Otrio
Otrio: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Drug interactions
- 14. Analogs
- 15. Terms and conditions of storage
- 16. Terms of dispensing from pharmacies
- 17. Reviews
- 18. Price in pharmacies
Latin name: Otrio
ATX code: C10AX09
Active ingredient: ezetimibe (Ezetimibe)
Producer: KhFK JSC "AKRIKHIN" (Russia)
Description and photo update: 2019-29-10
Prices in pharmacies: from 450 rubles.
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Otrio is a hypolipidemic drug that inhibits the absorption of cholesterol. It belongs to the representatives of a new class of lipid-lowering agents that selectively inhibit the intestinal absorption of cholesterol and some sterols of plant origin.
Release form and composition
The drug is produced in the form of tablets: round, flat-cylindrical, beveled, white or white with a yellowish tinge of color (10 pieces in blister packs, in a cardboard box 1, 2, 3, 6 or 9 blister packs and instructions for medical use Otriot).
Composition for 1 tablet:
- active substance: ezetimibe - 10 mg (in terms of 100% substance);
- auxiliary components: lactose monohydrate, sodium stearyl fumarate, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, povidone K30.
Pharmacological properties
Pharmacodynamics
Ezetimibe is a representative of a new class of lipid-lowering drugs. Its mechanism of action differs from that of other lipid-lowering agents (eg, fibrates, statins, plant stanols and bile acid sequestrants). The molecular target of the drug is the NPC1L1 protein (Niemann-Pick Cl-Like 1). It is a transport protein responsible for the absorption of plant sterols and cholesterol in the intestine.
Ezetimibe accumulates in the brush border of the small intestine and prevents the absorption of cholesterol. As a result, the intake of cholesterol from the intestine to the liver decreases, the stores of cholesterol in the liver decrease and its excretion from the blood increases. Otrio does not inhibit the synthesis of cholesterol in the liver (as statins do) and does not increase the excretion of bile acids (as, for example, occurs in the case of the use of bile acid sequestrants).
In clinical studies in patients with hypercholesterolemia, ezetimibe reduced the absorption of cholesterol in the intestine by 54% (in comparison with patients in the placebo group). Statins reduce the hepatic synthesis of cholesterol, and ezetimibe reduces its entry into the liver, therefore, with the combined use of drugs of these two groups, an additional decrease in the level of cholesterol is provided.
Concomitant use of statins and ezetimibe in patients with hypercholesterolemia leads to the following effects:
- the concentration of TC (total cholesterol) decreases;
- the concentration of LDL cholesterol (low density lipoprotein cholesterol) decreases;
- the concentration of apo-B (apolipoprotein B) decreases;
- the content of TG (triglycerides) decreases;
- the concentration of HDL cholesterol (high density lipoprotein cholesterol) increases;
- the content of non-HDL cholesterol (low-density lipoprotein cholesterol) decreases (non-HDL cholesterol is the difference between the concentrations of total cholesterol and HDL cholesterol).
When statins and ezetimibe are used together, these effects are more pronounced than when these drugs are used alone.
As a result of the simultaneous administration of ezetimibe and fenofibrate in patients with mixed hypercholesterolemia, plasma concentrations of total cholesterol, apo-B, LDL cholesterol, non-HDL cholesterol, and triglycerides increased, and the concentration of HDL cholesterol increased.
It has been proven that increased concentrations of LDL cholesterol, total cholesterol and apo-B (this is the main protein component of LDL), as well as a reduced concentration of HDL cholesterol, increase the risk of atherosclerosis and contribute to its development.
As a result of the studies, it has been shown that the incidence of cardiovascular pathologies and mortality due to these diseases are in direct proportion to the content of total cholesterol and LDL cholesterol and inversely to the level of HDL cholesterol. VLDL (very low density lipoproteins), IDLs (intermediate density lipoproteins), and remnants (residues) of chylomicrons containing cholesterol can also contribute to the development of atherosclerosis.
In a series of preclinical studies, the selectivity of ezetimibe was determined precisely in relation to inhibition of absorption of cholesterol. As a result of such studies, it was shown that the drug inhibited the absorption of [14 C] -cholesterol, but did not affect the absorption of fatty acids, fat-soluble vitamins (A and D), TG, progesterone, bile acids and ethinyl estradiol.
Pharmacokinetics
After taking Otrio, the active substance of the drug is rapidly absorbed and actively metabolized in the liver and small intestine by conjugation to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
After 1–2 hours, the maximum concentration of ezetimibe-glucuronide is observed in the blood plasma, and the maximum plasma concentration of ezetimibe is observed after 4–12 hours.
Determination of the absolute bioavailability of ezetimibe is not possible, since this substance is almost insoluble in aqueous solvents that are used to prepare solutions for injection.
