Atorvastatin-ALSI, 40 mg 30 pcs

Prevention of heart attacks and strokes, Reducing cholesterol

Atorvastatin is used:

• .in combination with diet to reduce elevated levels of total cholesterol, cholesterol/LDL, apolipoprotein B, and triglycerides and increase HDL cholesterol levels in patients with primary hypercholesterolemia, heterozygous familial and nonfamilial hypercholesterolemia and combined (mixed) hyperlipidemia (Fredrickson types IIa and IIb);
• in combination with diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV) and patients with dysbetalipoproteinemia (Fredrickson type III), in whom diet therapy is not adequately effective;
To decrease total cholesterol and LDL cholesterol/LDL levels in patients with homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological therapies are not effective enough

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Active ingredient

Composition

1 film-coated tablet contains:

the active ingredient:

atorvastatin calcium trihydrate – 43.4 mg, which corresponds to 40 mg of atorvastatin;

excipients:

Calcium carbonate 35.4 mg,

Microcrystalline cellulose 24.0 mg,

StarCap1500 [corn starch and pregelatinized starch] 53.6 mg,

silica colloidal dioxide (aerosil) 400 µg,

talc 1.6 mg,

magnesium stearate 1.6 mg,

Opadray II (series 85) (polyvinyl alcohol 2.56 mg, macrogol 1.29 mg, talc 0.94 mg, titanium dioxide 1.56 mg, iron oxide yellow dye 0.032/mg, iron oxide red dye 0.00128 mg) 6.4 mg.

Interaction

When concomitant use of atorvastatin with cyclosporine, HIV protease inhibitors (indinavir, ritonavir), antibiotics (erythromycin, clarithromycin, quinupristine/dalfopristine), antifungal drugs from azole group (fluconazole, itraconazole, ketoconazole), nefazodone, fibric acid derivatives, nicotinic acid or diltiazem plasma concentration of atorvastatin increases, which increases the risk of myopathy with rhabdomyolysis and acute renal failure.

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.

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

Concomitant use of colestipol decreased plasma concentrations of Atorvastatin by approximately 25%. However, the hypolipidemic effect of combination of Atorvastatin and colestipol was superior to that of each drug separately.

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 using digoxin in combination with Atorvastatin at a dose of 80 mg/day, digoxin concentrations increased by approximately 20%. Patients receiving digoxin in combination with Atorvastatin should be monitored.

In concomitant use of Atorvastatin and erythromycin (500 mg 4 times/day) or clarithromycin (500 mg 2 times/day), which inhibit cytochrome Р450 3A4, increased Atorvastatin plasma concentrations were observed.

Atorvastatin had no clinically significant effect on plasma concentrations of terfenadine, which is metabolized primarily by cytochrome Р450 3A4; in this regard, it seems unlikely that Atorvastatin can significantly affect pharmacokinetic parameters of other cytochrome Р450 3A4 substrates.

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

In studies of interactions of Atorvastatin with warfarin and cimetidine, no evidence of clinically significant interaction was found.

The pharmacokinetics of Atorvastatin 80 mg and amlodipine 10 mg in equilibrium have not changed in concomitant use.

The concomitant use of Atorvastatin with protease inhibitors known as cytochrome P450 3A4 inhibitors (grapefruit juice) was accompanied by an increase in plasma concentration of Atorvastatin, in this regard, consumption of this juice should be avoided.

No clinically significant adverse interactions of Atorvastatin with hypotensive agents and with estrogens have been noted. Studies of interaction with all specific drugs have not been conducted.

The concomitant use of Atorvastatin with inducers of CYP3A4 isoenzyme (efavirenz, rifampicin) leads to increased plasma concentration of the drug.

Pharmaceutical incompatibility is not known.

Directions for use

Before Atorvastatin is prescribed, 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 once daily. The dose varies from 10 to 80 mg once daily. The maximum daily dose of the drug is 80 mg.

The drug can be taken at any time of the day with food or regardless of the time of meals. The dose is adjusted taking into account the initial cholesterol/LDL levels, the purpose of therapy and individual effect. At the beginning of treatment and/or during dose increase of Atorvastatin, plasma lipid levels should be monitored every 2-4 weeks and the dose should be adjusted accordingly. In order to ensure the following dosing regimen of the drug it is possible to use Atorvastatin in another dosage form: film-coated tablets of 10 and 20 mg.

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

Primary hypercholesterolemia and mixed hyperlipidemia

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

The use of the drug in patients with renal insufficiency and renal diseases does not influence the plasma level of Atorvastatin or degree of cholesterol/LDL decrease with its use, therefore no change of drug dose is required.

In case of hepatic impairment, the dose should be reduced (see section “Caution” and “Special Precautions”).

There were no differences in safety, efficacy, or achievement of hypolipidemic therapy goals when using the drug in elderly patients compared to the general population.

