Expiration date: 03/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substance:

atorvastatin (calcium salt) 10, 20 or 40  mg

other ingredients: microcrystalline cellulose — 250 mg lactose monohydrate — 34.8 mg sodium croscarmellose is 19.2 mg hydroxypropyl cellulose 2 mg Polysorbate 80 and 2.6 mg of magnesium oxide and 26 mg of silicon oxide colloidal — 1.2 mg magnesium stearate 1 mg 

shell: hypromellose — 2,976 mg hydroxypropyl cellulose — 0,744 mg titanium dioxide (E171) of 1.38/1,368 mg polyethylene glycol 6000 — 0.6 mg talc 0.3 mg iron oxide yellow (E172, for tablets of 20 mg) to 0.012 mg 

blistere in 10 PCs. in cardboard pack of 3, 6, 9 blisters.

Description pharmaceutical form:

Tablets 10 mg: white or almost white, round, biconvex, film-coated, with the inscription "HLA 10" on one side.

Tablet 20 mg: light yellow, round, biconvex, film-coated, with the inscription "HLA 20" on one side.

Pharmacokinetics:

Absorption and distribution

Absorption — high. Cmax in plasma after ingestion is achieved through 1-2 h. the Cmax of women is higher by 20%, AIS 10% lower than that of men. Cmax in patients with alcoholic cirrhosis of the liver (class b on a scale child-Pugh) in 16 times, and AIS — 11 times above the norm.

Food intake reduces the rate and extent of absorption of the drug (25 and 9%, respectively), but the decrease of LDL cholesterol similar to that in the application of atorvastatin without simultaneous food intake.

After oral administration of atorvastatin in the evening time concentration in blood plasma is lower (Cmax and AUC by approximately 30%) than after administration in the morning hours, however, the decrease in the concentration of LDL cholesterol does not depend on the time of day in which to take the drug. The identified linear relationship between level of intake and dose.

Bioavailability of 12%, system bioavailability inhibiting activity for HMG-COA reductase is about 30%. Low systemic bioavailability due to presystemic metabolism in the gastrointestinal tract and first pass through the liver.

Average Vd — 381 l, the relationship with blood plasma proteins is 98%.

Predominantly metabolized in the liver by cytochrome P4503A4 c with the formation of pharmacologically active metabolites (ortho - and parahydroxylated derivatives, products of beta-oxidation). Tulip (tablets 10 and 20 mg) causes a decrease in total cholesterol levels by 29 and 33%, LDL cholesterol — by 39 and 43%, apolipoprotein b by 32 and 35% and triglycerides by 14 and 26%. Levels of HDL-cholesterol with increased respectively by 6 and 9%. Excreted mainly in bile following hepatic and/or extrahepatic metabolism (atorvastatin is not subject to pronounced enterohepatic recirculation cannot be removed by hemodialysis). T1/2 is 14 h. the Inhibitory activity against HMG-COA reductase inhibitors remains about 20-30 h due to the presence of active metabolites. Less than 2% of an oral dose of the drug is determined in the urine.

Description pharmacological action:

Atorvastatin is a selective competitive inhibitor of HMG-COA reductase, the enzyme involved in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme a to mevalonate, a precursor of steroids including cholesterol. Cholesterol and triglycerides (TG) circulate in the bloodstream, composed of molecules called lipoproteins. Triglycerides and cholesterol in the liver synthesizes VLDL. From the liver they get into the blood plasma and delivered to peripheral tissues. LDL is formed from VLDL, their catabolism is accomplished mainly through interaction with LDL receptors. Atorvastatin reduces the synthesis and content of LDL cholesterol, total cholesterol, apolipoprotein b In patients with homozygous and heterozygous familial hypercholesterolemia, primary hypercholesterolemia and mixed hyperlipidemia. It also causes decrease in level of cholesterol VLDL and triglycerides and increased levels of HDL-cholesterol and apolipoprotein A. Atorvastatin reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apolipoprotein b, triglycerides and non-HDL-cholesterol and increases HDL-cholesterol in patients with isolated hypertriglyceridemia, the level LPSP-cholesterol in patients with dysbetalipoproteinemia. Like LDL, lipoproteins, cholesterol-enriched triglyceride-rich (VLDL, intermediate density lipoprotein and remnants of chylomicrons) may also contribute to progression of atherosclerosis. The elevation of triglycerides in plasma is often combined with a decrease in HDL and LDL particles of small size, as well as other lipidnami metabolic risk factors for coronary artery disease.