The bioavailability of ezetimibe is unaffected by a high or low fat meal, so Otrio can be taken whenever you want, regardless of meal time.
Ezetimibe is 99.7% bound to plasma proteins. The connection of ezetimibe-glucuronide with plasma proteins is slightly lower and averages 88–92%.
The main metabolism occurs in the liver and small intestine by conjugation with glucuronides (this is a phase II reaction) and subsequent excretion in the bile. The drug is minimally subject to oxidative metabolism (this is a phase I reaction). Both ezetimibe and ezetimibe-glucuronide are determined in the patient's blood plasma. Their concentrations are 10–20% and 80–90%, respectively (based on the total plasma concentration of ezetimibe). The active substance and its metabolite are slowly eliminated from the plasma during recirculation between the intestines and the liver. The half-life is about 22 hours.
In children over 6 years of age, Otrio's pharmacokinetic parameters were similar to those in adults. There are no data on the pharmacokinetics of the drug in children under 6 years of age.
In patients over 65 years of age, the plasma concentration of total ezetimibe was approximately two times higher than in patients aged 18–45 years. The reduction in LDL cholesterol and the safety profile of the drug were comparable in older patients and younger people who took ezetimibe. No special dose adjustment is required for persons over 65 years of age.
With mild liver failure (5-6 points on the Child-Pugh scale) after taking Otrio at a dose of 10 mg, the average AUC (area under the concentration-time curve) of the total ezetimibe increased 1.7 times. With a moderate degree of liver failure (7-9 points on the Child-Pugh scale), this indicator increased 4 times on days 1 and 14 (in a 14-day study). No dose adjustment is required in patients with mild hepatic impairment. The drug is not recommended for patients with moderate and severe hepatic impairment.
For impaired renal function, Otrio is used in normal doses. A single dose of 10 mg of ezetimibe led to an increase in the AUC of the total ezetimibe by about 1.5 times, but this result has no clinical significance.
After kidney transplantation in patients receiving complex treatment, including cyclosporine, the AUC of total ezetimibe increased 12-fold.
The plasma concentration of total ezetimibe in women is slightly higher than in men. However, the safety profile and the degree of decrease in the concentration of LDL cholesterol were the same and did not depend on the gender of the patient.
Indications for use
- prevention of cardiovascular disease (in combination with statins in patients with coronary heart disease to reduce the risk of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction and hospitalization due to unstable angina pectoris or the need for myocardial revascularization);
- primary hypercholesterolemia (in children and adolescents aged 10–17 years, adults with primary hypercholesterolemia, in monotherapy, as an addition to the diet, or in combination with statins);
- mixed hypercholesterolemia (together with fenofibrate and in addition to a special diet);
- homozygous familial hypercholesterolemia (in children and adolescents aged 10-17 years, and adults, in combination with statins or other auxiliary therapies, such as LDL apheresis);
- prevention of cardiovascular complications in people with chronic kidney disease (together with simvastatin to reduce the risk of stroke, cardiac death, or non-fatal myocardial infarction).
Contraindications
Absolute contraindications:
- moderate and severe hepatic failure (7-9 points or more on the Child-Pugh scale);
- children under 6 years of age;
- deficiency of the enzyme lactase, lactose intolerance, glucose-galactose malabsorption syndrome;
- hypersensitivity to the main or auxiliary components of the tablets.
Otrio tablets 10 mg are used with caution in case of simultaneous administration of indirect anticoagulants, cyclosporine and fibrates. Patients who take fenofibrate with ezetimibe should be informed about the likelihood of gallbladder disease.
Otrio, instructions for use: method and dosage
Before starting therapy, as well as throughout the entire period of treatment with the drug, a special lipid-lowering diet must be followed.
Otrio tablets are taken orally once a day, regardless of the meal time (morning, afternoon or evening).
For the treatment of primary hypercholesterolemia, the recommended dose is 10 mg (1 tablet) once a day. Otrio is used as monotherapy or as part of a combination treatment in conjunction with fenofibrate or statin. The maximum dose of fenofibrate in combination with ezetimibe is 160 mg once daily.
In ischemic heart disease, Otrio is used in conjunction with statins to further reduce the risk of cardiovascular events in persons with impaired myocardial blood supply. The recommended dose is 10 mg once a day.
Patients with chronic kidney disease and / or impaired renal function during monotherapy do not need to adjust the dose of Otrio. As part of a complex treatment with simvastatin, a dose of simvastatin or ezetimibe is not required for persons with mild renal impairment. If the glomerular filtration rate is less than 60 ml / min / 1.73 m 2, simvastatin is prescribed at a dose of no more than 20 mg once a day, and Otrio at a dose of 10 mg once a day (in the evening). Reception of higher doses of simvastatin is possible only under the condition of careful monitoring of the patient's condition and his renal function.
