defecate, steatorrhea, flatulence, loose stools, frequent defecation, often-pain or discomfort in the rectum, soft stools, fecal incontinence, tooth damage, gum damage, bloating*.

From the kidneys and urinary tract: often — urinary tract infections.

From the genitals and breast: often-irregular menstruation.

General disorders and disorders at the injection site: often-weakness.

In patients with type 2 diabetes, the nature and frequency of adverse events were comparable to those in individuals without diabetes with overweight and obesity.

The frequency of gastrointestinal disorders increases with an increase in the fat content in the diet. Patients should be informed about the possibility of adverse reactions from the gastrointestinal tract and taught how to eliminate them by better following the diet, especially with regard 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 and thus helps patients to control and regulate their fat intake.

As a rule, these adverse reactions were 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.

In the 4-year clinical trial, the overall safety profile did not differ from that obtained in the 1 - and 2-year studies. At the same time, the overall frequency of adverse events from the gastrointestinal tract decreased annually during the 4-year period of taking orlistat.

Post-marketing surveillance

The following adverse events were detected in spontaneous post-registration messages, the frequency of development is unknown.

On the part of the immune system: hypersensitivity reactions, the main clinical symptoms of which were pruritus, skin rash, urticaria, angioedema, bronchospasm and anaphylaxis.

From the digestive system: rectal bleeding, diverticulitis, pancreatitis.

From the liver and biliary tract: cholelithiasis, isolated, possibly serious, cases of liver damage, leading to its transplantation or death.

From the skin and subcutaneous tissues: bullous rash.

From the kidneys and urinary tract: oxalate nephropathy, which can sometimes lead to the development of kidney failure.

Laboratory data: an increase in the activity of hepatic transaminases and alkaline phosphatase, a decrease in the concentration of prothrombin in blood plasma, an increase in the values of INR and cases of unbalanced therapy with anticoagulants, which led to changes in hemostatic parameters (see "Interaction"). Cases of hyperoxaluria have been reported.

From the musculoskeletal system and connective tissue: with the simultaneous use of orlistat and antiepileptic drugs, cases of convulsions have been observed (see "Interaction").

* The only new adverse events in patients with obesity and type 2 diabetes were hypoglycemic conditions (very common) and bloating (common), occurring with a frequency of >2% and an incidence of ≥1% compared to placebo.

In clinical studies in individuals with normal body weight and obese patients, taking single doses of 800 mg or multiple doses of 400 mg 3 times a day for 15 days was not accompanied by the appearance of significant adverse events. In addition, there is an experience of using orlistat 240 mg 3 times a day for 6 months in obese patients, which was not accompanied by a significant increase in the frequency of adverse events.

Symptoms: in cases of overdose, either no adverse events were reported, or the adverse events did not differ from those observed when taking the drug in therapeutic doses.

Treatment: in the case of a severe overdose of Allia, it is recommended to monitor the patient for 24 hours.

According to studies in humans and animals, any systemic effects that could be associated with the lipase-inhibiting properties of orlistat should be quickly reversible.

In clinical studies in individuals with normal body weight and obese patients, taking single doses of 800 mg or multiple doses of orlistat 400 mg 3 times a day for 15 days was not accompanied by the appearance of significant adverse events. In addition, patients with obesity have experience of using orlistat 240 mg 3 times a day for 6 months, which was not accompanied by a significant increase in the frequency of adverse events.

Symptoms: either no adverse events were reported, or the adverse events did not differ from those observed when taking orlistat at therapeutic doses.

Treatment: it is recommended to observe the patient for 24 hours. According to studies in humans and animals, any systemic effects that could be associated with the lipase-inhibiting properties of orlistat should be quickly reversible.

Alli-a specific inhibitor of gastrointestinal lipases, which has 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. In this case, 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 non-split triglycerides are not absorbed, the resulting decrease in the intake of calories 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 bloodstream

Judging by the results of the fat content in the feces, the effect of orlistat begins 24-48 hours after administration. After discontinuation of the drug, the fat content in the feces usually returns to the level that occurred before the start of therapy after 48-72 hours.

Alli drug^® - a powerful, 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. In this case, 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 non-split triglycerides are not absorbed, the resulting decrease in the intake of calories 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 administration. After the withdrawal of orlistat, the fat content in the feces usually returns to the level that occurred before the start of therapy after 48-72 hours.

