Rosulip Plus capsules 10mg + 10mg, No. 30

Primary hypercholesterolemia (Fredrickson type IIa, including familial heterozygous hypercholesterolemia), homozygous familial hypercholesterolemia (Fredrickson type IIb).

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

Inside. The dose should be selected individually depending on the indications and the therapeutic response, taking into account the current generally accepted recommendations for target lipid concentrations.

Active ingredients:

Rosuvastatin zinc -10.68 mg, which corresponds to the content of rosuvastatin - 10 mg

Ezetimibe - 10 mg

Excipients : microcrystalline cellulose 63.33 mg + 30.3 mg, colloidal anhydrous silicon dioxide - 0.11 mg, magnesium stearate - 0.88 mg + 1 mg, povidone K25 - 5 mg, croscarmellose sodium - 19 mg, mannitol - 30.3 mg, sodium lauryl sulfate - 4.4 mg , hyprolosis - 10 mg.

The composition of the capsule shell: the base of the capsule: iron dye yellow oxide - 0.18%, titanium dioxide - 1%, gelatin - up to 100%; capsule cap: iron dye yellow oxide (E172) - 0.18%, titanium dioxide - 1%, gelatin - up to 100%.

Pregnancy and the period of breastfeeding; female patients with childbearing potential who do not use effective methods of contraception; liver disease in the active phase or a sustained increase in the serum activity of hepatic transaminases of unknown etiology (more than 3 times compared with VGN); dysfunction of the liver of medium (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) severity; severe impairment of renal function (CC <30 ml / min); myopathy; simultaneous use with cyclosporine; age up to 18 years.

Carefully

Conditions indicating the development of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled convulsions); hypothyroidism; age over 70; conditions in which there is an increase in the concentration of rosuvastatin in the blood plasma; patients of the Mongoloid race; simultaneous use with fibrates, indirect anticoagulants (warfarin) or fluindione; myotoxicity while taking other inhibitors of HMG-CoA reductase or fibrates in history; excessive alcohol consumption; a history of liver disease or liver failure; renal failure of mild and moderate severity (CC> 30 ml / min);renal failure of mild severity (CC> 60 ml / min) (for a dosage of 40 mg + 10 mg).

Description:

CONI-SNAP 0 hard gelatin capsules , unlabeled, self-closing, with a yellow base and a light brown with a pinkish tint cap, containing two tablets: rosuvastatin 5 mg tablets - white or almost white, oblong, engraved with a stylized letter E and numbers 597 on one side of the tablet, odorless or almost odorless ; ezetimibe 10 mg tablets - white or almost white, round flat, beveled, engraved with the stylized letter E on one side of the tablet and the number 612 on the other side of the tablet, with little or no odor.

Composition:

Active ingredients:

Rosuvastatin zinc -10.68 mg, which corresponds to the content of rosuvastatin - 10 mg

Ezetimibe - 10 mg

Excipients : microcrystalline cellulose 63.33 mg + 30.3 mg, colloidal anhydrous silicon dioxide - 0.11 mg, magnesium stearate - 0.88 mg + 1 mg, povidone K25 - 5 mg, croscarmellose sodium - 19 mg, mannitol - 30.3 mg, sodium lauryl sulfate - 4.4 mg , hyprolosis - 10 mg.

The composition of the capsule shell: the base of the capsule: iron dye yellow oxide - 0.18%, titanium dioxide - 1%, gelatin - up to 100%; capsule cap: iron dye yellow oxide (E172) - 0.18%, titanium dioxide - 1%, gelatin - up to 100%.

Clinical and pharmacological group: Lipid-lowering drug

Pharmaco-therapeutic group: Hypolipidemic combined agent (HMG-CoA reductase inhibitor + cholesterol absorption inhibitor)

pharmachologic effect

Combined lipid-lowering agent (HMG-CoA reductase inhibitor + cholesterol absorption inhibitor).

