Torvacard - instructions for use, dose, side effects, contraindications

auxiliary substances: core: magnesium oxide -14,000 mg; cellulose microcrystalline - 70.00 mg; lactose monohydrate - 26,300 mg; croscarmellose sodium - 4,500 mg; giprolose low-substituted - 14,000 mg; silicon dioxide colloidal - 0,500 mg; magnesium stearate - 0.700 mg;

film membrane: hypromellose 2910/5 - 3,500 mg, macrogol 6000 - 0,600 mg, titanium dioxide - 0,350 mg, talc - 0,050 mg.

Each tablet coated with a film coating of 20 mg contains:

active substance: atorvastatin - 20,000 mg (in the form of atorvastatin calcium 20.680 mg); auxiliary substances: core: magnesium oxide - 28,000 mg; cellulose microcrystalline - 140,000 mg; lactose monohydrate - 52,600 mg; croscarmellose sodium - 9,000 mg; giprolose low-substituted - 28,000 mg; silicon dioxide colloid - 1,000 mg; magnesium stearate -1.400 mg;

film membrane: hypromellose 2910/5 - 7,000 mg, macrogol 6000 - 1,200 mg, titanium dioxide - 0,700 mg, talc - 0,100 mg.

Each 40 mg film-coated tablet contains:

active substance: atorvastatin 40,000 mg (in the form of atorvastatin calcium 41,360 mg); auxiliary substances: core: magnesium oxide - 56,000 mg; cellulose microcrystalline - 280,000 mg; lactose monohydrate - 105,200 mg; croscarmellose sodium - 18,000 mg; giprolose low-substituted 56,000 mg; silicon dioxide colloid - 2,000 mg; magnesium stearate - 2,800 mg; film membrane: hypromellose 2910/5 - 14,000 mg, macrogol 6000 - 2,400 mg, titanium dioxide -1,400 mg, talc - 0,200 mg.

Description:From white to almost white, oval biconvex tablets, covered with a film membrane.

Pharmacotherapeutic group:Hypolipidemic agent - inhibitor of HMG-CoA reductase

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.05 Atorvastatin

Pharmacodynamics:

A hypolipidemic agent from the group of statins. A selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are included in the composition of very low density lipoproteins (VLDL), enter the blood plasma and transport to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL in the course of interaction with LDL receptors. Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase, the synthesis of cholesterol in the liver and increasing the number of "liver" LDL receptors on the cell surface, which leads to increased capture and catabolism of LDL. Reduces the formation of LDL, causes a pronounced and persistent increase in the activity of LDL receptors. Reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to therapy, lipid-lowering drugs.Reduces the concentration of total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50% and TG by 14-33%; causes an increase in the concentration of HDL cholesterol (high-density lipoproteins) and apolipoprotein A. Dozozavisimo lowers the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Pharmacokinetics:

Absorption is high. The maximum concentration (Cmah) in the blood plasma is achieved after 1-2 hours, Cmah in women is higher by 20%, the area under the curve "concentration - time" (AUC) - lower by 10%; FROMmah in patients with alcoholic cirrhosis of the liver 16 times, AUC - 11 times higher than normal. Food slightly reduces the speed and duration of absorption of the drug (by 25% and 9%, respectively), but the reduction in LDL cholesterol is similar to that with atorvastatin without food. The concentration of atorvastatin when used in the evening is lower than in the morning (about 30%). A linear relationship between the degree of absorption and the dose of the drug has been revealed.

Bioavailability - 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase - 30%. Low systemic bioavailability is due to presystemic metabolism in the mucous membrane of the gastrointestinal tract and "first pass" through the liver.

The average volume of distribution is 381 liters, communication with plasma proteins is 98%. Metabolized mainly in the liver under the action of isoenzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products). In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin.

The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

It is excreted through the intestine with bile after hepatic and / or extrahepatic metabolism (it does not undergo significant intestinal hepatic recirculation).

The half-life is 14 hours. The inhibitory activity against HMG-CoA reductase is maintained for about 20-30 hours due to the presence of active metabolites. Less than 2% of the dose taken internally is determined in the urine. It is not excreted during hemodialysis.