Indications:

• primary hypercholesterolemia (Fredrickson type IIA)
  
• combined hyperlipidemia (Fredrickson type IIb)
  
• heterozygous and homozygous familial hypercholesterolemia (as a Supplement to the diet).
  

Contraindications:

• hypersensitivity to atorvastatin and other auxiliary substances of the drug
  
• liver disease in the active stage (including chronic active hepatitis, chronic alcoholic hepatitis) increased activity of ALT or AST (more than 3 times compared with the upper limit of normal) of unknown origin, hepatic failure (severity A and b on a scale child-Pyuga)
  
• women of reproductive age not using adequate methods of contraception.
  

Caution: liver disease, a history of alcohol abuse, serious violations elektrolitnogo balance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, diseases of skeletal muscles, extensive surgical interventions, injuries, children (efficacy and safety not established).

Application of pregnancy and breast-feeding:

Use in pregnancy and lactation is contraindicated.

Side effects:

Digestive system: in more 2% cases — nausea in less than 2% — heartburn, constipation or diarrhea, flatulence, abdominal pain, anorexia, decreased or increased appetite, dry mouth, burp, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosivno-azwenne defeat of the oral cavity, gastroenteritis, hepatitis, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, impaired liver function tests, melena, bleeding gums, tenesmus.

Respiratory system: in more 2% cases — bronchitis, rhinitis less common — pneumonia, dyspnea, asthma, epistaxis.

Nervous system: in more 2% cases — insomnia, dizziness in less than 2% — headache, asthenia, malaise, drowsiness, unusual dreams, paresthesia, amnesia, emotional lability, peripheral neuropathy, ataxia, paralysis of the facial nerve, hyperkinesis, depression, hyperesthesia, loss of consciousness.

Musculoskeletal system: in more 2% cases — arthritis in less than 2% — muscle cramps feet, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, joint contractures, rigidity of the neck muscles, rhabdomyolysis.

Allergic reactions: in less 2% cases — skin itching, skin rash, contact dermatitis rarely urticaria, anaphylaxis, angioedema, multiforme exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity.

Skin: in less 2% cases — alopecia, sweating, eczema, seborrhea, ekhimozy, petechiae.

Genitourinary system: in more 2% cases — urogenital infections, peripheral edema in less 2% cases — dysuria (W. pollakiuria, nocturia, incontinence or urinary retention, imperative urges to urination), jade, hematuria, vaginal bleeding, urolithiasis, epididymitis, decreased libido, abnormal ejaculation, impotence, uterine bleeding.

The senses: in less 2% cases — amblyopia, tinnitus, dryness of the conjunctiva, violation ccomodation, bleeding in the eye, deafness, increased intraocular pressure, parosmia, taste perversion, loss of taste sensations.

Cardiovascular system: in more 2% cases of chest pain in less than 2% — heartbeat, vasodilation, orthostatic hypotension, phlebitis, arrhythmia, angina, increased blood pressure.

Hematopoietic system: in less 2% cases — anemia, lymphadenopathy, thrombocytopenia.

Laboratory findings: in less 2% cases — hyperglycemia, hypoglycemia, increased levels of creatine phosphokinase (CPK), albuminuria.

Other: in less 2% cases — increased body mass index, gynecomastia, the worsening gout, mastodinia.

Drug interactions:

Antacids: when concomitant administration of atorvastatin and antacid preparations in the form of a suspension containing magnesium and aluminium hydroxide, the concentration of atorvastatin in plasma is reduced by approximately 35%, while the degree of reduction of LDL cholesterol remains unchanged.

Colestipol: with simultaneous use of atorvastatin and colestipol atorvastatin concentration in plasma decreased by approximately 25%, while the hypolipidemic effect of combination of atorvastatin and colestipol surpasses itself each drug separately.

Digoxin: when multiple concomitant administration of atorvastatin and digoxin the concentration of digoxin in plasma is increased by about 20%, therefore the patient should be kept under observation.

Erythromycin: when concomitant administration of atorvastatin and erythromycin, has inhibiting effects on the cytochrome P450 CYP3A4, atorvastatin concentration in plasma is increased by approximately 40%.