If necessary, the simultaneous use of bile acid sequestrants Otrio should be taken in a dose of not more than 10 mg once a day 2 hours before or 4 hours after taking bile acid sequestrants.
Side effects
Otrio tablets are well tolerated. Undesirable side effects are usually mild and go away on their own.
Side effects that were observed with Otrio in monotherapy more often than with placebo or concomitant use of statins, and also more often than with statin monotherapy:
- digestive system: often - loose stools, abdominal pain, flatulence; infrequently - nausea, dyspeptic disorders, gastroesophageal reflux;
- metabolism and nutrition: infrequently - decreased appetite;
- respiratory system: infrequently - cough;
- cardiovascular system: infrequently - increased blood pressure, rush of blood to the skin of the face;
- musculoskeletal system: infrequently - muscle spasms, arthralgia, neck pain;
- data from laboratory and instrumental studies: infrequently - increased activity of liver enzymes, gamma-glutamyltransferase and creatine phosphokinase, impaired liver function indicators;
- other reactions: often - fatigue; infrequently - pains of various localization, chest pain.
Possible side effects of ezetimibe when taken with statins:
- digestive system: infrequently - gastritis, dryness of the oral mucosa;
- musculoskeletal system: often - muscle pain; infrequently - muscle weakness, back pain, pain in the arms and legs;
- nervous system: often - headache; infrequently - paresthesia;
- skin and subcutaneous fat: infrequently - skin rash, urticaria, itching;
- data of laboratory and instrumental studies: often - an increase in the activity of liver enzymes;
- other reactions: infrequently - peripheral edema, asthenia.
In patients taking fenofibrate at the same time as Otrio, the most common side effect is abdominal pain. In addition, in 2.7% of such patients, there is an increase in the activity of liver enzymes (more than 3 times compared with the upper limit of the norm). The frequency of operations to remove the gallbladder in the group of patients who simultaneously took fenofibrate with ezetimibe was 1.7%. No increase in creatine phosphokinase activity was observed in any of the groups.
In patients with coronary heart disease who took Otrio together with simvastatin, the following side reactions were noted: myopathy, rhabdomyolysis, increased liver enzyme activity, adverse events from the gallbladder, and malignant tumors.
During the post-marketing application of Otrio, the following adverse reactions were reported (causal relationship not specified):
- digestive system: pancreatitis, constipation;
- hepatobiliary system: cholelithiasis, hepatitis, cholecystitis;
- nervous system and psyche: dizziness, depression, paresthesia;
- lymphatic system and blood: thrombocytopenia;
- musculoskeletal system: myopathy / rhabdomyolysis, myalgia;
- immune system: skin rash, urticaria, Quincke's edema, anaphylactic reactions;
- skin and subcutaneous fat: erythema multiforme;
- other reactions: asthenia.
Overdose
There have been several cases of ezetimibe overdose, but none of them has been found to cause serious adverse reactions. All adverse events were mild and resolved on their own.
If necessary, symptomatic and supportive therapy is carried out in case of intoxication.
special instructions
When prescribing Otrio along with fenofibrate or statin, it is recommended to carefully study the instructions for use of these drugs.
In the case of the combined use of ezetimibe with statins, a consistent increase in the activity of liver enzymes is observed (3 or more times compared to the upper limit of the norm), therefore, regular monitoring of liver function is required at the beginning of therapy and then regularly in accordance with the instructions for the statin used.
The incidence of rhabdomyolysis or myopathy did not exceed the incidence of these side effects in the control group (statin monotherapy or placebo group). However, myopathy and rhabdomyolysis are known to be known adverse reactions to other lipid-lowering drugs (including statins). Most patients who develop rhabdomyolysis took statins before starting Otrio. Rhabdomyolysis is very rare with ezetimibe monotherapy.
Patients should be warned of the risk of developing rhabdomyolysis and myopathy, and should inform their doctor about any muscle pain of unknown origin, weakness or tenderness. If myopathy is suspected or the diagnosis is confirmed, treatment with ezetimibe and any statin taken simultaneously should be discontinued. An increase in the activity of creatine phosphokinase more than 10 times compared with the upper limit of the norm, as well as the presence of the symptoms listed above, indicates the development of myopathy.
Influence on the ability to drive vehicles and complex mechanisms
Special studies on the effect of Autrio on the ability to drive vehicles and work with other potentially dangerous and complex mechanisms have not been conducted. However, some of the side effects that occur with the drug may affect the psychomotor functions of individual patients.