Indications:

- in combination with a diet to reduce the elevated concentrations of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides and increase HDL cholesterol concentrations in patients with primary hypercholesterolemia,heterozygous familial and non-family hypercholesterolemia and combined (mixed) hyperlipidemia (types IIa and IIb by Frederickson);

- In combination with a diet for the treatment of patients with elevated serum concentrations of triglycerides (familial endogenous hypertriglyceridemia of type IV according to Frederickson) and patients with disbetalipoproteinemia (type III according to Frederickson), in which diet therapy does not provide an adequate effect;

- To reduce the concentration of total cholesterol and cholesterol / LDL in patients with homozygous familial hypercholesterolemia, when dietotherapy and other non-pharmacological treatments are not effective enough (as an adjunct to lipid lowering therapy, including autogemotransfusion of LDL-purified blood)

- Diseases of the cardiovascular system (in patients with increased risk factors for IHD - elderly age over 55 years, smoking, hypertension, diabetes, peripheral vascular disease, stroke, left ventricular hypertrophy, protein / albuminuria, coronary artery disease in close relatives ), incl.on the background of dyslipidemia - secondary prophylaxis in order to reduce the total risk of death, myocardial infarction, stroke, repeated hospitalization for angina pectoris and the need for a revascularization procedure.

Contraindications:

- Hypersensitivity to the active substance or to any of the auxiliary components of the drug;

- Active liver disease or increased serum activity of "hepatic" transaminases (more than 3 times compared with the upper limit of the norm) of an unknown genesis. hepatic insufficiency (classes A and B on the Child-Pugh scale);

- Hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose in the composition);

- Pregnancy, the period of breastfeeding;

- Use in women of reproductive age not using adequate methods of contraception;

- Age under 18 years (efficiency and safety not established).

Carefully:

With caution in the abuse of alcohol; liver diseases in anamnesis; hypothyroidism; severe acute infections (sepsis); extensive surgical interventions; injuries; diseases of skeletal muscles; diabetes mellitus; in patients without ischemic heart disease (CHD),recent stroke or transient ischemic attack (TIA); when applied simultaneously with fusidic acid preparations.

Pregnancy and lactation:

The use of the drug TORVACARD® in women of reproductive age is possible only if reliable methods of contraception are used and the patient is informed of the possible risk of treatment for the fetus. The drug TORVACARD® is contraindicated during pregnancy. Safety of use in pregnant women is not established. Controlled clinical trials of the use of atorvastatin in pregnant women have not been conducted. Rare reports of congenital anomalies of fetal development after exposure inhibitors of HMG-CoA reductase.

Studies conducted on animals showed the presence of toxic effects of atorvastatin on reproductive function.

Treatment of mothers with the drug TORVACARD® can reduce the formation of mevalonate in the fetal liver cells, which is the precursor of cholesterol.

Atherosclerosis is a chronic process, and usually the cessation of the use of lipid-lowering drugs during pregnancy should have little effect on the remote risk associated with primary hypercholesterolemia.

For these reasons, the drug TORVACARD® ns should be used by women who plan pregnancy and who do not exclude pregnancy. Treatment with TORVACARD® should be suspended for the period of pregnancy or until it is determined that the woman is not pregnant.

The drug TORVACARD® is contraindicated in the period of breastfeeding. It is not known whether atorvastatin or its metabolites into breast milk. In rats, concentrations of atorvastatin and its active metabolites in blood plasma are similar to those in milk. Due to the possibility of developing serious adverse reactions in a child, women taking the drug TORVACARD® should stop breastfeeding.

Fertility

In studies conducted on animals, atorvastatin did not affect the fertility of males or females.

Dosing and Administration:

Prior to the appointment of the drug TORVACARD®, the patient should be recommended a standard hypocholesterolemic diet, which he must continue to observe throughout the period of therapy.

The drug should be taken orally at any time of the day, regardless of the time of ingestion.

The initial dose is on average 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 time / day. The dose is selected taking into account the initial concentrations of cholesterol / LDL, the purpose of therapy and individual effect. At the beginning of treatment and / or while increasing the dose of TORVACARD® it is necessary to monitor the plasma lipid concentrations every 2-4 weeks and adjust the dose accordingly. The maximum daily dose is 80 mg per 1 dose.