Efficiency

Obese patients. In clinical studies, patients taking orlistat experienced greater weight loss compared to patients on diet therapy. Weight loss began within the first 2 weeks after the start of treatment and lasted from 6 to 12 months even in patients with a negative response to diet therapy. For 2 years, there was a statistically significant improvement in the profile of metabolic risk factors associated with obesity. In addition, compared to taking a placebo, there was a significant reduction in the amount of fat in the body. Orlistat is effective in preventing repeated weight gain. Repeated weight gain, no more than 25% of the lost weight, was observed in about half of the patients, and in half of these patients, repeated weight gain was not observed or even there was a further decrease in it

Patients with obesity and type 2 diabetes. In clinical studies lasting from 6 months to 1 year, patients with overweight or obesity and type 2 diabetes mellitus taking orlistat experienced greater weight loss compared to patients treated with diet therapy alone. The loss of body weight was mainly due to a decrease in the amount of fat in the body. It should be noted that before the start of the study, despite the use of hypoglycemic agents, patients often had insufficient glycemic control. However, with orlistat therapy, there was a statistically and clinically significant improvement in glycemic control. In addition, against the background of orlistat therapy, there was a decrease in the doses of hypoglycemic agents, the concentration of insulin in the blood plasma, as well as a decrease in insulin resistance

Reducing the risk of developing type 2 diabetes in obese patients. In a 4-year clinical trial, orlistat was shown to significantly reduce the risk of developing type 2 diabetes (approximately 37% compared to placebo). The degree of risk reduction was even more significant in patients with an initial glucose tolerance disorder (approximately 45%).%).. Maintaining body weight at a new level was observed throughout the study period. Moreover, compared with placebo, patients treated with orlistat showed a significant improvement in the profile of metabolic risk factors

Pubertal obesity. In a 1-year clinical trial in obese adolescents, a decrease in BMI was observed when taking orlistat compared to the placebo group, where there was even an increase in BMI. In addition, patients in the orlistat group showed a decrease in fat mass, as well as waist and hip circumference compared to the placebo group. Also, patients treated with orlistat showed a significant decrease in dBP compared to the placebo group.

Suction

In volunteers with normal body weight and obesity, the systemic effect of the drug is minimal. After 8 hours after oral administration of the drug, unchanged orlistat in the plasma could not be determined, which means that its concentrations are below the level of 5 ng/ml.

In general, after taking therapeutic doses, it was possible to detect unchanged orlistat in plasma only in rare cases, while its concentrations were extremely low (<10 ng/ml or 0.02 mmol). There were no signs of accumulation, which confirms that the absorption of the drug is minimal.

Distribution

The volume of distribution can not be determined, because the drug is very poorly absorbed. In vitro orlistat is more than 99% bound to plasma proteins (mainly lipoproteins and albumin). In minimal amounts, orlistat can penetrate into red blood cells.

Metabolism

Judging by the data obtained in an animal experiment, the metabolism of orlistat is carried out mainly in the intestinal wall. In a study in obese individuals, it was found that approximately 42% of the minimum fraction of the drug that undergoes systemic absorption is accounted for by two main metabolites — M1 (a four-membered hydrolyzed lactone ring) and M3 (M1 with a cleaved N-formylleucine residue).

The M1 and M3 molecules have an open beta-lactone ring and are extremely weak in inhibiting lipase (1000 and 2500 times weaker, respectively, than orlistat). Given such low inhibitory activity and low plasma concentrations (on average 26 and 108 ng / ml, respectively) after therapeutic doses, these metabolites are considered pharmacologically inactive.

Output

Studies in individuals with normal and overweight body weight have shown that the main route of elimination is the elimination of non-absorbed drug with feces. About 97% of the dose of the drug was excreted in the feces, and 83% - in the form of unchanged orlistat.

The total renal excretion of all substances structurally related to orlistat is less than 2% of the dose taken. The time to complete elimination of the drug from the body (with feces and urine) is 3-5 days. The ratio of the pathways of orlistat excretion in normal and overweight volunteers was the same. Both orlistat and the M1 and M3 metabolites can be excreted with bile.

Pharmacokinetics in special clinical groups

Plasma concentrations of orlistat and its metabolites (M1 and M3) in children, they do not differ from those in adults when comparing the same doses of the drug. The daily excretion of fat in the feces was 27% of the intake with food with orlistat therapy and 7% - with placebo.

Suction. In volunteers with normal body weight and obesity, the systemic effect of the drug is minimal. After a single oral administration of orlistat at a dose of 360 mg, unchanged orlistat in plasma could not be determined, which means that its concentrations are below the level of 5 ng/ml. In general, after taking therapeutic doses, it was possible to detect unchanged orlistat in blood plasma only in rare cases, while its concentrations were extremely low (<10 ng/ml or 0.02 mmol). There were no signs of accumulation, which confirms the minimal absorption of orlistat.

Distribution. V_d it can not be determined, because the drug Alli^® very poorly absorbed. In the conditions of in vitro orlistat is more than 99% bound to plasma proteins (mainly lipoproteins and albumin). In minimal amounts, orlistat can penetrate into red blood cells.

Metabolism. Judging by the data obtained in an animal experiment, the metabolism of orlistat is carried out mainly in the intestinal wall. In a study in obese individuals, it was found that approximately 42% of the minimum fraction of orlistat that undergoes systemic absorption is accounted for by 2 main metabolites — M1 (four-membered hydrolyzed lactone ring) and M3 (M1 with a cleaved N-formylleucine residue).

