Atorvastatin-SZ, 10 mg 30 pcs

Cholesterol, Atherosclerosis, Cholesterol Reduction, Prevention of heart attacks and strokes

– Primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (type IIa according to Fredrickson classification);

– Combined (mixed) hyperlipidemia (Fredrickson classification types IIa and IIb);

– Dysbetalipoproteinemia (Fredrickson classification type III) (as an adjunct to diet);

– Familial endogenous hypertriglyceridemia (Fredrickson classification type IV), resistant to diet;

– Homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological treatments are not effective;

– Prevention of cardiovascular disease:

– Primary prevention of cardiovascular complications in patients without clinical signs of coronary heart disease (CHD) but who have several risk factors for its development: age over 55 years, nicotine addiction, arterial hypertension, diabetes mellitus, genetic predisposition, including on the background of dyslipidemia;

– Secondary prevention of cardiovascular complications in patients with CHD to reduce the total mortality rate, myocardial infarction, stroke, repeated hospitalization for angina and the need for revascularization.

Active ingredient

Composition

dosage of 10 mg of the active substance:

atorvastatin calcium in terms of atorvastatin – 10 mg

auxiliary substances (core):

Lactose monohydrate (milk sugar), 62.0 mg; calcium carbonate, 33.0 mg; povidone K 30 (polyvinylpyrrolidone medium molecular), 6.0 mg; croscarmellose sodium (primellose), 6.75 mg; Sodium stearyl fumarate – 1.5 mg; colloidal silica (aerosil) – 0.75 mg; microcrystalline cellulose – 30.0 mg;

accompanied substances (coating):

Opadray II (polyvinyl alcohol, partially hydrolyzed, 2.2 mg; macrogol (polyethylene glycol) 3350, 0.6175 mg; talc, 1.0 mg; titanium dioxide E 171, 0.9585 mg; soy lecithin E 322, 0.175 mg; aluminum varnish based on the dye indigo carmine – 0.003 mg; aluminum varnish based on the dye azorubin – 0.0255 mg; aluminum varnish based on the dye crimson [Ponceau 4R] – 0.0205 mg).

The film-coated tablets are pink, round, biconvex.

On cross section the tablet core is white or almost white.

How to take, the dosage

Ingestion.

Take at any time of the day regardless of meals. Before starting treatment with Atorvastatin-SZ, an attempt should be made to achieve control of hypercholesterolemia by diet, exercise and weight reduction in obese patients, as well as by therapy of the underlying disease.

The standard hypocholesterolemic diet should be recommended to the patient when prescribing the drug and the patient should adhere to it during the whole period of therapy.

The dose of the drug varies from 10 mg to 80 mg once daily and is titrated taking into account baseline concentration of LDL-C, purpose of therapy and individual effect on therapy. Maximum daily dose of the drug for single administration is 80 mg. At the beginning of treatment and / or during increasing the dose of Atorvastatin-SZ it is necessary to monitor plasma lipid concentrations every 2 to 4 weeks and adjust the drug dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

For most patients, 10 mg once daily; the therapeutic effect is seen within 2 weeks and usually reaches a maximum within 4 weeks. With prolonged treatment, the effect persists.

Homozygous familial hypercholesterolemia

The initial dose is adjusted individually depending on the severity of the disease. In most cases the optimal effect is observed when using the drug in a dose of 80 mg once daily (decrease of HDL-C concentration by 18-45%).

Inadequate liver function

Inadequate liver function requires caution (due to delayed elimination of the drug from the body). Clinical and laboratory parameters should be monitored carefully (regular monitoring of “hepatic” transaminases activity: aspartate aminotransferase (AST) and alanine aminotransferase (ALT)). In case of significant increase in “hepatic” transaminases, the dose of Atorvastatin-CZ should be decreased or the treatment should be discontinued.

Kidney function impairment does not affect the plasma concentration of atorvastatin or the degree of decrease in LDL-C concentration during therapy with Atorvastatin-SZ, so no dose adjustment is required. Elderly patients No differences in efficacy, safety or therapeutic effect of Atorvastatin-SZ have been found in elderly patients compared to the general population and no dose adjustment is required (see section “Pharmacokinetics”).

The use in combination with other medicinal products

If simultaneous use with cyclosporine, telaprevir or tipranavir/ritonavir combination is necessary, the dose of Atorvastatin-SZ should not exceed 10 mg/day. Caution should be exercised and the lowest effective dose of atorvastatin used concomitantly with HIV protease inhibitors, hepatitis C inhibitors, clarithromycin and itraconazole. (see section “Special indications”).

Interaction

The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of cyclosporine, fibrates, antibiotics (erythromycin, clarithromycin, quinupristine/dalfopristine), nefazodone, HIV protease inhibitors (indinavir, ritonavir), colchicine, antifungal agents – azole derivatives – and nicotinic acid at lipid-lowering doses (more than 1 g/day) (see See section “Special Precautions”).

