Instructions for Atoris film-coated tablets 20 mg No. 30
Composition
active ingredient: atorvastatin;
1 film-coated tablet contains 10 mg, 20 mg, 40 mg of atorvastatin in the form of atorvastatin calcium;
excipients:
10 mg, 20 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate;
shell: talc, polyvinyl alcohol, macrogol 3000, titanium dioxide (E 171);
40 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, crospovidone, magnesium stearate;
shell: hypromellose, macrogol 400, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: white, round, slightly convex, film-coated tablets.
Pharmacotherapeutic group
Lipid-lowering agents. HMG-CoA reductase inhibitors. Atorvastatin. ATC code C10A A05.
Pharmacological properties
Pharmacodynamics
The drug contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, which is a precursor of sterols, in particular cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) molecules, enter the blood plasma and are transported to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolized mainly by interaction with high-affinity LDL receptors (LDL receptors).
Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL.
Atorvastatin reduces LDL formation and LDL particle number. Atorvastatin causes a marked and sustained increase in LDL receptor activity combined with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, a group that has not always responded to lipid-lowering therapy.
In addition to its effect on plasma lipids, atorvastatin has other effects that enhance its antiatherosclerotic effect. It inhibits the synthesis of isoprenoids - substances that act as growth factors on the proliferation of vascular smooth muscle cells, reduces plasma viscosity and the activity of some coagulation and aggregation factors. Due to this action, it improves hemodynamics and contributes to the normalization of blood coagulation processes. In addition, HMG-CoA reductase inhibitors affect the metabolism of macrophages and, thus, inhibit their activation, which reduces the risk of rupture of atherosclerotic plaques.
Atorvastatin has been shown to reduce total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), with variable increases in HDL-C and apolipoprotein A in a dose-response study. These results are consistent with data in patients with heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus.
It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and mortality from cardiovascular disease.
Pharmacokinetics
Absorption
Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentrations within 1–2 hours. The extent of absorption and plasma concentrations of atorvastatin depend on the dose of atorvastatin. The bioavailability of atorvastatin in tablet form compared to the solution is 95 and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 12–14%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during first-pass metabolism in the liver.
Distribution
The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is >98%. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes.
Metabolism
Atorvastatin is extensively metabolized to form ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro, ortho- and parahydroxylated metabolites exhibit inhibitory activity against HMG-CoA reductase equivalent to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.
Atorvastatin and its metabolites are mainly excreted in the bile after hepatic and/or extrahepatic biotransformation, but do not undergo gastrohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. Inhibitory activity against HMG-CoA reductase is maintained for 20–30 hours due to the presence of active metabolites. After oral administration, less than 2% of the dose is excreted in the urine.
Atorvastatin is a substrate of the hepatic transporters organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin has also been identified as a substrate of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.
Patient populations
Elderly patients
Plasma concentrations of atorvastatin in healthy elderly volunteers (aged
> 65 years) was higher than in younger patients, while the lipid-lowering effects were comparable to those observed in younger patients.
Children
Apparent oral clearance of atorvastatin in children was similar to that in adults when scaled allometrically for body weight, as body weight was the only significant covariate in a population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 6 to 17 years).
Sex
The plasma concentration of atorvastatin in women differs from that in men (the maximum plasma concentration (Cmax) is approximately 20% higher and the area under the curve (AUC) is 10% lower). However, these differences are not clinically significant, and the lipid-lowering effect of the drug in men and women is almost the same.
Kidney failure
Renal disease does not affect the plasma concentrations or lipid-lowering effects of atorvastatin and its active metabolites.
Hemodialysis: Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase clearance of the drug, as atorvastatin is extensively bound to plasma proteins.
Liver failure
Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values 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 values are increased approximately 16-fold and 11-fold, respectively (see Contraindications).
Indication
Prevention of cardiovascular disease
In adult patients without clinically significant coronary heart disease (CHD) but with multiple risk factors for CHD, such as older age, smoking, hypertension, low HDL, or a family history of early CHD, the drug is indicated for:
- reducing the risk of myocardial infarction;
- reducing the risk of stroke;
- reducing the risk of angina and the need for myocardial revascularization procedures.