Primary hypercholesterolemia and mixed hyperlipidemia

In most cases, it may be sufficient to administer a dose of 10 mg of TORVACARD ® once a day. A significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. With prolonged treatment, this effect persists.

When determining the goal of treatment, the following recommendations can be used.

A. Recommendations of the National Cholesterol Education Program (USA)

Diagnosed atherosclerosis of vessels *	Presence of 2 or more risk factors **	Cholesterol / LDL, mg / dL (mmol / L)
		Initial concentration	The minimum target
No	No	>190 (>4,9)	<160(<4,1)
No	Yes	>160(>4,1)	<130 (<3,4)
Yes	Yes or no	>130*** (>3.4)	<100(<2,6)

* IHD or peripheral vascular atherosclerosis "(including carotid artery disease, accompanied by clinical symptoms).

** Include the following: age (men> 45 years, women> 55 years or early menopause, which does not carry estrogen replacement therapy), cases of early development of CHD in relatives, smoking, hypertension, confirmed cholesterol / HDL <35 mg / dL <0.91 mmol / L) and diabetes mellitus. One risk factor should be subtracted if the cholesterol / HDL value is> 60 mg / dL (> 1.6 mmol / L).

*** In patients with CHD with a cholesterol / LDL value of 100 to 129 mg / dl, the question of prescribing drug therapy is decided by a physician in the light of clinical experience.

B. Recommendations of the European Society of Atherosclerosis (EAS) concerning the diagnosis and treatment of metabolic disorders

- goals of hypolipidemic therapy of the European Society of Atherosclerosis

In patients with confirmed CHD and other patients at high risk of ischemic complications, the goal of treatment is to lower the cholesterol / LDL value <3 mmol / L (or <115 mg / dL) and total cholesterol <5 mmol / L (or <190 mg / dl ).

AT.National treatment guidelines

Homozygous familial hypercholesterolemia.

In a study in adult patients with homozygous familial hypercholesterolemia, atorvastatin at a dose of 80 mg per day in most cases led to a decrease in the cholesterol / LDL value by more than 15% (18-45%).

The use of the drug in patients with renal insufficiency and kidney disease does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in the value of cholesterol / LDL when it is used, so a dose change is not required.

When using the drug in elderly patients, there were no differences in safety, effectiveness, or achievement of lipid-lowering therapy goals in comparison with the general population.

Side effects:

Adverse reactions are divided into system-organ classes in accordance with the Medical Dictionary of Regulatory Activities (MedDRA). The incidence of adverse reactions listed below was determined according to the classification of the World Health Organization: very often more than 1/10, often from more than 1/100 to less than 1/10, infrequently from more than 1/1000 to less than 1/100, from more than 1/10000 to less than 1/1000, very rarely - from less than 1/10000, including individual messages.

Infectious and parasitic diseases: often - nasopharyngitis.

Violations of the blood and lymphatic system: rarely - thrombocytopenia.

Immune system disorders: often - allergic reactions; very rarely anaphylaxis.

Disorders from the metabolism and nutrition: often - hyperglycemia; infrequently - hypoglycemia, weight gain, anorexia.

Disorders from the psyche: infrequently - sleep disturbances, including insomnia and "nightmarish" dreams.

Disturbances from the nervous system: often - headache; infrequently - dizziness, paresthesia, hypoesthesia, taste perversion, loss or loss of memory; rarely peripheral neuropathy.

Disturbances on the part of the organ of vision: infrequent - reduced clearness of vision; rarely - visual impairment.

Violations from the side of the hearing organ and labyrinthine disturbances: infrequently - noise in the ears; very rarely - hearing loss.

Disturbances from the respiratory system, chest and mediastinum: often - pain in the pharynx and trachea, nosebleeds.

Disorders from the digestive system: often - constipation, flatulence, dyspepsia, nausea, diarrhea; often - vomiting, pain in the upper and lower abdomen, belching, pancreatitis.

Disorders from the liver and biliary tract: infrequently - hepatitis; rarely - cholestasis; very rarely liver failure.

Disturbances from the skin and subcutaneous tissues: infrequently - hives, skin rash, itching, alopecia; rarely angioedema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Disorders from the musculoskeletal and connective tissue: often - myalgia, arthralgia, pain in the extremities, muscle spasms, swelling of the joints, back pain; infrequently - pain in the neck, muscle weakness; rarely - myopathy, myositis, rhabdomyolysis, tendopathy (sometimes complicated by a rupture of the tendon).

