Levostor film-coated tablets 20 mg blister No. 30

Instructions for use: Livostor film-coated tablets 20 mg blister No. 30

Composition

active ingredient: atorvastatin;

1 tablet contains atorvastatin calcium trihydrate, equivalent to atorvastatin 20 mg;

excipients: hydroxypropylcellulose, polysorbate-80, sodium lauryl sulfate, lactose monohydrate, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate;

shell: Opadry II White film coating mixture (hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide (E 171), triacetin).

Dosage form

Film-coated tablets.

Main physicochemical properties: round tablets with a biconvex surface, coated with a white or almost white film coating.

Pharmacotherapeutic group

Drugs that lower serum cholesterol and triglyceride levels. HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological properties

Pharmacodynamics

Atorvastatin is a synthetic lipid-lowering drug. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early, rate-limiting step in cholesterol biosynthesis.

Levostor is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that regulates the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream in a complex with lipoproteins. These complexes are separated by ultracentrifugation into HDL (high-density lipoprotein), LDL (intermediate-density lipoprotein), LDL (low-density lipoprotein) and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the blood plasma for transport to peripheral tissues. LDL is formed from VLDL and catabolized by interaction with high-affinity LDL receptors. Elevated levels of total cholesterol (TC), LDL cholesterol (LDL-C), and apolipoprotein B (apo B) in blood plasma have been shown to contribute to the development of atherosclerosis in humans and are risk factors for the development of cardiovascular disease, while elevated levels of HDL cholesterol are associated with a reduced risk of cardiovascular disease.

Levostor lowers plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; the drug also reduces LDL production and particle size. Levostor reduces LDL cholesterol levels in some patients with homozygous familial hypercholesterolemia, a group of people who rarely respond to treatment with other lipid-lowering drugs.

Elevated levels of total cholesterol, LDL cholesterol, and apo B (the membrane complex for LDL cholesterol) are known to promote the development of atherosclerosis. Similarly, decreased levels of HDL cholesterol (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiological studies have shown that cardiovascular morbidity and mortality vary directly with total cholesterol and LDL cholesterol levels and inversely with HDL cholesterol levels.

Levostor reduces total cholesterol, LDL-cholesterol, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed dyslipidemia. Levostor also reduces VLDL-cholesterol and TG, and causes transient increases in HDL-cholesterol and apolipoprotein A-1. Levostor reduces total cholesterol, LDL-cholesterol, VLDL-cholesterol, apo B, triglycerides, and non-HDL-C (cholesterol that is not part of HDL), and increases HDL-C in patients with isolated hypertriglyceridemia. Levostor reduces LDL-C in patients with dysbetalipoproteinemia.

Like LDL, cholesterol- and triglyceride-rich lipoproteins, including VLDL, HDL, and the rest, may also contribute to atherosclerosis. Elevated plasma triglyceride levels are often found in the triad of low HDL-C and small LDL particles, and in association with nonlipid metabolic risk factors for coronary heart disease. Total plasma triglycerides per se have not been consistently shown to be an independent risk factor for coronary heart disease. Furthermore, no independent effect of increasing HDL or decreasing triglycerides on the risk of coronary and cardiovascular morbidity and mortality has been established.

Pharmacokinetics

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1-2 hours. The extent of absorption increases proportionally to the dose of Atorvastatin. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is attributed to presystemic clearance in the gastrointestinal mucosa and/or presystemic biotransformation in the liver. Although food reduces the rate and extent of absorption of the drug by approximately 25% and 9%, respectively, based on Cmax and AUC, the reduction in LDL-C is similar whether Atorvastatin is taken with or without food. When atorvastatin is administered in the evening, its plasma concentration is lower (approximately 30% for Cmax and AUC) than when administered in the morning. However, the reduction in LDL-C is the same regardless of the time of administration (see section 4.2).

Distribution. The mean volume of distribution of Livostor is approximately 381 liters. More than 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Livostor is able to penetrate into breast milk (see sections “Contraindications”, “Use during pregnancy or lactation” and “Special instructions”).

Metabolism. Levostor is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In in vitro studies, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites was equivalent to that of Levostor. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with active metabolites. In vitro studies indicate the importance of the metabolism of Levostor by cytochrome P450 3A4, which is consistent with the increased plasma concentrations of Levostor in humans after concomitant administration with erythromycin, a known inhibitor of this isoenzyme (see section 4.5).