In patients with type 2 diabetes mellitus and without clinically significant coronary heart disease, but with several risk factors for the development of coronary heart disease, such as retinopathy, albuminuria, smoking or arterial hypertension, the drug is indicated for:
- reducing the risk of myocardial infarction;
- reducing the risk of stroke.
In patients with clinically significant ischemic heart disease, the drug is indicated for:
- reducing the risk of non-fatal myocardial infarction;
- reducing the risk of fatal and non-fatal stroke;
- reducing the risk of the need for myocardial revascularization procedures;
- reducing the risk of hospitalization due to congestive heart failure;
- reducing the risk of angina pectoris.
Hyperlipidemia
- Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to the Fredrickson classification). As an adjunct to diet to reduce elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B and triglycerides, and to increase high-density lipoprotein cholesterol (HDL-C).
- Hypertriglyceridemia (type IV according to the Fredrickson classification). As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels.
- Primary dysbetalipoproteinemia (type III according to the Fredrickson classification). For the treatment of patients when diet is not effective enough.
- Homozygous familial hypercholesterolemia. To reduce total cholesterol and LDL-C as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
- Heterozygous familial hypercholesterolemia in pediatric patients (aged 10-17 years). As an adjunct to diet to reduce LDL-C, LDL-C and apolipoprotein B levels in adolescent boys and postmenarcheal girls aged 10 to 17 years, if, after appropriate diet therapy, the test results are as follows:
b) LDL cholesterol ≥ 160 mg/dL (≥ 4.14 mmol/L) and:
family history of early cardiovascular disease or
two or more other risk factors for cardiovascular disease are present in the pediatric patient.
Contraindication
Hypersensitivity to any ingredient of the drug.
Liver disease in the acute phase or a persistent increase (of unknown origin) in serum transaminase levels by 3 times or more.
The drug is contraindicated in pregnant women, women who are breastfeeding, and women of reproductive age who do not use adequate contraception (see section "Use during pregnancy or breastfeeding").
Treatment with antiviral drugs glecaprevir/pibrentasvir against hepatitis C.
Interaction with other medicinal products and other types of interactions
Atorvastatin is a substrate of CYP3A4 and transporters (e.g. OATP1B1/1B3, P-gp or BCRP). Plasma levels of atorvastatin may be significantly increased by concomitant use of inhibitors of CYP3A4 and transporters. Table 1 lists drugs that may increase the exposure of Atoris® and the risk of myopathy and rhabdomyolysis with concomitant use, and recommendations for the treatment and prevention of such risks (see sections 4.4 and 5.1).
Table 1
Interaction of the drug Atoris® with other drugs, which increases the risk of developing myopathy and rhabdomyolysis Atoris®.
| Cyclosporine or gemfibrozil |
| Clinical impact | Plasma levels of atorvastatin were significantly increased when ATORIS was co-administered with cyclosporine, an inhibitor of CYP3A4 and OATP1B1 (see section 5.1). Monotherapy with gemfibrozil may cause myopathy. There is an increased risk of myopathy and rhabdomyolysis when ATORIS is co-administered with cyclosporine or gemfibrozil. |
| Activities | The simultaneous use of cyclosporine or gemfibrozil with Atoris® is not recommended. |
| Antivirals |
| Clinical impact | Plasma levels of atorvastatin were significantly increased when Atoris was co-administered with many antiviral agents that are inhibitors of CYP3A4 and/or transporters (e.g. BCRP, OATP1B1/1B3, P-gp, MRP2, OAT2) (see section 5.1). Myopathy and rhabdomyolysis have been reported with the concomitant use of ledipasvir + sofosbuvir with Atoris. |
| Activities | · The simultaneous use of the combination of tipranavir + ritonavir or glecaprevir + pibrentasvir with the drug Atoris® is not recommended. · In patients receiving lopinavir + ritonavir or simeprevir, the benefit/risk of co-administration with atorvastatin should be assessed. In patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir or letermovir, the dose of Atoris® should not exceed 20 mg. In patients receiving nelfinavir, the dose of Atoris® should not exceed 40 mg (see section “Method of administration and dosage”). · It is necessary to assess the benefit/risk of concomitant use of the combination of ledipasvir + sofosbuvir with the drug Atoris®. · All patients should be monitored for signs and symptoms of myopathy, especially at the beginning of treatment and during dose increases of any drug. |