General disorders and disorders at the injection site: infrequently - malaise, asthenia, chest pain, peripheral edema, fatigue, fever.

Laboratory and instrumental data: often - increased activity of "liver" transaminases, increased activity of creatine phosphokinase (CK); infrequently - leukocyturia, an increase in the concentration of glycosylated hemoglobin.

The following adverse events have been reported with some statins;

- sexual dysfunction;

- Depression;

- gynecomastia;

- cases of immuno-mediated necrotizing myopathy;

- single cases of interstitial lung disease (especially with prolonged use).

Diabetes mellitus: the frequency of development depends on the presence or absence of risk factors (fasting blood glucose 5,6-6,9 mmol / l, body mass index (BMI)> 30 kg / m², hypertriglyceridemia, arterial hypertension in the anamnesis).

Overdose:

Specific treatment with an overdose of TORVACARD® is absent. In case of an overdose, the patient's treatment should be symptomatic, supportive therapy should be conducted as needed. It is necessary to monitor the activity indicators of "liver" transaminases and CK. Hemodialysis is not effective (atorvastatin 98% bound to blood plasma proteins). There is no specific antidote for overdose of atorvastatin.

Interaction:

Atorvastatin is metabolized by cytochrome P450 isoenzyme CYP3A4 and is a substrate for transport proteins, for example, the transporter for the "hepatic" capture of OATP1I1. Simultaneous use of medicines,which are inhibitors of the CYP3A4 isoenzyme or transport proteins, can lead to an increase in the concentration of atorvastatin in the blood plasma and an increased risk of myopathy. The risk may also increase with simultaneous use of atorvastatin with other drugs that can cause myopathy, such as fibrolic acid derivatives and ezetimibe.

Inhibitors of the isoenzyme CYP3A4

It has been shown that potent inhibitors of the CYP3A4 isoenzyme result in a significant increase in the concentration of atorvastatin in the blood plasma. If possible avoid simultaneous use of potent inhibitors of the CYP3A4 isoenzyme (eg, cyclosporine, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir etc.). In cases where simultaneous use of these drugs can not be avoided and atorvastatin, it is recommended to use lower initial and maximum doses of atorvastatin. When applying a daily dose of TORVACARD ® over 40 mg, it is recommended that a thoroughclinical monitoring of patients.

Moderate inhibitors of the isoenzyme CYP3A4 (eg, erythromycin, diltiazem, verapamil and fluconazole) can increase the concentration of atorvastatin in the blood plasma.

An increased risk of myopathy is observed with the use of erythromycin in combination with inhibitors of HMG-CoA reductase (statins). Studies on drug interactions assessing the effect of amiodarone or verapamil on atorvastatin, were not held. Both drugs, and amiodarone, and verapamilare known to inhibit the activity of the isoenzyme CYP3A4, and combined use with atorvastatin may lead to an increase in the concentration of atorvastatin in the blood plasma. Therefore, a lower maximum dose of atorvastatin should be given and proper clinical monitoring of the patient's condition should be carried out while using with moderate inhibitors of the isoenzyme CYP3A4. It is recommended to conduct a thorough clinical observation after the initiation of therapy or during the selection of the dose of the inhibitor.

Grapefruit juice

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and can increase the concentration of drugs in the blood plasma metabolized by the CYP3A4 isoenzyme.The consumption of one glass of grapefruit juice (240 ml) also leads to a 20.4% decrease in AUC for the active orthohydroxy metabolite. Large volumes of grapefruit juice (more than 1.2 liters per day for 5 days) increased the atorvastatin AUC 2.5 times and the active AUC (atorvastatin and metabolites). It is not recommended the combined use of large volumes of grapefruit juice and TORVACARD®.