Rosuvastatin

Rosuvastatin is a hypolipidemic agent from the statin group. Selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts HMG-CoA into mevalonate, a precursor of cholesterol.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, which leads to increased uptake and catabolism of LDL, inhibition of VLDL synthesis, reducing the total concentration of LDL and VLDL. Reduces the concentration of cholesterol-LDL, cholesterol-not-HDL, cholesterol-VLDL, cholesterol, TG, TG-VLDL, apoV, reduces the ratio of cholesterol-LDL / HDL cholesterol, cholesterol / cholesterol-HDL, cholesterol-not-HDL / cholesterol- HDL, ApoB / apolipoprotein AI (ApoAI), increases the concentration of HDL-C and ApoAI. The therapeutic effect appears within 1 week after the start of therapy, after 2 weeks it reaches 90% of the maximum, by 4 weeks it reaches a maximum and after that it remains constant.

Ezetimibe

Ezetimibe inhibits intestinal absorption of cholesterol and is effective when taken orally. The mechanism of action of ezetimibe differs from that of other classes of lipid-lowering agents (for example, HMG-CoA reductase inhibitors (statins), bile acid sequestrants, fibrates, and plant stanols). The molecular target of ezetimibe is a transport protein (Niemann-Pick C1-Like 1, NPC1L1), which is responsible for the absorption of cholesterol and phytosterols in the intestine.

Ezetimibe is localized in the brush border of the cells of the small intestine and interferes with the absorption of cholesterol, leading to a decrease in the flow of cholesterol from the intestine to the liver, thereby reducing its stores in the liver and increasing absorption from the blood, while statins inhibit cholesterol synthesis in the liver. These various mechanisms complement each other, leading to a decrease in its concentration in blood plasma.

Pharmacokinetics

Rosuvastatin

Cmax of rosuvastatin is achieved approximately 5 hours after oral administration. The absolute bioavailability of rosuvastatin is approximately 20%.

Rosuvastatin is intensively captured by liver cells, which is the main site of cholesterol synthesis and clearance of LDL-C. The Vd of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Rosuvastatin is biotransformed in the liver to a small extent (about 10%), since it is a non-core substrate for isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. Isoenzymes CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism to a lesser extent.

The main metabolites of rosuvastatin are N-dismethylrosuvastatin and lactone metabolites. N-dismethylrosuvastatin is approximately 50% less active than rosuvastatin, the effect of lactone metabolites is not clinically significant. More than 90% of the pharmacological activity in inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest is provided by its metabolites.

About 90% of the dose of rosuvastatin is excreted unchanged through the intestines, the remainder - by the kidneys. T1 / 2 is approximately 19 hours, does not change with increasing dose of the drug. The geometric mean plasma clearance is approximately 50 L / h (coefficient of variation 21.7%). As in the case of other inhibitors of HMG-CoA reductase, a specific membrane polypeptide is involved in the process of hepatic uptake of the drug - the OATP-C transporter, which plays an important role in its hepatic elimination.

Ezetimibe

After oral administration, ezetimibe is rapidly absorbed and intensively conjugated to form a pharmacologically active phenolic glucuronide (ezetimibe glucuronide). Cmax is reached within 1-2 hours for ezetimibe-glucuronide and after 4-12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined because the substance is practically insoluble in water. Food intake (with or without high fat content) did not affect the bioavailability of ezetimibe when taken in tablet form. Ezetimibe can be taken with food or on an empty stomach.

Ezetimibe and ezetimibe-glucuronide bind to blood plasma proteins by 99.7% and 88-92%, respectively.

Ezetimibe metabolism occurs mainly in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by excretion in the bile. Ezetimibe undergoes minimal oxidative metabolism (phase I reaction). The concentrations of ezetimibe and ezetimibe-glucuronide (the main derivatives of ezetimibe, determined in blood plasma) are 10-20% and 80-90%, respectively, of the total concentration of ezetimibe in blood plasma. Ezetimibe and ezetimibe-glucuronide are slowly excreted from the body during intestinal hepatic recirculation. T1 / 2 for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Indications

Primary hypercholesterolemia (Fredrickson type IIa, including familial heterozygous hypercholesterolemia), homozygous familial hypercholesterolemia (Fredrickson type IIb).

Dosage regimen

The method of application and dosage regimen of a particular drug depends on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly observe the compliance of the used dosage form of a particular drug with the indications for use and the dosage regimen.

Inside. The dose should be selected individually depending on the indications and the therapeutic response, taking into account the current generally accepted recommendations for target lipid concentrations.

