Atorvastatin, 10 mg 30 pcs

Pharmacological action is hypolipidemic.

Competitively selectively inhibits HMG-CoA reductase, which converts 3- hydroxy-3-methylglutaryl-CoA into mevalonic acid (precursor of sterols, including cholesterol). Triglycerides and cholesterol in the liver are incorporated into LPLONP, enter the plasma, and are transported to peripheral tissues. LDLNP is formed from LDLNP, which is catabolized by interaction with high-affinity LDL receptors. Elevated plasma levels of total cholesterol, LDL cholesterol, and apolipoprotein B contribute to atherosclerosis and are risk factors for cardiovascular disease, whereas increased levels of HDL are associated with reduced risk of cardiovascular complications.

Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and inhibits cholesterol synthesis in the liver by increasing the number of LDL receptors on the cell surface and enhances LDL uptake and catabolism. Suppresses the formation of LDL and the number of LDL particles. Reduces LDL-cholesterol levels in patients with homozygous familial hypercholesterolemia, which is usually resistant to therapy with hypolipidemic agents.

In most patients the effect is manifested 2 weeks after the start of therapy, the maximum effect develops by the 4th week and lasts for the whole period of treatment.

Toxic effect on CNS. Brain hemorrhage was observed in dogs when using atorvastatin for 3 months at a dose of 120 mg/kg/day, brain hemorrhage and formation of optic nerve vacuoles – in female dogs after 11 months of atorvastatin use at doses up to 280 mg/kg/day. The dose of 120 mg/kg/day created a systemic exposure approximately 16 times greater than that of the maximum therapeutic dose for humans (80 mg/day) in terms of AUC _{(0-24 h)}. In a two-year study, single tonic seizures were reported in two dogs (one at a dose of 10 mg/day, the other at a dose of 120 mg/day). There was no evidence of CNS damage in mice when atorvastatin was chronically administered for up to 2 years at doses up to 400 mg/day and in rats at doses up to 100 mg/day. These doses produced exposures 6-fold (mice) and 11-fold (rats) greater than those in humans at the recommended therapeutic dose of 80 mg per AUC_{(0-24 h)}.

Vascular damage in the CNS, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of the perivascular spaces, has been reported in dogs given other drugs of this class. Chemically similar substances of the same class as atorvastatin caused dose-dependent degeneration of the optic nerve at a dose producing plasma concentrations 30 times greater than those in humans at the maximum recommended dose.

Carcinogenicity, mutagenicity, effects on fertility

In two-year studies of carcinogenicity in rats using doses of atorvastatin 10, 30 and 100 mg/kg/day, two rare tumors in muscle were found in females at the maximum dose: in one case it was rhabdomyosarcoma and in another, fibrosarcoma. This dose corresponded to systemic exposure values (plasma AUC_{0-24 h}) 16 times greater than those in humans at an oral dose of 80 mg. In two-year studies of carcinogenicity in mice at doses of atorvastatin 100, 200, and 400 mg/kg/day, there was a significant increase in the incidence of liver adenoma at the maximum dose in males and liver carcinoma at the maximum dose in females. These cases were observed at a plasma AUC_{0 -24 h} value approximately 6 times that of human exposure at an oral dose of 80 mg.

In vitro atorvastatin showed no mutagenic or clastogenic properties in the following tests (with/without metabolic activation): Ames test with Salmonella typhimurium and Escherichia coli, hypoxanthine-guanine phosphoribosyltransferase test and chromosome aberration test on Chinese hamster ovary cells. No in vivo mutagenicity was detected in a micronucleus test in mice.

In studies in rats at doses of atorvastatin up to 175 mg/kg (exposure 15 times higher than in humans) no adverse effects on fertility were found. When rats were injected with atorvastatin at a dose of 100 mg/kg/day (16 times the AUC in humans at a dose of 80 mg) for 3 months, aplasia and aspermia in the testicular appendages were recorded in 2 of 10 rats; testicular weight was significantly reduced at doses of 30 and 100 mg/kg and appendage weight was lower at the 100 mg/kg dose. Male rats that received atorvastatin at a dose of 100 mg/kg/day for 11 weeks before mating had decreased sperm motility and concentration, and the number of abnormal spermatozoa was increased. Atorvastatin had no adverse effects on sperm parameters and reproductive organs in dogs receiving it at doses of 10, 40, and 120 mg/kg for 2 years.

Atorvastatin is rapidly absorbed after oral administration, the degree of absorption increases in proportion to increasing dose, C_max is reached within 1-2 hours. Absolute bioavailability is approximately 14%, systemic availability with respect to HMG-CoA reductase inhibition is approximately 30%. Low systemic availability is due to presystemic metabolism in the gastrointestinal mucosa and/or during “first passage” through the liver. Mean volume of distribution of atorvastatin is approximately 381 l. Binding to plasma proteins is ≥98%. Blood/plasma level ratio is approximately 0.25, which indicates poor atorvastatin penetration into erythrocytes. In the liver atorvastatin is extensively metabolized with the participation of cytochrome P450 isoenzyme CYP3A4 to form ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect against HMG-CoA reductase, comparable with that of atorvastatin. The inhibitory effect against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites. Atorvastatin and its metabolites are excreted mainly with bile after hepatic and/or extrahepatic metabolism (not subjected to marked hepatic recirculation). T_1/2 atorvastatin is 14 h. Due to the presence of active metabolites, inhibitory activity against HMG-CoA reductase persists for about 20-30 hours. Less than 2% of the oral dose of atorvastatin is detected in urine. It is not excreted during hemodialysis.