Inductors of the isoenzyme CYP3A4

The simultaneous use of atorvastatin with inducers of the cytochrome P450 isoenzyme CYP3A4 (for example, efavirenz, rifampicin, St. John's wort) can lead to various decreases in the concentration of atorvastatin in the blood plasma. Due to the double mechanism of interaction of rifampicin, (induction of the isoenzyme CYP3A4 and inhibition of the transporter of the "hepatic" capture of OATP1B1), simultaneous administration of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after the administration of rifampicin was accompanied by a significant decrease in the concentration of atorvastatin in the blood plasma. While there is no evidence of the effect of rifampicin on the concentration of atorvastatin in hepatocytes, and if joint therapy can not be avoided, the patient should be closely monitored to monitor the effectiveness of the drug.

Inhibitors of transport proteins

Inhibitors transport proteins (for example, ciclosporin) may increase the systemic effect of atorvastatin). The effect of inhibition of hepatic transport proteins on the concentration of atorvastatin in hepatocytes is unknown. Neoli joint therapy can not be avoided, in order to achieve a therapeutic goal, the dose of atorvastatin should be reduced and careful monitoring of the patient's condition should be established.

Gemfibrosil / fibroic acid derivatives

Monotherapy with fibrates is sometimes accompanied by the appearance of undesirable phenomena from the skeletal musculature, including rhabdomyolysis. The risk of these phenomena can thus increase with combined therapy with derivatives of fibrolic acid and atorvastatin. If joint therapy can not be avoided, the lowest doses of atorvastatin should be used and careful monitoring of the patient's condition should be made.

Ezetimibe

The monotherapy of ezetimibe is accompanied by the appearance of undesirable phenomena from the skeletal musculature, including rhabdomyolysis. The risk of these events may thus increase with combined therapy with ezetimibe and atorvastatin.If joint therapy can not be avoided, the lowest doses of atorvastatin should be used and careful monitoring of the patient's condition should be made.

Kolestypol

The concentrations of atorvastatin and its active metabolites in blood plasma were lower (by approximately 25%) with the combined use of colestipol and atorvastatin. Nevertheless, the effect on lipids was more pronounced with combined therapy with atorvastatin and colestipol than with monotherapy with each drug.

Fusidic acid

Studies on the drug interaction of atorvastatin and fusidic acid have not been conducted. As with other statins, undesirable phenomena from the skeletal musculature, including rhabdomyolysis, were recorded during the post-marketing application of atorvastatin together with fusidic acid. The mechanism of this interaction is unknown. The condition of patients should be closely monitored, and if possible consider the advisability of a temporary cessation of joint treatment with these drugs.

The effect of atorvastatin on concomitant drug therapy

Digoxin

With repeated intake of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentration of digoxin slightly increased. Patients receiving digoxin, should be under proper medical supervision.

Oral contraceptives

Simultaneous use of atorvastatin and oral contraceptives led to an increase in the concentrations of norethisterone and ethinylestradiol in blood plasma. This effect should be considered when choosing an oral contraceptive for women receiving the drug TORVACARD®.

Warfarin

In a clinical study conducted in patients who received warfarin for a long time, the simultaneous use of atorvastatin at a dose of 80 mg per day and warfarin caused a slight decrease in prothrombin time (about 1.7 seconds) during the first 4 days of treatment, which returned to normal within 15 days of atorvastatin therapy. Despite very rare reports of cases of clinically significant anticoagulant interactions, prothrombin time should be determined in patients taking coumarinic anticoagulants before initiating therapy and regularly at the beginning of atorvastatin therapy to ensure that there is no significant change in prothrombin time.After the stable value of prothrombin time is fixed, it can be monitored at standard intervals recommended for patients receiving coumarinic anticoagulants. If you change the dose of atorvastatin or cancel it, you should repeat the same procedure. Therapy with atorvastatin was not accompanied by the appearance of bleeding or changes in prothrombin time in patients not taking anticoagulants.

With simultaneous use of atorvastatin and antacid preparations containing magnesium and aluminum hydroxides, the concentration of atorvastatin in blood plasma decreased by about 35%, however, the degree of decrease in cholesterol / LDL concentration did not change.

Table 1: Effect of drugs on the pharmacokinetics of atorvastatin when used concomitantly.