Side effect

From the side of the blood and lymphatic system: rarely - thrombocytopenia.

From the immune system: rarely - hypersensitivity reactions, including angioedema.

From the endocrine system: often - diabetes mellitus.

From the side of metabolism and nutrition: infrequently - decreased appetite.

From the side of the psyche: the frequency is unknown - depression.

From the nervous system: often - headache, dizziness; infrequently - paresthesia; very rarely - polyneuropathy, memory impairment; frequency unknown - peripheral neuropathy, sleep disorders (including insomnia and nightmares).

From the side of the vessels: the frequency is unknown - 'hot flashes' of blood to the skin, arterial hypertension.

From the respiratory system, chest and mediastinal organs: infrequently - cough.

From the gastrointestinal tract: often - constipation, nausea, abdominal pain, diarrhea, bloating; infrequently - dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis; rarely - pancreatitis.

From the liver and biliary tract: rarely - increased activity of 'hepatic' transaminases; very rarely - jaundice, hepatitis; frequency unknown - cholelithiasis, cholecystitis.

On the part of the skin and subcutaneous tissues: infrequently - itching, skin rash, urticaria; frequency unknown - Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders: often - myalgia; infrequently - joint pain, muscle cramps, neck pain, back pain, muscle weakness, pain in the limbs; rarely - myopathy (including myositis), rhabdomyolysis; very rarely - joint pain; frequency unknown - immune-mediated necrotizing myopathy, tendon lesions, sometimes complicated by rupture, muscle pain, myopathy, rhabdomyolysis.

From the side of the kidneys and urinary tract: very rarely - hematuria.

On the part of the genitals and mammary gland: very rarely - gynecomastia.

Systemic reactions: often - asthenia, increased fatigue.

Influence on the results of laboratory and instrumental studies: often - increased ALT and / or ACT activity; infrequently - an increase in the activity of ALT and / or ACT, a dose-dependent increase in the concentration of CPK in the blood plasma, an increase in the activity of gamma-glutamyl transferase; deviation from the norm of indicators of liver function.

Contraindications for use

Pregnancy and the period of breastfeeding; female patients with childbearing potential who do not use effective methods of contraception; liver disease in the active phase or a sustained increase in the serum activity of hepatic transaminases of unknown etiology (more than 3 times compared with VGN); dysfunction of the liver of medium (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) severity; severe impairment of renal function (CC <30 ml / min); myopathy; simultaneous use with cyclosporine; age up to 18 years.

For a dosage of 40 mg + 10 mg

The presence of the following risk factors for the development of myopathy / rhabdomyolysis: moderate renal failure (CC <60 ml / min), hypothyroidism, myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates in history, excessive alcohol consumption, conditions that can lead to increase the plasma concentration of rosuvastatin, the simultaneous intake of fibrates; patients of the Mongoloid race; history of hereditary muscle diseases, incl. family.

Carefully

Conditions indicating the development of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled convulsions); hypothyroidism; age over 70; conditions in which there is an increase in the concentration of rosuvastatin in the blood plasma; patients of the Mongoloid race; simultaneous use with fibrates, indirect anticoagulants (warfarin) or fluindione; myotoxicity while taking other inhibitors of HMG-CoA reductase or fibrates in history; excessive alcohol consumption; a history of liver disease or liver failure; renal failure of mild and moderate severity (CC> 30 ml / min);renal failure of mild severity (CC> 60 ml / min) (for a dosage of 40 mg + 10 mg).

Application during pregnancy and lactation

Use during pregnancy and breastfeeding is contraindicated.

Application for violations of liver function

The use is contraindicated in case of violations of liver function of medium (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) severity.

Application for impaired renal function

The use is contraindicated in severe renal impairment (CC <30 ml / min).

Application in children

The drug is contraindicated for use in children and adolescents under the age of 18.

Use in elderly patients

Caution: over 70 years of age.

special instructions

If you suddenly develop muscle pain, muscle weakness, or spasms, you should see a doctor immediately, especially if you are feeling sick or feverish. When these conditions occur, it is necessary to determine the activity of CPK. Therapy should be discontinued if the CPK activity is significantly increased (more than 5 times higher than the ULN), or if the muscle symptoms are pronounced and cause daily discomfort (even if the CPK activity is increased less than 5 times compared to the ULN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing rosuvastatin or other HMG-CoA reductase inhibitors in lower doses with careful monitoring of the patient's condition.