| Examples | Tipranavir + ritonavir, glecaprevir + pibrentasvir, lopinavir + ritonavir, simeprevir, saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir, nelfinavir, and ledipasvir + sofosbuvir. |
| Certain azole antifungals or macrolide antibiotics |
| Clinical impact | Plasma levels of atorvastatin were significantly increased when Atoris was co-administered with certain azole antifungals or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters (see section 5.1). |
| Activities | In patients receiving clarithromycin or itraconazole, the dose of Atoris® should not exceed 20 mg (see section "Dosage and Administration"). The benefit/risk of concomitant use of individual azole antifungals or macrolide antibiotics with Atoris® should be assessed. All patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of any drug. |
| Examples | Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. |
| Niacin |
| Clinical impact | Cases of myopathy and rhabdomyolysis have been observed with the simultaneous use of lipid-modifying doses of niacin (> 1 g/day of niacin) with the drug Atoris®. |
| It should be considered whether the benefit of concomitant use of lipid-modifying doses of niacin with Atoris® outweighs the increased risk of myopathy and rhabdomyolysis. If a decision is made to co-administer, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug. |
| Fibrates (except gemfibrozil) |
| Clinical impact | The use of fibrates as monotherapy can cause myopathy. The risk of myopathy and rhabdomyolysis is increased when fibrates are used concomitantly with Atoris®. |
| Activities | It is necessary to consider whether the benefit of concomitant use of fibrates with Atoris® outweighs the increased risk of myopathy and rhabdomyolysis. If a decision is made to co-administer fibrates, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug. |
| Colchicine |
| Clinical impact | Cases of myopathy and rhabdomyolysis have been observed during the simultaneous use of colchicine with the drug Atoris®. |
| Activities | The benefits/risks of concomitant use of colchicine with Atoris® should be weighed. If a decision is made to co-administer colchicine, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug. |
| Grapefruit juice |
| Clinical impact | Consumption of grapefruit juice, especially in large quantities (more than 1.2 liters per day), may lead to increased plasma levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis. |
| Activities | Consumption of large amounts of grapefruit juice (more than 1.2 liters per day) should be avoided while taking Atoris®. |
Table 2
Interaction with drugs that may reduce the exposure of the drug Atoris®
| Rifampicin |
| Clinical impact | Concomitant use of Atoris® with rifampicin, an inducer of cytochrome P450 3A4 and an inhibitor of OATP1B1, may result in an unstable decrease in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, delayed administration of Atoris® after rifampicin administration was associated with a significant decrease in atorvastatin plasma concentrations. |
| Activities | The simultaneous use of Atoris® and rifampicin is recommended. |
Table 3
The effect of the drug Atoris® on other drugs
| Oral contraceptives |
| Clinical impact | Concomitant use of Atoris® and oral contraceptives increased the concentration of norethisterone and ethinyl estradiol in blood plasma (see section "Pharmacological properties"). |
| Activities | This fact should be taken into account when choosing an oral contraceptive for patients taking Atoris®. |
| Digoxin |
| Clinical impact | With simultaneous use of multiple doses of the drug Atoris® and digoxin, the equilibrium plasma concentrations of digoxin increase (see section "Pharmacological properties"). |
| Activities | Patients taking digoxin should be monitored appropriately. |
Diltiazem hydrochloride.
Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.
Cimetidine.
As a result of the conducted studies, no signs of interaction between atorvastatin and cimetidine were detected.
Antacids.
Simultaneous oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide is accompanied by a decrease in the concentration of atorvastatin in the blood plasma by approximately 35%. The hypolipidemic effect of atorvastatin was not changed.
Azithromycin
Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not accompanied by changes in atorvastatin plasma concentrations.
Transport protein inhibitors
Transporter protein inhibitors may increase systemic exposure to atorvastatin (see Table 1). Cyclosporine and letermovir are inhibitors of transporters involved in the distribution of atorvastatin, including OATP1B1/1B3, P-gp, and BCRP, resulting in systemic exposure to atorvastatin (see Table 1). The effect of inhibition of storage transporters on atorvastatin exposure in liver cells is unknown. If co-administration cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).