Simultaneously	Atorvastatin
used drug and dosing regimen	Dose (mg)	Change AUC ∞	Clinical recommendation
Tipranavir	40 mg	↑ in	In the cases.
500 mg 2 times	on	9,4	when
at	day	time	simultaneous
Day / Ritonavir	1 st,		application from
200 mg of 2 times	10 mg		atorvastatin
per day 8 days	on		is necessary.
(14-21 days)	day 20th		do not exceed the daily dose
Cyclosporin	10 mg	↑ in	atorvastatin
5,2 .mg / kt / day.	1 time	8,7	more than 10 mg.
stable	at	time	Recommended
dose	day at within 28 days		clinical monitoring of the condition of these patients
Lopinavir	20 mg	↑ in	In the cases.
400 mg 2 times	1 time	5,9	when
in a day/	AT	time	simultaneous
Ritonavir	day		application from
100 mg 2 times	at		atorvastatin
per day, 14	flow		it is necessary,
days	4 days		recommended application of least
Clarithromycin	80 mg	↑ in	support the
500 mg 2	1 time	4,4	their doses
once a day, 9	AT	times	atorvastatin.
days	day at within 8 days		With a dose of atorvastatin over 20 mg it is recommended that clinical monitoring state of these patients.
Saquinavir	40 mg	↑ in	In the cases.
400 mg 2 times	1 time	3,9	when
at	AT	time	combined
Day / Ritonavir	day		application from
(300 mg of 2	at		atorvastatin
once a day at days 5-7e, increase to 400 mg 2 times a day on day 8), days 5-18	flow not 4- X days		is necessary. recommended application of least supporting doses atorvastatin.
30 minutes after admission atorvastatin			At a dose of atorvastatin over 40 mg, it is recommended conducting clinical monitoring of the condition of these patients.
Darunavir 300 mg 2 times a day / Ritonavir 100 mg 2 times a day. 9 days	10 mg 1 time per day 4 days	↑ in 3,3 times
Itraconazole 200 mg once a day, 4 days	40 mg one leggings ABOUT	↑ in 3.3 times
Fosamprenavir 700 mg 2 times a day / Ritonavir 100 mg 2 times a day, 14 days	10 mg 1 time per day 4 days	↑ in 2,5 times
Fosamprenavir 1400 mg 2 times a day, 14 days	10 MI ' 1 time in day 4 days	↑ in 2,3 times
Nelfinavir 1250 mg 2 times per day, 14 days	10 mg 1 time at day 28 days	↑ in 1,7 times ^	Specials recommendations
Nelfinavir 1250 mg 2 times per day, 14 days	10 mg 1 time at day 28 days	↑ in 1,7 times ^	no
Grapefruit juice, 240 ml 1 time per day*	40 mg once	↑ on 37%	Not recommended
			combined
			application of large quantities grapefruit juice and atorvastatin.
Diltiazem 240 mg 1 time per day, 28 days	40 mg once	↑ on 51%	After the start treatment or
Diltiazem 240 mg 1 time per day, 28 days	40 mg once	↑ on 51%	after correction doses diltiazem recommended carrying out correspond to him clinical monitoring of these patients.
Erythromycin 500 mg 4 times a day, 7 days	10 mg once	↑ by 33% ^	Recommended application of the smallest the maximum dose and carrying out clinical monitoring of these patients.
Amlodipine 10 mg, single dose	80 mg once	↑ by 18%	Specials recommendations no
Cimetidine 300 mg 4 times a day, 2 weeks	10 mg 1 time per day 4 weeks	□↓ Less, than on 1% ^	Specials recommendations no
Suspensions of antacids. containing magnesium and aluminum hydroxides, 30 ml 4 times a day, 2 weeks	10 mg once a day 4 weeks	↓ on 35% ^	Specials recommendations no
Efavirenz 600 mg once a day, 14 days	10 mg 3 days	↓ by 41%	Specials recommendations no
Rifampicin 600 mg once a day, 7 days (simultaneous administration)	40 mg one multiply but	↑ by 30%	If you can not to avoid combined therapy, recommended simultaneous admission atorvastatin with rifampicin under clinical monitoring.
Rifampicin 600 mg once a day, 5 days (separate intake drugs)	40 mg one multiply but	↓ by 80%
1'emphnbrosil 600 mg 2 times a day, 7 days	40 mg one multiply but	↑ by 35%	The use of the lowest initial dose and clinical monitoring of these patients is recommended.
Fenofibrate 160 mg once a day, 7 days	40 mg one multiply but	1 by 3%	The use of the lowest initial dose and clinical monitoring of these patients is recommended.