The drug should not be used in patients with acute, dangerous conditions indicating the development of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances or uncontrolled convulsions ).

It is recommended to determine the indicators of liver function before the start of therapy and 3 months after the start of therapy. The drug should be discontinued or the dose should be reduced if the activity of 'hepatic' transaminases in the blood plasma exceeds the ULN by 3 times or more.

In patients receiving high doses of rosuvastatin (mainly 40 mg / day), the development of tubular proteinuria was reported, which in most cases was transient. The development of proteinuria was not indicative of acute kidney disease or progression of kidney disease. In patients taking the combination of rosuvastatin + ezetimibe at a dosage of 40 mg + 10 mg, it is recommended to regularly monitor the indicators of renal function during treatment.

With the use of statins, an increase in the concentration of glucose in the blood is possible. In some patients with a high risk of developing diabetes mellitus, such changes can lead to its manifestation, which is an indication for the appointment of hypoglycemic therapy. However, reducing the risk of vascular disease while taking statins outweighs the risk of developing diabetes mellitus, therefore, this factor should not serve as a reason for discontinuation of statin treatment. Patients at risk (fasting blood glucose concentration 5.6-6.9 mmol / l, BMI> 30 kg / m2, hypertriglyceridemia, history of arterial hypertension) should be monitored by a doctor and regularly monitored biochemical parameters.

With the use of some statins, especially for a long time, isolated cases of the development of interstitial lung disease have been reported, which can manifest itself in the form of shortness of breath, unproductive cough and deterioration in general well-being (weakness, weight loss and fever). If interstitial lung disease is suspected, the rosuvastatin + ezetimibe combination therapy should be discontinued.

Influence on the ability to drive vehicles and mechanisms

Due to the likelihood of dizziness when taking a combination of rosuvastatin + ezetimibe, care must be taken when driving vehicles and mechanisms.

Drug interactions

Contraindicated combinations

The simultaneous use of a combination of rosuvastatin + ezetimibe with cyclosporine is contraindicated.

Combinations not recommended

Fibrates and other lipid-lowering drugs

Patients receiving fenofibrate and ezetimibe should be aware of the possible risk of developing gallstones and gallbladder disease. If you suspect cholelithiasis, it is necessary to conduct a study of the gallbladder, and stop taking the drug.

The simultaneous use of fenofibrate or gemfibrozil with ezetimibe moderately increased the concentration of total ezetimibe (approximately 1.5 and 1.7 times, respectively).

vемфиброзил, фенофибрат, другие фибраты и липидснижающие дозы никотиновой кислоты (более 1 г в сутки) увеличивали риск возникновени¤ миопатии при одновременном применении с ингибиторами vћv- ој-редуктазы, возможно, в св¤зи с тем, что данные агенты могут самосто¤тельно вызывать миопатию при применении в качестве монотерапии. ќдновременное применение препарата в дозировке 40 мг + 10 мг с фибратами противопоказано.

»нгибиторы протеазы ¬»„

’от¤ точный механизм взаимодействи¤ неизвестен, одновременное применение с ингибиторами протеазы ¬»„ может приводить к значительному увеличению экспозиции розувастатина. ¬ фармакокинетическом исследовании одновременное применение 10 мг розувастатина и комбинированного препарата на основе двух ингибиторов протеазы (300 мг атазанавира/100 мг ритонавира) у здоровых добровольцев приводило к увеличению значений AUC и —max розувастатина приблизительно в 3 и 7 раз соответственно. ќдновременное применение розувастатина и комбинаций некоторых ингибиторов протеазы ¬»„ может быть рассмотрено после тщательной оценки коррекции дозы на основании ожидаемого увеличени¤ концентрации розувастатина в плазме крови.

»нгибиторы белка-переносчика

–озувастатин ¤вл¤етс¤ субстратом дл¤ определенных белков-переносчиков, включа¤ транспортер печеночного переноса ќј“–1¬1 и эффлюксный транспортер BCRP. ќдновременное применение розувастатина с другими лекарственными препаратами, которые ¤вл¤ютс¤ ингибиторами этих белков-переносчиков может приводить к повышению плазменных концентраций розувастатина и повышению риска миопатии.