Application during pregnancy and lactation
Animal experiments have not shown any direct or indirect adverse effects of ezetimibe in relation to pregnancy, fetal / embryonic development, childbirth and further postnatal development. No teratogenic effects were observed when ezetimibe was administered to pregnant female rats in conjunction with simvastatin, atorvastatin, lovastatin or pravastatin. In pregnant rabbits, the administration of the drug in some cases led to defects in the development of the fetal skeleton (the frequency of such cases is low).
Clinical data on the use of Otrio in pregnant women are absent, therefore, the drug is used with extreme caution during pregnancy.
When used together with a prescribed statin, it is also necessary to adhere to the recommendations for the use of this particular statin during pregnancy.
Ezitimibe is secreted in breast milk in female rats. There are no data on the excretion of the drug in breast milk in women, so Otrio is not recommended for use during breastfeeding. If it is necessary to use the drug during lactation, breastfeeding should be stopped.
Pediatric use
Esitimibe is contraindicated in children under 6 years of age, since there is no data on the safety and efficacy of Otrio in patients under 6 years of age.
The safety and efficacy rates of Otrio were studied in pediatric patients aged 6–10 years with heterozygous familial or nonfamilial hypercholesterolemia in a clinical study of 12 weeks duration. In childhood, the profile of side effects was comparable to that in adults who received ezetimibe. Otrio does not have a clear effect on puberty or growth in girls and boys (the effect of the drug on these parameters when treated for more than 12 weeks is unknown).
In children and adolescents aged 10–17 years with heterozygous familial hypercholesterolemia, the safety and efficacy of ezetimibe have been studied in combination with simvastatin. This study included adolescent boys and girls who had passed at least one year after their first menstrual bleeding. The side effect profile was similar to that in adults. The study revealed no clear effect of Otrio on adolescent puberty and growth or menstrual cycle duration in adolescent girls.
With impaired renal function
In patients with impaired renal function with monotherapy with the drug, dose adjustment is not required.
In the case of combination therapy with simvastatin in patients with a glomerular filtration rate of less than 60 ml / min / 1.73 m 2, Otrio is used in a dose of no more than 10 mg once a day, and simvastatin - in a dose of no more than 20 mg once a day. If it is necessary to use simvastatin in higher doses, it is recommended to carefully monitor the patient's condition.
For violations of liver function
In patients with mild hepatic impairment, Otrio dose adjustment is not required.
In moderate to severe liver dysfunction, the use of ezetimibe is not recommended.
Drug interactions
Otrio does not affect the pharmacokinetics of drugs that are metabolized by N-acetyltransferase or cytochrome P 450 isoenzymes. Ezitimibe does not alter the pharmacokinetics of digoxin, midazolam, dapsone, glipizide, oral contraceptives (levonorgestrel and ethinyl estradiol), dextromethorphan and tolbutamide. Concomitant administration of cimetidine does not reduce the bioavailability of ezetimibe.
Antacids reduce the absorption rate of ezetimibe, but do not affect its bioavailability, therefore, this decrease in the rate of absorption of the drug has no clinical significance.
Cholestyramine reduces the mean AUC of total ezetimibe by about 55%. Due to this interaction, it is possible to reduce the effect of an additional decrease in the level of LDL cholesterol with the simultaneous use of colestyramine and ezetimibe.
Co-administration with cyclosporine leads to an increase in the AUC value of total ezetimibe.
With simultaneous use with fibrates, an increase in the release of cholesterol with bile is possible, as a result of which there is a high probability of developing gallstone disease. Otrio is not recommended to be combined with fibrates (except fenofibrate).
There are no clinically significant interactions with the combined use of ezetimibe with lovastatin, simvastatin, rosuvastatin, atorvastatin and pravastatin.
Ezitimibe can increase the INR (International Normalized Ratio) when used simultaneously with indirect anticoagulants (fluindione or warfarin).
Analogs
Otrio's analogues are Ezetrol, Ineji, Lipobon.
Terms and conditions of storage
Keep out of the reach of children. Store at a temperature not exceeding 25 ° C.
The shelf life of the tablets is 2 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Otrio
There are very few reviews of Otrio, but from reports of a similar drug with the same active ingredient, it is known that this drug is very good and does an excellent job with the main task - reducing the concentration of bad cholesterol in the blood.
The main disadvantage, according to patients, is the cost of Otrio, since it is constantly increasing, and the tablets are recommended to be taken regularly.
Price for Otrio in pharmacies
The price of Otrio 10 mg (30 tablets per pack) is 440-460 rubles.
Otrio: prices in online pharmacies
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Drug name Price Pharmacy |
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Otrio 10 mg tablets 30 pcs. 450 RUB Buy |
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Otrio tab. 10 mg 30 pcs. 543 r Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