SYPCA4 isoenzyme inhibitors

Since atorvastatin is metabolized by CYPCA4 isoenzyme, co-administration of atorvastatin with CYPCA4 isoenzyme inhibitors may increase Atorvastatin plasma concentrations. The degree of interaction and potentiation effect are determined by the variability of effect on CYPCA4 isoenzyme.

Inhibitors of transport protein OATP1B1

Atorvastatin and its metabolites are substrates of transport protein OATP1B1. OATP1B1 inhibitors (e.g., cyclosporine) may increase the bioavailability of atorvastatin. Thus, co-administration of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in plasma concentration of atorvastatin by 7.7 times. If concomitant use with cyclosporine is necessary, the dose of Atorvastatin-SZ should not exceed 10 mg/day (see section “Dosage and administration”).

Eritromycin/clarithromycin

Concomitant administration of atorvastatin with erythromycin (500 mg 4 times daily) or clarithromycin (500 mg 2 times daily), which inhibit CYPCA4 isoenzyme, was observed to increase Atorvastatin plasma concentration (see sect. See section “Special indications”). Caution should be exercised and the lowest effective dose of atorvastatin should be used concomitantly with clarithromycin.

Protease inhibitors

Simultaneous use of atorvastatin with protease inhibitors, known as CYPZA4 isoenzyme inhibitors, is accompanied with increase of plasma concentration of atorvastatin (concomitant use with erythromycin increases Atorvastatin Cmax by 40%).

Combination of protease inhibitors

Patients taking HIV protease inhibitors and hepatitis C inhibitors should exercise caution and use the lowest effective dose of atorvastatin. In patients taking telaprevir or tipranavir/ritonavir combination drugs, the dose of Atorvastatin-CZ should not exceed 10 mg/day.

Patients taking the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C protease inhibitor telaprevir should avoid concomitant administration of Atorvastatin-SZ. Patients taking HIV protease inhibitors lopinavir plus ritonavir should be careful when prescribing Atorvastatin-CZ and the lowest dose necessary should be prescribed. In patients taking HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir or fosamprenavir plus ritonavir, the dose of Atorvastatin-ZS should not exceed 20 mg and the drug should be used with caution. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of Atorvastatin-CZ should not exceed 40 mg and close clinical monitoring is recommended.

Diltiazem

The co-administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg, leads to increased plasma concentrations of atorvastatin.

Ketoconazole, spironolactone and cimetidine

Caution should be exercised when concomitant use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

Itraconazole

The concomitant use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in dose 200 mg led to increase of AUC of atorvastatin. Caution should be exercised and the lowest effective dose of atorvastatin should be used concomitantly with itraconazole.

Grapefruit juice

Since grapefruit juice contains one or more components that inhibit CYPCA4 isoenzyme, its excessive consumption (more than 1.2 liters per day) may cause increase of plasma concentration of atorvastatin.

CYPCA4 isoenzyme inducers

The co-administration of atorvastatin with CYPCA4 isoenzyme inducers (e.g., efavirenz, phenytoin or rifampicin) may lead to decreased plasma concentration of atorvastatin. Due to dual mechanism of interaction with rifampicin (inducer of CYPCA4 isoenzyme and inhibitor of hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after rifampicin administration leads to significant decrease of plasma concentration of atorvastatin.

Antacids

Concomitant oral administration of suspension containing magnesium hydroxide and aluminum hydroxide decreased plasma concentration of atorvastatin by approximately 35%, but the degree of decrease in LDL-C concentration was not changed.

Phenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, so no interaction with other drugs metabolized by the same cytochrome isoenzymes is expected.

Colestipol

Concomitant use of colestipol decreased plasma concentrations of atorvastatin by approximately 25%; however, the hypolipidemic effect of combining atorvastatin and colestipol was superior to that of each drug alone.

Digoxin

The equilibrium plasma concentrations of digoxin and atorvastatin at a dose of 10 mg did not change when digoxin and atorvastatin were repeatedly administered. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased by approximately 20%.

Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.

Azithromycin

The concomitant use of atorvastatin in dose of 10 mg once daily and azithromycin in dose of 500 mg once daily did not change concentration of atorvastatin in plasma.

In concomitant use of atorvastatin and oral contraceptive containing norethisterone and ethinylestradiol a significant increase in AUC of norethisterone and ethinylestradiol by approximately 30% and 20%, respectively, was observed. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.

Terfenadine

There were no clinically significant changes in the pharmacokinetics of terfenadine when concomitant use of atorvastatin and terfenadine.

Warfarin

The concomitant use of atorvastatin with warfarin may in the first days increase the effect of warfarin on blood clotting (decrease in prothrombin time). This effect disappears after 15 days of concomitant use of these drugs.

Amlodipine

The pharmacokinetics of atorvastatin at a dose of 80 mg and amlodipine 10 mg have not changed in equilibrium.

Other concomitant therapy

In clinical trials atorvastatin was used in combination with hypotensive agents and estrogens within substitution therapy; no signs of clinically significant adverse interaction were observed; no studies of interaction with specific drugs were conducted.