‘узидова¤ кислота

–иск развити¤ миопатии, включа¤ развитие рабдомиолиза может быть повышен при одновременном применении с фузидовой кислотой. ѕри необходимости систематического применени¤ фузидовой кислоты, розувастатин должен быть исключен из терапии.

?ругие взаимодействи¤

»зоферменты системы цитохрома –450

–езультаты исследований in vivo и in vitro показали, что розувастатин не ¤вл¤етс¤ ни ингибитором, ни индуктором изоферментов системы цитохрома –450.  роме того, розувастатин ¤вл¤етс¤ непрофильным субстратом дл¤ этих изоферментов. ѕоэтому не ожидаетс¤ взаимодействи¤ розувастатина с другими лекарственными средствами на уровне метаболизма с участием изоферментов системы цитохрома –450. Ќе отмечено клинически значимого взаимодействи¤ розувастатина с флуконазолом (ингибитором изоферментов CYP2C9 и CYP3A4) и кетоконазолом (ингибитором изоферментов CYP2A6 и CYP3A4).
¬ доклинических исследовани¤х было показано, что эзетимиб не индуцирует изоферменты цитохрома –450. Ќе наблюдалось каких-либо клинически значимых взаимодействий между эзетимибом и другими лекарственными препаратами на уровне метаболизма с участием изоферментов CYP1A2, CYP2D6, CYP2C8. CYP2C9 и CYP3A4 или N-ацетилтрансферазой.

јнтациды

ќдновременное применение антацидов снижало скорость абсорбции эзетимиба, но не оказывало какого-либо воздействи¤ на биодоступность эзетимиба. “акое снижение скорости абсорбции не рассматриваетс¤ как клинически значимое.
ќдновременное применение розувастатина и суспензии антацидов, содержащей магни¤ и алюмини¤ гидроксид, приводит к снижению плазменной концентрации розувастатина приблизительно на 50%. ?анный эффект выражен слабее, если антациды примен¤ютс¤ через 2 ч после приема розувастатина.  линическое значение подобного взаимодействи¤ не изучалось.

 олестирамин

ќдновременное применение колестирамина уменьшало средний показатель AUC суммарного эзетимиба (эзетимиб + эзетимиба глюкуронид) приблизительно на 55%. Ёффект снижени¤ концентрации ’—-ЋѕЌѕ при добавлении эзетимиба к колестирамину может быть уменьшен этим взаимодействием.

јнтикоагул¤нты, антагонисты витамина  

—опутствующее применение эзетимиба (10 мг один раз в сутки) не оказывало значимого воздействи¤ на биодоступность варфарина и протромбиновое врем¤ в исследовании с участием 12 здоровых взрослых мужчин. ќднако имеютс¤ пострегистрационные сообщени¤ о повышении ћЌќ у пациентов, принимавших эзетимиб одновременно с варфарином или флуиндионом. ѕри добавлении эзетимиба к терапии варфарином (или другим кумариновым антикоагул¤нтом) или флуиндионом следует осуществл¤ть мониторинг ћЌќ.
 ак и при применении других ингибиторов vћv- ој редуктазы, начало лечени¤ розувастатином или повышение его дозы у пациентов, одновременно получающих лечение антагонистами витамина   (например, варфарином или другим кумариновым антикоагул¤нтом), может приводить к повышению ћЌќ. ѕрекращение применени¤ розувастатина или уменьшение его дозы может приводить к снижению ћЌќ. ¬ таких случа¤х рекомендуетс¤ проводить регул¤рный контроль ћЌќ.

Ёритромицин

ќдновременное применение розувастатина и эритромицина приводит к снижению AU—(0-t) розувастатина на 20% и —max розувастатина на 30%. Ёто взаимодействие может быть вызвано усилением перистальтики кишечника, св¤занного с применением эритромицина.

ѕероральные контрацептивы/«v“

The simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and the AUC of norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives.
Pharmacokinetic data on the simultaneous use of rosuvastatin and 3GT are absent, therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Storage conditions

At a temperature not exceeding 25 ? C.

Keep out of the reach of children.

Shelf life

3 years.

Do not use after the expiration date printed on the package.