∞ The data given as a multiple change is a simple relationship between concomitant use and monotherapy atorvastatin (i.e., 1-fold = without changes). Data given as% change, reflect% difference in relation to monotherapy atorvastatin (ie 0% = no change).

* Contains one or more components that inhibit isoenzyme CYP3A4 and can increase the concentration of drugs in blood plasma metabolized under the influence of isoenzyme CYP3A4. Use

One glass of grapefruit juice (240 ml) also leads to a decrease AUC active orthohydroxy metabolite to 20.4%. Large volumes of grapefruit juice (more than 1.2 liters per day for 5 days) increased AUC atorvastatin 2.5 times and AUC active atorvastatin and metabolites.

^ Total equivalent activity of atorvastatin.

The increase is denoted by "↑", decrease as "↓"

Children

Research on the drug interactions were conducted only in adults. The degree of interaction in children is unknown. When treating children, the above interactions and precautions for adults.

Special instructions:

Before starting therapy with TORVACARD® it is necessary to try to achieve control of hypercholesterolemia by adequate dietotherapy, increase physical activity, weight loss in obese patients and treatment of other conditions. The use of HMG-CoA reductase inhibitors to reduce lipid concentrations in plasma blood can lead to a change in the biochemical parameters of liver function, which should be monitored before the start of therapy, 6 and 12 weeks after starting the drug TORVACARD® and after each dose increase, and also periodically, for example, every 6 months. An increase in the activity of "hepatic" transaminases in the serum can be observed during therapy with the drug TORVACARD® usually in the first three months. Patients who have an increased activity of "liver" transaminases should be under the supervision of a doctor before returning to normal.

In a retrospective analysis of stroke subtypes in patients without IHD who had recently undergone a stroke or TIA, a high incidence of hemorrhagic stroke in patients who received atorvastatin in a dose of 80 mg, compared with placebo. An increased risk was noted at the beginning of the study in patients with previous hemorrhagic stroke or lacunar cerebral infarction. The ratio of risk and benefit when taking atorvastatin 80 mg in patients who underwent hemorrhagic stroke or lacunar infarction of the brain, not determined,and you should carefully evaluate the potential risk hemorrhagic stroke before starting treatment with TORVACARD®.

Influence on skeletal musculature

Treatment with TORVACARD® In rare cases, it can cause myalgia, myositis and myopathy, which can progress to rhabdomyolysis, a condition potentially life-threatening, characterized by a significant increase in CKK activity (> 10 times the upper limit of normal), myoglobinemia, and Myoglobinuria, which can lead to kidney failure. The drug TORVACARD® can cause an increase in the activity of serum CK, which should be taken into account in differential diagnosis chest pain. Patients should be warned that they should immediately consult a doctor if unexplained pain or weakness in the muscles, especially if they are accompanied by malaise or fever. Drug therapy TORVACARD® should be temporarily discontinued or completely canceled, if there are signs of possible myopathy or the presence of a risk factor for developing renal failure against rhabdomyolysis (for example, severe acute infection, hypertension, serious surgical interference, trauma, severe metabolic, endocrine and water-electrolyte disorders and uncontrolled convulsions).

Before starting treatment

The drug TORVACARD® follows prescribe with caution patients with factors predisposing to the development of rhabdomyolysis. The activity of CK should be measured before starting treatment with statins in the following situations:

- with renal insufficiency;

- with hypothyroidism;

- in the presence of personal or family history of hereditary muscle diseases;

- if there is evidence of a previous toxic effect on skeletal musculature caused by taking statins or fibrates;

- with liver disease and / or alcohol abuse in history;

- in patients older than 70 years, such a measurement is necessary in the presence of other predisposing factors of rhabdomyolysis;

- In situations where there may be an increase in the concentration of atorvastatin in the blood plasma, for example, in drug interactions and in special populations, including genetic subpopulations.

In such situations, the risk ratio of adverse reactions to the possible benefits of treatment should be assessed, in addition, careful monitoring of the patient's condition is recommended.

If the initial indices of CPK activity are significantly increased (> 5 times compared with the upper limit of the norm), treatment should not be started.