Special Instructions

Before starting therapy with Atorvastatin, a standard hypocholesterolemic diet should be prescribed for 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 administration and after each dose increase as well as periodically, e.g., every 6 months. Elevation of serum hepatic enzymes activity may be observed during Atorvastatin therapy. Patients with increased enzyme activity should be monitored until enzyme levels return to normal. In case if values of alanine aminotransferase (ALT) or asparagine aminotransferase (AST) exceed more than 3 times the upper limit of acceptable, 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 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 with other drugs of this class was increased with concomitant use of cyclosporine, fibrates, erythromycin, nicotinic acid or antifungal agents, azole derivatives. 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, antifungal agents, azole derivatives or nicotinic acid in hypolipidemic doses, the expected benefits and risks of treatment should be carefully weighed and patients should be regularly observed to detect 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 dietary 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.

Impact on driving and operating machinery

Caution should be exercised when driving or operating machinery because of the risk of dizziness.

Synopsis

Features

Absorption is high. Maximal concentration (Cmax) in plasma is reached after 1-2 hours, Cmax in women is 20% higher, area under the curve/concentration, time (AUC) is 10% lower; Cmax in patients with alcoholic cirrhosis is 16 times higher than normal, AUC – 11 times higher.

Food slightly reduces speed and duration of drug absorption (by 25% and 9%, respectively), but decrease of LDL cholesterol is similar to that with atorvastatin without food. Concentration of atorvastatin when administered in the evening is lower than in the morning (approximately by 30%). A linear relationship between the degree of absorption and the dose of the drug was found.

The absolute bioavailability is 12%, the systemic bioavailability of HMG-CoA reductase inhibitory activity is 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and during “primary passage” through the liver.

The average volume of distribution is 381 liters, the binding to plasma proteins is 98%. It is metabolized mainly in liver with participation of CYP3A4, CYP3A5 and CYP3A7 cytochrome isoenzymes with formation of pharmacological active metabolites (ortho- and parahydroxylated derivatives, beta-oxidation products). In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable with that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

In impairment of liver function significantly increased (Cmax approximately 16-fold, AUC approximately 11-fold) in patients with alcoholic cirrhosis (class B according to Child-Pugh scale); Atorvastatin concentration is higher (Cmax approximately 40%, AUC approximately 30%) in elderly patients older than 65 years old than in adult patients of young age; renal impairment does not influence atorvastatin concentration in plasma or its influence on lipid profile indexes, due to this the dose adjustment is not required in patients with renal impairment.

Extracted with bile after hepatic and/or extrahepatic metabolism (not subjected to marked intestinal-hepatic recirculation).

The elimination half-life is 14 hours. Inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Less than 2% of the oral dose is detected in the urine. It is not excreted during hemodialysis.

Contraindications

With caution: alcohol abuse, history of liver disease, severe electrolyte-water balance disorders, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, major surgical interventions, injuries, skeletal muscle diseases.

Side effects

Nervous system disorders: more frequently 1% – insomnia, dizziness; less frequently 1% – headache, asthenia, malaise, somnolence, nightmares, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial nerve paralysis, hyperkinesia, depression, hyperesthesia, loss of consciousness.

Senses: less frequently 1% – amblyopia, tinnitus, dry conjunctiva, accommodation disorder, bleeding in the eye, deafness, glaucoma, parosmia, loss of sense of taste, perversion of taste.

Cardiovascular system: more often 1% – chest pain; less often 1% – palpitations, vasodilation, migraine, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.

Hematopoietic system disorders: rarely 1% – anemia, lymphoadenopathy, thrombocytopenia, leukocyturia.

Respiratory system: more often 1% – bronchitis, rhinitis; less often 1% – pneumonia, dyspnea, bronchial asthma, nasal bleeding.

Digestive system disorders: more often 1% – nausea; less frequently 1% – heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, anorexia, decreased or increased appetite, dry oral mucosa, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive-ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, bleeding gums, tenesmus.

Musculoskeletal system: more often 1% – arthritis; less often 1% – leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonus, joint contractures, joint swelling, tendopathy (in some cases with tendon rupture).

Urogenital system disorders: more frequently 1% – urogenital infections, peripheral edema; less frequently 1% – dysuria (including Pollakiuria, nycturia, urinary incontinence or urinary retention, imperative urge to urinate), nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorders.

Skin disorders: more often 1% – alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymoses, petechiae.

Allergic reactions: less than 1% – skin itch, skin rash, contact dermatitis, rarely – urticaria, angioedema, edema localized in the face, photosensitization, anaphylaxis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Laboratory measures: rarely 1% – hyperglycemia, hypoglycemia, increased serum CPK, albuminuria.

Others: less than 1% – weight gain, gynecomastia, mastodynia, gout exacerbation.

Overdose

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

Hemodialysis is ineffective.

Similarities