Special Instructions

Before starting therapy with Atorvastatin, a standard hypocholesterolemic diet should be prescribed to the patient, which should be followed during the entire period of treatment. The use of HMG-CoA reductase inhibitors to reduce blood lipid levels may lead to changes in biochemical parameters reflecting liver function.

Liver function should be monitored before the start of therapy, at 6 weeks, 12 weeks after the start of Atorvastatin and after each dose increase, as well as periodically, such as every 6 months. Elevation of serum hepatic enzymes activity may be observed during Atorvastatin therapy. Patients with increased enzyme levels should be monitored until enzyme levels return to normal.

If alanine aminotransferase (ALT) or asparagine aminotransferase (AST) values are more than 3 times higher than the upper limit, it is recommended to reduce Atorvastatin dose or discontinue treatment. Atorvastatin should be used with caution in patients who abuse alcohol and/or have liver disease.

Active liver disease or persistent increase in aminotransferase activity of unclear genesis are contraindications to Atorvastatin administration. Treatment with Atorvastatin may cause myopathy. The diagnosis of myopathy (pain and weakness in muscles combined with an increase in creatine phosphokinase (CPK) activity more than 10 times the upper limit of normal) should be discussed in patients with widespread myalgia, muscle soreness or weakness and/or a marked increase in CPK activity. Patients should be warned to inform their physician immediately of unexplained muscle pain or weakness if accompanied by malaise or fever.

Atorvastatin therapy should be discontinued in case of marked increase in CPK activity or in the presence of confirmed or suspected myopathy. Risk of myopathy during treatment by other drugs of this class was increased with concomitant use of cyclosporine, fibrates, erythromycin, nicotinic acid or azole antifungal agents. Many of these drugs inhibit cytochrome P450 3A4-mediated metabolism and/or drug transport.

Atorvastatin is biotransformed by CYP 3A4. Prescribing Atorvastatin in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungal agents or nicotinic acid in hypolipidemic doses, the expected benefits and risks of treatment should be carefully weighed and patients should be regularly observed for muscle pain or weakness, especially during the first months of treatment and during periods of increasing dose of any drug. In such situations, periodic determination of CPK activity may be recommended, although such monitoring does not prevent the development of severe myopathy.

In Atorvastatin, as well as other drugs of this class, there have been cases of rhabdomyolysis with acute renal failure due to myoglobinuria. Atorvastatin therapy should be temporarily discontinued or completely discontinued in case of signs of possible myopathy or in presence of risk factor of renal failure during rhabdomyolysis (for example, severe acute infection, arterial hypotension, serious surgery, trauma, severe metabolic, endocrine and electrolyte disorders and uncontrolled convulsions).

Before starting therapy with Atorvastatin, an attempt should be made to achieve control of hypercholesterolemia through adequate diet therapy, increasing physical activity, reducing body weight in obese patients and treating other conditions. Patients should be warned to seek immediate medical attention if they experience unexplained muscle pain or weakness, especially if accompanied by malaise or fever.

Contraindications

Hypersensitivity to any component of the drug. Active liver disease or increase in the activity of “hepatic” transaminases in plasma of unknown genesis more than 3 times compared to the upper limit of normal. Age under 18 years old (insufficient clinical data on the efficacy and safety of the drug in this age group). Lactose intolerance, lactase deficiency, glucose-galactose malabsorption. Hypersensitivity to soy and peanuts. Pregnancy and breast-feeding. Use in women who are planning a pregnancy and do not use reliable methods of contraception.

With caution

. Alcohol abuse, history of liver disease, muscle diseases (history of other representatives of the group of HMG-CoA reductase inhibitors), severe water-electrolyte balance disorders, endocrine (hyperthyroidism) and metabolic disorders, severe acute infections (sepsis), arterial hypotension, diabetes, uncontrolled epilepsy, extensive surgical interventions, injuries.

Side effects

In controlled clinical trials (n=2502) less than 2% of patients discontinued treatment due to atorvastatin-induced adverse effects.

The most frequent adverse effects associated with taking atorvastatin were constipation, flatulence, dyspepsia, and abdominal pain.

Nervous system and sense organs: ≥2% – headache, asthenic syndrome, insomnia, dizziness;

Cardiovascular system: ≥2% – chest pain;BP, phlebitis, arrhythmia, angina pectoris, anemia, lymphadenopathy, thrombocytopenia.

Respiratory system: ≥2% – sinusitis, pharyngitis, bronchitis, rhinitis;

Gastrointestinal organs: ≥2% – abdominal pain, constipation or diarrhea, dyspepsia, flatulence, nausea;

Musculoskeletal disorders: ≥2% – arthralgia, myalgia, arthritis;

Urinary system disorders: ≥2% – urogenital infections, peripheral edema;

Skin disorders:

Allergic reactions: ≥2% – skin rash;

Other: ≥2% – infections, accidental trauma, flu-like syndrome, back pain; ALT, ALT or AST elevation, gout exacerbation.

Side effects noted in post-marketing studies on atorvastatin therapy: anaphylaxis, angioneurotic edema, bullous rash (including erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis), rhabdomyolysis, tendon rupture.

Overdose

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