Measurement of creatine phosphokinase

The determination of the activity of CK should not be performed after physical exertion or in the presence of any likely alternative cause of its increase, as this makes it difficult to interpret the results of the test. If the baseline CPK activity is significantly increased (> 5 times, as compared to the upper limit of the norm), a second analysis should be performed 5-7 days later to confirm the results.

During the treatment period

Patients should be warned that they should seek medical attention immediately if pain, cramps or muscle weakness occurs, especially if they are accompanied by a malaise or fever.

If such symptoms occur in patients during treatment with TORVACARD®, they should evaluate the activity of CK. With a significant increase in indices (> 5 times, compared with the upper limit of the norm), treatment with TORVACARD® should be discontinued.

If the muscle symptoms are severe and cause daily discomfort,even if the CKK activity indices ns exceed the upper limit of the norm by less than 5 times, consideration should be given to discontinuing treatment with TORVACARD®.

When resolving the symptoms and returning the CK values to normal values, a decision may be made to prescribe a second course of atorvastatin or administration alternative statin at the lowest dose under close supervision.

Treatment with atorvastatin should be discontinued with a clinically significant increase in CPK activity (> 10 times, as compared with the upper limit of the norm), or in diagnosing rhabdomyolysis, or if it is suspected.

Concomitant treatment with other drugs

Risk of rhabdomyolysis increases with simultaneous application atorvastatin and certain drugs that can increase the concentration of atorvastatin in the blood plasma, such as potent inhibitors of the isoenzyme CYP3A4 or transport proteins (for example, ciclosporin, telithromycin, clarithromycin, delavirdine, styipentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir etc.).The risk of myopathy can also increase with simultaneous application of gemfibrozil and other derivatives of fibroic acid, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g per day) and ezetimibe. Where possible, instead of these drugs should be used alternative (non-interacting) drugs.

In cases where simultaneous application of these lmedicines and Atorvastatin, the potential benefit and risk of concomitant therapy should be carefully evaluated. When patients receive medications that increase the concentration of atorvastatin in blood plasma, it is recommended to prescribe the drug TORVACARD® in the minimum maximum dose. In addition, in the case of powerful inhibitors isoenzyme CYP3A4, recommended apply the minimum initial dose of the drug TORVACARD® and establish a clinical observation of the condition of these patients.

The simultaneous use of the drug TORVACARD® and fusidic acid is not recommended, therefore, it may be decided to temporarily stop the drug treatment TORVACARD® for the period of therapy with fusidic acid.

Use in children

The safety of the drug in children is not established.

Interstitial lung disease

With the use of certain HMG-CoA reductase inhibitors, especially with prolonged therapy, there were rare cases of interstitial lung disease have been reported. Its manifestations may include shortness of breath, an unproductive cough and a worsening of the general condition (increased fatigue, weight loss and fever). If suspected of interstitial lung disease, therapy with TORVACARD® should be discontinued.

Diabetes

Preparations of the class of statins are capable of cause an increase in the concentration of glucose in the blood. In some patients at high risk of developing diabetes, such changes can lead to its manifestation, which is an indication for the appointment hypoglycemic therapy. However, a reduction in the risk of cardiovascular disease when taking inhibitors of HMG-CoA reductase (statins) exceeds the risk of developing diabetes, so this factor should not serve as a basis for the abolition of statin treatment. For patients at risk (fasting blood glucose 5,6-6,9 mmol / l, body mass index (BMI)> 30 kg / m², hypertriglyceridemia, history of arterial hypertension), medical follow-up should be established and regularly monitor biochemical parameters.

Patients with rare hereditary diseases

The drug TORVACARD® contains lactose. Patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the use of this drug is contraindicated.

Effect on the ability to drive transp. cf. and fur:

The drug TORVACARD® has a negligible effect on the ability to drive and work with machinery.

Form release / dosage:

Tablets film-coated 10 mg, 20 mg and 40 mg.

Packaging:For 10 tablets in a blister of A1 / A1. For 3 or 9 blisters are placed in a cardboard box together with instructions for use.

Storage conditions:

Does not require special storage conditions.

Keep out of the reach of children!

Shelf life:4 years. The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000438

Date of registration:29.06.2010

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, a.s. Czech Republic

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp02.06.2015

Illustrated instructions

Instructions

Torvacard® (Torvacard®)