The M1 and M3 molecules have an open beta-lactone ring and are extremely weak in inhibiting lipase (1000 and 2500 times weaker than orlistat, respectively). Taking into account such low inhibitory activity and low plasma concentrations (on average 26 and 108 ng/ml, respectively) after taking therapeutic doses, these metabolites are considered pharmacologically inactive.

Output. Studies in individuals with normal and overweight have shown that the main route of elimination is the elimination of unabsorbed orlistat through the intestine. About 97% of the dose of the drug was excreted through the intestine, and 83% - in the form of unchanged orlistat. The total renal excretion of all substances structurally related to orlistat is less than 2% of the dose taken. The time to complete elimination of orlistat from the body (through the intestines and kidneys) is 3-5 days. The ratio of the ways of excretion of orlistat in volunteers with normal and overweight was the same. Both orlistat and the M1 and M3 metabolites can be excreted with bile

Pharmacokinetics in special clinical groups

Plasma concentrations of orlistat and its metabolites (M1 and M3) in children, they do not differ from those in adults when comparing the same doses of orlistat. The daily excretion of fat in the feces was 27% of the intake with food with orlistat therapy and 7% - with placebo.

Preclinical safety data

According to preclinical data, no additional risks for patients related to the safety profile, toxicity, genotoxicity, carcinogenicity and reproductive toxicity were identified. In animal studies, no teratogenic effect was also detected. Due to the absence of a teratogenic effect in animals, it is unlikely to be detected in humans.

No interaction detected with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine GITS (gastro-intestinal therapeutic system) and slow-release nifedipine, sibutramine or alcohol (based on studies of drug interaction). However, it is necessary to monitor the indicators of INR with concomitant therapy with warfarin or other oral anticoagulants.

When taken simultaneously with Alli, a decrease in absorption was noted vitamins A, D, E, K and beta-carotene. If multivitamins are recommended, they should be taken at least 2 hours after taking Allia or before bedtime.

When taking Allia and cyclosporine there was a decrease in plasma concentrations of cyclosporine, so it is recommended to more frequently determine the concentrations of cyclosporine in plasma while taking cyclosporine and Allia.

When assigning amiodarone During Alliom therapy, there was a decrease in the systemic exposure of amiodarone and desethylamiodarone (by 25-30%), but due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear. The addition of Allia to long-term amiodarone therapy may lead to a decrease in the therapeutic effect of amiodarone.

Avoid concomitant administration of Allia and acarboses due to the lack of data from pharmacokinetic studies.

With the simultaneous use of orlistat and cyclosporine, there was a decrease in the concentration of cyclosporine in the blood plasma, which may lead to a decrease in the immunosuppressive effectiveness of cyclosporine. Thus, the concomitant use of orlistat and cyclosporine is not recommended. However, if such concomitant use is necessary, it is recommended to conduct more frequent monitoring of the concentration of cyclosporine in the blood plasma both when it is used simultaneously with orlistat, and after stopping the use of orlistat. The concentration of cyclosporine in the blood plasma should be monitored until it is stabilized.

When used concomitantly with Alli^® there was a decrease in the absorption of vitamins D, E and beta-carotene. If multivitamins are recommended, they should be taken at least 2 hours after taking Alli^® or before going to bed.

When using amiodarone orally during orlistat therapy, there was a decrease in the systemic exposure of amiodarone and desethylamiodarone (by 25-30%), but due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is unclear. Adding the Alli drug^® long-term therapy with amiodarone may lead to a decrease in the therapeutic effect of amiodarone (no studies have been conducted).

Concomitant administration of Alli should be avoided^® and acarbose due to the lack of data from pharmacokinetic studies.

When taking orlistat and antiepileptic drugs at the same time, cases of seizures were observed. 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.. According to clinical studies, there is no interaction of orlistat with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, nifedipine GITS (gastrointestinal therapeutic system) and nifedipine with slow release, sibutramine or ethanol

However, with the simultaneous use of orlistat and warfarin or other anticoagulants, a decrease in the concentration of prothrombin and an increase in the INR index may be observed, which may lead to a change in hemostatic parameters. It is necessary to monitor the INR indicator with concomitant therapy with warfarin or other anticoagulants for oral administration.

There have been rare cases of hypothyroidism and/or disorders of its control. The mechanism of development of this phenomenon is unknown, but may be due to a decrease in the absorption of iodized salt and / or levothyroxine sodium.

There have been cases of decreased effectiveness of antiretroviral drugs for the treatment of HIV, antidepressants and neuroleptics (including lithium preparations), coinciding with the beginning of the use of orlistat in previously compensated patients. Therapy with orlistat should be initiated only after a thorough assessment of its possible effect on such patients.

Orlistat can indirectly reduce the effectiveness of oral contraceptives, which in some cases can lead to unplanned pregnancy. It is recommended to use an additional method of contraception also in the case of severe diarrhea.