Excretion: Levostor and its metabolites are excreted primarily in the bile after hepatic and/or extrahepatic metabolism, but the drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of Levostor from human plasma is approximately 14 hours, but the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. After oral administration, less than 2% of the dose is excreted in the urine.

Certain groups of patients.

Elderly patients. Plasma concentrations of Levostor are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly patients (aged 65 years and older) than in young adult patients. Clinical data suggest a greater degree of LDL-C reduction at any dose in elderly patients compared to young patients (see section 4.4).

Children: Pharmacokinetic data for pediatric patients are not available.

Gender: Plasma concentrations of Levostor in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in LDL-C reduction with Levostor in men and women.

Renal impairment: Renal disease does not affect the plasma concentrations of Levostor or the LDL-C reduction, and therefore no dose adjustment is required for patients with renal impairment (see sections 4.2 and 4.4).

Hemodialysis: Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase the clearance of Livostor, as the drug is highly bound to plasma proteins.

Hepatic impairment. Plasma concentrations of Levostor are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC are 4-fold higher in patients with Child-Pugh class A liver disease. In patients with Child-Pugh class B liver disease, Cmax and AUC are increased approximately 16-fold and 11-fold, respectively (see Contraindications).

Indication

Prevention of cardiovascular disease.

In adult patients without clinically evident coronary heart disease but with multiple risk factors for coronary heart disease, such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, Livostor is indicated for:

In patients with type 2 diabetes mellitus and without clinically significant coronary heart disease, but with multiple risk factors for coronary heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the drug Livostor is indicated for:

reducing the risk of myocardial infarction; reducing the risk of stroke.

In patients with clinically significant coronary heart disease, Livostor is indicated for:

reduced risk of non-fatal myocardial infarction; reduced risk of fatal and non-fatal stroke; reduced risk of revascularization procedures; reduced risk of hospitalization for congestive heart failure; reduced risk of angina.

Hyperlipidemia.

As an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides, and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).

As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to the Fredrickson classification).

For the treatment of patients with primary dysbetalipoproteinemia (type III according to the Fredrickson classification) in cases where diet is not effective enough.

To reduce total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.

As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B levels in boys and postmenarcheal girls aged 10 to 17 years with heterozygous familial hypercholesterolemia, if, after appropriate diet therapy, the test results are as follows:

LDL cholesterol remains ≥ 190 mg/dL or LDL cholesterol ≥ 160 mg/dL and: there is a family history of early cardiovascular disease or the patient has two or more other risk factors for cardiovascular disease as a child.

Contraindication

Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology. Hypersensitivity to any of the components of the drug.

Interaction with other medicinal products and other types of interactions

The risk of myopathy during statin treatment is increased by concomitant use of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or potent CYP 3A4 inhibitors (e.g. clarithromycin, HIV protease inhibitors, and itraconazole) (see sections 4.4 and 5.1).

Potent CYP 3A4 inhibitors. Livostor is metabolized by cytochrome P450 3A4. Concomitant use of Livostor with potent CYP 3A4 inhibitors may result in increased plasma concentrations of atorvastatin. The extent of interaction and potentiation depend on the variability of the effect on CYP 3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use of these medicinal products with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended.

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to evaluate the effects of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity, and therefore, co-administration of these medicinal products with atorvastatin may result in increased exposure to atorvastatin. Therefore, lower maximum doses of atorvastatin should be considered when atorvastatin is co-administered with these moderate CYP3A4 inhibitors. Clinical monitoring of the patient is also recommended. Clinical monitoring of the patient is recommended after initiation of treatment with an inhibitor or after dose adjustment.

Clarithromycin: Atorvastatin AUC was significantly increased when clarithromycin (500 mg twice daily) was co-administered with atorvastatin 80 mg compared to atorvastatin alone (see section 5.1). Therefore, atorvastatin doses above 20 mg should be used with caution in patients receiving clarithromycin (see sections 4.4 and 4.2).

Combination of protease inhibitors. The AUC of atorvastatin is significantly increased when Livostor is co-administered with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to Livostor alone (see section 5.1). Therefore, for patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C protease inhibitor telaprevir, co-administration with Livostor should be avoided. The drug should be prescribed with caution to patients taking the HIV protease inhibitor lopinavir + ritonavir and used at the lowest effective dose. For patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, the dose of Livostor should not exceed 20 mg; Caution should be exercised when using them together (see sections "Special instructions for use" and "Method of administration and dosage"). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of Livostor should not exceed 40 mg; careful clinical monitoring of patients is also recommended.