The use of atorvastatin in patients taking letermovir concomitantly with cyclosporine is not recommended (see Precautions).
The use of fibrates as monotherapy is associated with the development of muscular events, including rhabdomyolysis. The risk of such events may be increased by concomitant administration of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin should be used to achieve a therapeutic dose and patients should be monitored appropriately (see section 4.4).
Ezetimibe
The use of ezetimibe as monotherapy has been associated with the development of muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is recommended.
Colestipol
Plasma concentrations of atorvastatin were lower (approximately 25%) when atorvastatin and colestipol were coadministered. The lipid-lowering effects of the combination of atorvastatin and colestipol were greater than those of either drug alone.
Fusidic acid
Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle-related events (including rhabdomyolysis) have been reported in the post-marketing setting with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction remains unknown. Patients should be monitored closely and temporary discontinuation of atorvastatin may be necessary.
Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin should be prescribed with caution with colchicine.
Effect of atorvastatin on concomitant medications
Digoxin
When multiple doses of the drug are administered simultaneously with digoxin, steady-state plasma concentrations of digoxin increase by approximately 20%. Patients taking digoxin should be monitored closely.
Oral contraceptives
Concomitant use of atorvastatin with oral contraceptives has been shown to increase plasma concentrations of norethisterone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin
In a clinical study in patients receiving long-term warfarin therapy, co-administration of 80 mg of atorvastatin daily with warfarin resulted in a small decrease (approximately 1.7 seconds) in prothrombin time during the first 4 days of therapy, but this index returned to normal within the next 15 days of atorvastatin therapy. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before initiating atorvastatin therapy in patients receiving coumarin anticoagulants and quite often at the beginning of therapy to confirm that there is no significant change in the index. Once a stable prothrombin time has been established, the index can be monitored at intervals usually recommended for patients receiving coumarin anticoagulants. In the event of discontinuation of therapy or a change in the dose of atorvastatin, this procedure should be repeated. In patients not taking anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.
Application features
Myopathy and rhabdomyolysis
The drug may cause myopathy (muscle pain, tenderness, or weakness in association with an elevation of creatine kinase (CK) greater than 10 times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare cases of fatal rhabdomyolysis have been reported with statins, including Atoris®.
Risk factors for developing myopathy
Risk factors for the development of myopathy include age 65 years and older, uncontrolled hypothyroidism, impaired renal function, concomitant use with certain other drugs, and use of increased doses of Atoris® (see section “Interaction with other medicinal products and other types of interactions”).
Exposure to Atoris® may be increased by interactions with other drugs through inhibition of the cytochrome P450 3A4 enzyme (CYP3A4) and/or transporters (e.g., breast cancer resistance protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3], P-glycoprotein [P-gp]), which increases the risk of myopathy and rhabdomyolysis. Concomitant use of Atoris® with cyclosporine, gemfibrozil, tipranavir + ritonavir or glecaprevir + pibrentasvir is not recommended. Dosage adjustments with Atoris® are recommended in patients taking certain antivirals, azole antifungals, or macrolide antibiotics (see section 4.2). Myopathy/rhabdomyolysis has been reported with concomitant use of atorvastatin with lipid-modifying doses (> 1 g/day) of niacin, fibrates, colchicine, and the combination of ledipasvir + sofosbuvir. It should be assessed whether the benefit of using these drugs outweighs the increased risk of myopathy and rhabdomyolysis (see section 4.5).
The simultaneous intake of grapefruit juice in large quantities (more than 1.2 liters per day) is not recommended for patients taking Atoris® (see section “Interaction with other medicinal products and other types of interactions”).
Atoris® should be discontinued if markedly elevated CK levels are observed or myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve after discontinuation of atorvastatin. Atoris® should be temporarily discontinued in patients with acute or serious conditions at high risk of developing renal failure caused by rhabdomyolysis (e.g. sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine or electrolyte disturbances; uncontrolled epilepsy).
Patients should be informed of the risk of myopathy and rhabdomyolysis at the beginning of treatment or when the dose of Atoris® is increased. Patients should be advised to immediately report any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.