Oral contraceptives: with simultaneous use of atorvastatin and oral contraceptive agents AUC values increased by approximately 30% for the norethisterone and 20% for ethinyl estradiol. These data should be considered when selecting contraceptives to patients receiving atorvastatin.

Warfarin: in patients receiving long-term warfarin, atorvastatin reduces the prothrombin time in the first few days after beginning its use, however, after 15 days this indicator will return to normal. After the appointment of atorvastatin patients taking warfarin should have more frequent than normal, control vessels.

In concurrent use of cyclosporine, fibrates, clarithromycin, antifungals (belonging to azoles) and nicotinamide concentration of atorvastatin in plasma (risk of myopathy) increases.

Method of application and dose:

Before treatment, the patient should be transferred to a diet low in cholesterol. Inside, at any time of the day regardless of the meal.

The dose varies from 10 to 80 mg once a day, choosing taking into account the initial levels of Cholesterol-LDL, the goal of therapy and individual effect. To change the dose should be spaced at least 4 weeks.

Primary hypercholesterolemia and combined hyperlipidemia

The recommended starting dose Tulip is 10 mg once a day. Then individually selected dose component is 10-80 mg per day depending on the target level of cholesterol and the effectiveness of the drug. After 2-4 weeks after the start of treatment and/or dose selection Tulip should be undertaken to determine the level of blood lipids and in accordance with it to adjust the dose of the drug.

Familial hypercholesterolemia — heterozygous. Tulip initial dose is 10 mg daily, the dose may be increased to 80 mg per day.

- homozygous. Dosage range is the same as in other types of hyperlipidemia. The initial dose selected individually, depending on the severity of the disease. The maximum daily dose of 80 mg.

Dosage for patients with renal insufficiency. If the patient has kidney disease, the concentration of atorvastatin in plasma and its effect on LDL cholesterol are not changed. In this context, dose adjustment for patients with kidney disease is not required.

Dosage for patients with hepatic failure. In patients with impaired liver function care must be taken in connection with the slow excretion of the drug from the body. Should carefully monitor clinical and laboratory parameters in detecting significant changes in dose should be reduced or treatment should be discontinued.

Patients in the older age group. Dose adjustment for patients older than 70 years is not required.

Overdose:

Specific treatment in case of overdose Tulip no. Treatment is symptomatic to take measures to maintain vital functions and prevent further absorption of the drug (gastric lavage, reception activated carbon). Due to the fact that the drug actively binds to plasma proteins, hemodialysis is not effective way to speed up removing it from the body.

Special instructions:

The liver dysfunction. Inhibitors of HMG-COA reductase to reduce the level of lipids in blood may lead to changes in biochemical parameters reflecting liver function.

Liver function should be monitored before treatment, after 6 weeks, 12 weeks after the start of Tulip and after each dosage increase, and periodically, e.g. every 6 months. The change in the activity of liver enzymes is usually observed during the first three months after the start of Tulip. Patients who show increased levels of transaminases should be monitored prior to returning the enzyme levels to normal. In that case, if the values of ALT or AST more than 3 times higher than the level of the upper margin, the lower dose Tulip or to stop treatment.

Skeletal musculature. Patients with diffuse myalgia, lethargy or muscle weakness and/or marked elevation of CPK are a risk for the development of myopathy (defined as muscle pain with a concomitant increase in CPK level more than 10 times compared with the upper limit of normal).

In the appointment of combination therapy with cyclosporine and Tulip, fiber acid derivatives, erythromycin, clarithromycin, immunodepressantami and anti-fungal drugs Soloway structure, as well as causing a decrease in the level of lipid doses of Niacin, should weigh the potential benefit and risk in this treatment and to monitor patients who develop signs or symptoms of muscle pain, lethargy or weakness, particularly during the first months of treatment and when the dose of any of drugs.

Tulip treatment must be temporarily suspended or terminated during the development of the serious condition that can result from myopathy, and the presence of risk factors for development of acute renal failure due to rhabdomyolysis (e.g. severe acute infection, arterial hypotension, extensive surgical interventions, injuries, severe metabolic and endocrine disorders, as well as violations elektrolitnogo balance).

The patient should immediately consult doctor at the appearance of unexplained pain or weakness in muscles, particularly if accompanied by malaise and fever. Women of reproductive age should use reliable methods of contraception.

Effects on ability to drive vehicles and engage in other activities that require concentration and speed of psychomotor reactions

Tulip has no effect on the ability to drive a car and machinery.