Itraconazole: The AUC of atorvastatin is significantly increased when Livostor 40 mg is co-administered with itraconazole 200 mg (see section 5.1). Therefore, caution should be exercised when Livostor doses exceed 20 mg in patients taking itraconazole (see sections 4.4 and 4.2).

Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. OATP1B1 inhibitors (e.g. cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin is significantly increased when Livostor 10 mg is co-administered with cyclosporine 5.2 mg/kg/day compared to Livostor alone (see section 5.1). Concomitant use of Livostor and cyclosporine should be avoided (see section 4.4).

Medical recommendations for the use of interacting drugs are summarized in the table (see also sections “Method of administration and dosage”, “Special instructions for use”, “Pharmacological properties”).

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis.

*Use with caution and in the lowest effective dose.

Gemfibrozil: Due to the increased risk of myopathy/rhabdomyolysis with the concomitant use of HMG-CoA reductase inhibitors with gemfibrozil, the concomitant use of Levostor with gemfibrozil should be avoided (see section 4.4).

Other fibrates: Since the risk of myopathy during treatment with HMG-CoA reductase inhibitors is known to be increased by concomitant use of other fibrates, Levostor should be used with caution when used concomitantly with other fibrates (see section 4.4).

Niacin: The risk of skeletal muscle adverse events may be increased when the drug is used in combination with niacin, and therefore, in such conditions, a dose reduction of Livostor should be considered (see section 4.4).

Diltiazem hydrochloride: Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Cimetidine: No evidence of interaction between atorvastatin and cimetidine has been identified.

Antacids: Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxides results in a decrease in plasma concentrations of atorvastatin by approximately 35%. The lipid-lowering effects of atorvastatin are not altered.

Colestipol. Plasma concentrations of atorvastatin are lower (approximately 25%) when atorvastatin and colestipol are coadministered. The lipid-lowering effect of the combination of atorvastatin and colestipol is greater than that of either drug alone.

Azithromycin. Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) is not accompanied by changes in atorvastatin plasma concentrations.

Transporter protein inhibitors. Transporter protein inhibitors (e.g., cyclosporine) may increase systemic exposure to atorvastatin. The effect of inhibition of storage transporters on atorvastatin concentrations in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended.

Ezetimibe: Ezetimibe monotherapy has been associated with muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring is recommended in these patients.

Fusidic acid. Interaction studies between atorvastatin and fusidic acid have not been conducted. As with other statins, muscular disorders (including rhabdomyolysis) have been reported with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction is unknown. Patients should be monitored closely and temporary discontinuation of atorvastatin may be necessary.

Digoxin: Concomitant administration of multiple doses of Livostor and digoxin increases steady-state plasma concentrations of digoxin by approximately 20%. Patients receiving digoxin should be monitored closely.

Oral contraceptives. Concomitant use of Levostor with oral contraceptives increases the AUC values for norethisterone and ethinylestradiol (see section "Pharmacological properties"). This information should be taken into account when choosing an oral contraceptive for a woman using Levostor.

Warfarin: Levostor has no clinically significant effect on prothrombin time when administered to patients receiving long-term warfarin therapy.

Colchicine: Myopathy, including rhabdomyolysis, has been reported with concomitant use of atorvastatin with colchicine, and therefore atorvastatin should be administered with caution with colchicine.

Other medicinal products. Concomitant use of atorvastatin and antihypertensive medicinal products and its use during estrogen replacement therapy was not accompanied by clinically significant side effects. Interaction studies of atorvastatin with other medicinal products have not been conducted.

Application features

Skeletal muscles.

There have been isolated reports of rhabdomyolysis with acute renal failure secondary to myoglobinuria with the use of Levostor and other drugs of this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle disorders.

Atorvastatin, like other statins, has occasionally been associated with myopathy, defined as muscle pain or weakness in association with an elevation of creatine phosphokinase (CPK) levels greater than 10 times the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain drugs, such as cyclosporine and potent CYP3A4 inhibitors (e.g. clarithromycin, itraconazole, and HIV protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

The possibility of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness and/or a significant increase in CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever, or if signs and symptoms of muscle disease persist after discontinuation of Levostor. Treatment with the drug should be discontinued in the event of a significant increase in CPK, diagnosis of myopathy or suspicion of it.

The risk of myopathy during treatment with drugs of this class is increased with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or azole antifungals. Physicians considering the combination of Livostor and fibric acid derivatives, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and monitor patients closely for any signs or symptoms of muscle pain, tenderness, or weakness, especially during the first months of therapy and during any up-titration periods of either drug. Low initial and maintenance doses of atorvastatin should be considered when co-administered with the above-mentioned drugs (see Interactions). In such situations, periodic CPK determination may be considered, but there is no guarantee that such monitoring will help prevent cases of severe myopathy.