Immune-mediated necrotizing myopathy
Rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with some statins. Clinically, IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin therapy; positive HMG-CoA reductase antibodies; muscle biopsy reveals necrotizing myopathy and improvement with immunosuppressants. Additional neuromuscular and serological studies may be necessary. Immunosuppressant therapy may be required. The risk of IMNM should be carefully weighed before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.
Liver dysfunction
It is recommended that liver enzyme tests be obtained before initiating therapy and periodically thereafter. Patients who develop symptoms suggestive of liver injury should have liver function tests performed. Patients who develop elevated transaminases should have liver function monitored until the abnormalities resolve. If persistent elevations of serum transaminases to 3 or more times the upper limit of normal (ULN) occur, discontinuation of therapy is recommended (see Adverse Reactions).
Atorvastatin should be prescribed with caution to patients who abuse alcohol and/or have a history of liver disease.
Stroke Prevention by Dramatically Lowering Cholesterol Levels (SPARCL)
In a post-hoc analysis of stroke subtypes in patients without coronary artery disease (CAD) who had a recent stroke or transient ischemic attack (TIA), a higher rate of hemorrhagic stroke was reported in the atorvastatin 80 mg group compared with the placebo group. The increased risk was particularly pronounced in patients with prior hemorrhagic stroke or lacunar infarction at study entry. For patients with prior hemorrhagic stroke or lacunar infarction, the balance of risks and benefits of atorvastatin 80 mg has not been established, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment.
Skeletal muscles
Atorvastatin, like other HMG-CoA reductase inhibitors, may occasionally affect skeletal muscle and cause myalgia, myositis, and myopathy, which may progress to rhabdomyolysis, a potentially life-threatening condition characterized by markedly elevated creatine kinase (CK) levels (> 10 times the upper limit of normal), myoglobinemia, and myoglobinuria, which may lead to renal failure.
Before starting treatment
- impaired kidney function;
- hypothyroidism;
- hereditary disorders of the muscular system in family or personal history;
- previous cases of muscle toxicity from statins or fibrates;
- past history of liver disease and/or alcohol abuse;
When treating 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.
Increased plasma levels of the drug are possible, in particular, in the event of interaction (see section "Interaction with other medicinal products and other types of interactions") and use in special groups of patients, including patients with hereditary diseases (see section "Pharmacokinetics").
In such cases, it is recommended to assess the risk-benefit ratio of treatment and conduct clinical monitoring of the patient's condition.
If the CK level is significantly elevated before the start of treatment (exceeds the ULN by more than
5 times), treatment should not be started.
Creatine kinase level measurement
The CK level should not be measured after intense exercise or in the presence of any possible alternative causes of the CK level increase, as this may complicate the interpretation of the results. If the CK level is significantly elevated at baseline (more than 5 times the ULN), a repeat measurement should be performed after 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 ULN), treatment should be discontinued.
- The feasibility of stopping treatment should also be considered if the increase in CK levels does not reach 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 starting an alternative statin may be considered, provided the lowest possible dose 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, such as potent CYP3A4 inhibitors or transport proteins (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, strypentol, ketoconazole, voriconazole, itraconazole, posaconazole, ritonavir and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc.). The risk of myopathy may also be increased with concomitant use of gemfibrozil and other fibric acid derivatives, antiviral agents for the treatment of hepatitis C (HCV) (e.g. boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin or ezetimibe. If possible, alternative (non-interacting) treatments should be considered instead of these medications.
If concomitant treatment with atorvastatin and these drugs is necessary, the benefits and risks of their concomitant use should be carefully weighed. If patients are taking drugs that increase the concentration of atorvastatin in the blood plasma, it is recommended to reduce the dose of atorvastatin to the minimum. In addition, in the case of the use of potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered and appropriate clinical monitoring of these patients should be carried out (see section "Interaction with other medicinal products and other forms of interaction").
Atorvastatin should not be used concomitantly with systemic fusidic acid or within 7 days of stopping fusidic acid. In patients for whom fusidic acid treatment is considered essential, statin therapy should be discontinued for the duration of fusidic acid treatment. Rhabdomyolysis (including some fatalities) has been reported in patients receiving fusidic acid and statins concomitantly (see section 4.5). Patients should seek medical advice immediately if they experience muscle weakness, pain or tenderness.
Statin therapy can be resumed 7 days after