Peculiarities of pharmacokinetics in specific groups of patients

In elderly patients plasma concentrations of atorvastatin are higher (approximately 40% for C_max and 30% for AUC) than in elderly patients. C_max values are 20% higher in women and AUC values are 10% lower (not clinically relevant). Renal diseases do not influence on plasma concentrations of atorvastatin or its effect on lipid metabolism parameters. In patients with alcoholic cirrhosis concentrations of atorvastatin are significantly increased: in mild degree of liver dysfunction (Child Pugh Class A) – 4 times (both C_max and AUC), in moderate degree of dysfunction (Child Pugh Class B) – C_max 16 times, AUC – 11 times higher than normal.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

the active substance: atorvastatin calcium trihydrate – 10.85 mg, which corresponds to 10 mg of atorvastatin;

excipients: calcium carbonate, microcrystalline cellulose, milk sugar (lactose), starch 1500, colloidal silica (aerosil), magnesium stearate, opadray II (polyvinyl alcohol, macrogol (polyethylene glycol), talc, titanium dioxide).

How to take, the dosage

Ingestion.

Before prescribing Atorvastatin, a standard hypolipidemic diet should be recommended for the patient, which the patient should continue to follow during the entire period of therapy.

The initial dose is on average 10 mg/day. The dose varies from 10 to 80 mg/day.

The drug can be taken at any time of the day with food or regardless of the time of meals. The dose is adjusted with regard to baseline cholesterol/LDL levels, the goal of therapy, and individual effect. At the beginning of treatment and/or during dose increase of Atorvastatin it is necessary to monitor plasma lipid levels every 2-4 weeks and adjust the dose accordingly.

In order to ensure the following dosing regimen of the drug it is possible to use Atorvastatin in other dosage forms: film-coated tablets 10 mg and 20 mg. The maximum daily dose of the drug is 80 mg.

In concomitant use with cyclosporine, the daily dose of Atorvastatin should not exceed 10 mg.

Primary hypercholesterolemia and mixed hyperlipidemia. In most cases, it is sufficient to prescribe a dose of 10 mg of Atorvastatin once daily. Significant therapeutic effect is observed after 2 weeks, and the maximum therapeutic effect is usually observed after 4 weeks. With long-term treatment this effect is maintained.

Patient special groups

Kidney function disorders. Administration of the drug in patients with renal insufficiency and renal diseases does not influence on plasma levels of Atorvastatin or degree of cholesterol/LDL decrease with its use, therefore no change of drug dose is required.

Hepatic disorders. In case of hepatic insufficiency, the dose should be reduced.

Elderly patients. No differences in safety, efficacy or achievement of hypolipidemic therapy goals have been noted when using the drug in elderly patients compared to the general population.

Interaction

The risk of myopathy during treatment with statins is increased when used in combination with cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses, strong CYP3A4 inhibitors (including clarithromycin, HIV protease inhibitors, itraconazole).

When using atorvastatin in combination with CYP3A4 isoenzyme inhibitors (e.g. cyclosporine, macrolide antibiotics – erythromycin and clarithromycin; itraconazole, HIV protease inhibitors) may increase plasma concentrations of atorvastatin (atorvastatin is metabolized with the participation of CYP3A4); special caution should be exercised when using atorvastatin in combination with the above-mentioned drugs (see “Cautionary notes. See “Special Precautions”).

In combined use of atorvastatin in dose of 40 mg and itraconazole in dose of 200 mg once a day it was stated 3-fold increase of Atorvastatin AUC in comparison with AUC in monotherapy.

Concomitant use of atorvastatin with protease inhibitors (lopinavir/ritonavir, ritonavir/saquinavir) was accompanied by increased plasma concentration of atorvastatin. In concurrent administration of atorvastatin in dose 40 mg and lopinavir+ritonavir combination (in dose 400/100 mg 2 times per day) it was stated 5.9 times increased AUC of atorvastatin in comparison with AUC during monotherapy. When using atorvastatin at a dose of 40 mg with a combination of ritonavir + saquinavir (in a dose of 400/400 mg 2 times a day) its AUC was increased by 3.9 times.

Antacids decrease the concentration of atorvastatin by 35% (effect on LDL cholesterol is not changed).

Recurrent administration of digoxin and atorvastatin increases Css of digoxin by approximately 20% (patients should be monitored).

In coadministration of atorvastatin and oral contraceptives, the AUC of norethindrone and ethinylestradiol is increased by approximately 30 and 20% (this effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin).

In concomitant administration with erythromycin (CYP3A4 inhibitor) plasma concentration of atorvastatin is increased by about 40%. Hypolipidemic effect of combination of atorvastatin and colestipol is superior for each drug separately. Concomitant use with drugs that reduce concentration or activity of endogenous steroid hormones (including ketoconazole, spironolactone, cimetidine), increases the risk of reducing endogenous steroid hormone production (caution should be observed).

Concomitant oral administration of atorvastatin and suspension containing magnesium and aluminum hydroxide decreased plasma concentrations of atorvastatin by approximately 35%, but the degree of decrease in cholesterol/LDL levels did not change.

Special Instructions

Contraindications

Side effects

In controlled clinical trials (n=2502) less than 2% of patients discontinued treatment due to atorvastatin-induced adverse effects. The most common adverse effects associated with atorvastatin administration 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, anemia, lymphadenopathy, thrombocytopenia.

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

Gastrointestinal system disorders: ≥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, elevated ALT or AST, gout exacerbation.

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

Overdose

Treatment: there is no specific antidote, symptomatic therapy is carried out.

Hemodialysis is ineffective.

Similarities