Myopathy, including rhabdomyolysis, has been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin should be administered with caution to patients receiving colchicine (see section 4.5).

Levostor therapy should be temporarily or permanently discontinued in any patient with an acute, serious condition suggestive of myopathy or in the presence of a risk factor for renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, and uncontrolled seizures).

Liver dysfunction.

Statins, like some other lipid-lowering agents, are known to be associated with abnormal liver function tests. It is recommended that liver enzyme tests be obtained prior to initiating therapy with Livostor and repeated as clinically indicated. There have been isolated reports of fatal and non-fatal hepatic failure in patients treated with statins, including atorvastatin. In the event of severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during treatment with Livostor, treatment should be discontinued immediately. Unless an alternative etiology is identified, treatment with the drug should not be restarted.

Levostor should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Levostor is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section 4.3).

Endocrine function.

Increased HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Livostor.

Statins inhibit cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Atorvastatin does not reduce basal plasma cortisol levels and does not impair adrenal reserve. The effect of statins on sperm fertilisation has not been studied in a sufficient number of patients. It is not known how, or if, the drug affects the gonad-pituitary-hypothalamic axis in premenopausal women. Caution should be exercised when co-administering statins with drugs that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

Use in elderly patients.

Since older age (over 65 years) is a predisposing factor for myopathy, Levostor should be prescribed with caution to elderly patients.

Liver failure.

Levostor is contraindicated in patients with active liver disease, including persistent elevations of hepatic transaminases of unknown etiology (see sections "Contraindications" and "Pharmacological properties").

Atorvastatin should be used with caution in patients with a predisposition to rhabdomyolysis. Before initiating statin treatment in patients with a predisposition to rhabdomyolysis, creatine kinase (CK) levels should be measured in:

impaired renal function; hypothyroidism; hereditary disorders of the muscular system in the family or personal history; previous cases of toxic effects of statins or fibrates on muscles; previous liver disease and/or consumption of large amounts of alcohol.

For elderly patients (over 70 years of age), the need for these measures should be assessed taking into account the presence of other predisposing factors for the development of rhabdomyolysis.

An increase in the level of the drug in the blood plasma is possible, in particular, in the case of interaction and use in special groups of patients, including patients with hereditary diseases.

In such cases, it is recommended to assess the risk-benefit ratio of treatment and conduct clinical monitoring of the patient. If the CK level is significantly elevated (more than 5 times the upper limit of normal (ULN)) before starting treatment, treatment should not be started.

Measurement of creatine kinase levels.

Creatine kinase levels should not be measured after strenuous exercise or in the presence of any possible alternative causes of elevated CK levels, as this may complicate interpretation of the results. If CK levels are significantly elevated at baseline (>5 times the upper limit of normal), repeat testing should be performed in 5-7 days to confirm the result.

During treatment.

Patients should be advised to immediately report the development of muscle pain, cramps, or weakness, especially when accompanied by malaise or fever.

If these symptoms occur during treatment with atorvastatin, the patient's CK level should be determined. If the CK level is significantly elevated (more than 5 times the upper limit of normal), treatment should be discontinued.

Discontinuation of treatment should also be considered if the CK level is less than five times the upper limit of normal, but muscle symptoms are severe and cause daily discomfort.

After symptoms resolve and CK levels normalize, resuming atorvastatin treatment or initiating treatment with an alternative statin may be considered, provided that the lowest possible dose of the drug is used and the patient is closely monitored.

Atorvastatin treatment should be discontinued if a clinically significant increase in CK levels is observed (more than 10 times the upper limit of normal) or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medications.

The risk of rhabdomyolysis is increased when atorvastatin is used concomitantly with certain medicinal products that may increase atorvastatin plasma concentrations. Examples of such medicinal products include potent inhibitors of CYP3A4 or transport proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir. Concomitant use with gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe also increases the risk of myopathy. If possible, other medicinal products (that do not interact with atorvastatin) should be used instead of the above.

If concomitant treatment with atorvastatin and these medicinal products is necessary, the benefits and risks of concomitant treatment should be carefully weighed. If patients are taking medicinal products that increase the plasma concentration of atorvastatin, it is recommended to reduce the dose of atorvastatin to the minimum required. In addition, in the case of the use of potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered. It is also recommended that