Atoris
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Atoris® (Atoris®)
Composition:
Active substance: atorvastatin;
One film-coated tablet contains 10 mg, 20 mg, or 40 mg of atorvastatin as atorvastatin calcium;
Excipients:
10 mg, 20 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate;
Coating: talc, polyvinyl alcohol, macrogol 3000, titanium dioxide (E 171);
40 mg: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, crospovidone, magnesium stearate;
Coating: hypromellose, macrogol 400, titanium dioxide (E 171).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white, round, slightly convex, film-coated tablets.
Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors. Atorvastatin. ATC code C10AA05.
Pharmacological properties.
Pharmacodynamics.
The medicinal product contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase — the enzyme that determines the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoprotein (VLDL) particles, enter the blood plasma, and are transported to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily via interaction with high-affinity LDL receptors (LDL receptors).
Atorvastatin reduces plasma concentrations of cholesterol and serum lipoprotein by inhibiting HMG-CoA reductase, thereby suppressing cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, resulting in enhanced uptake and catabolism of LDL.
Atorvastatin reduces the formation of LDL and the number of LDL particles. Atorvastatin induces a pronounced and sustained increase in LDL receptor activity in combination with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia — a group that has not always responded to therapy with lipid-lowering agents.
In addition to its effects on plasma lipids, atorvastatin has other effects that enhance its antiatherosclerotic action. It inhibits the synthesis of isoprenoids — substances that act as growth factors for vascular smooth muscle cell proliferation — and reduces plasma viscosity and the activity of certain coagulation and aggregation factors. Through these actions, it improves hemodynamics and promotes normalization of blood coagulation processes. Furthermore, HMG-CoA reductase inhibitors affect macrophage metabolism and thereby suppress their activation, reducing the risk of atherosclerotic plaque rupture.
It has been demonstrated that atorvastatin reduces total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), while causing variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A levels in dose-response studies. These results are consistent with data from patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.
It has been established that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and cardiovascular mortality.
Pharmacokinetics.
Absorption
Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentration within 1–2 hours. The extent of absorption and plasma concentration of atorvastatin is dose-dependent. The bioavailability of atorvastatin in tablet form compared to solution is 95% and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 12–14%, and 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 through the liver.
Distribution
The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is > 98%. The blood-to-plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes.
Metabolism
Atorvastatin is extensively metabolized, forming ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro, ortho- and para-hydroxylated metabolites exhibit HMG-CoA reductase inhibitory activity equivalent to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% attributable to the activity of circulating metabolites.
Elimination
Atorvastatin and its metabolites are primarily excreted in bile following hepatic and/or extrahepatic biotransformation, but do not undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. The inhibitory activity against HMG-CoA reductase persists for 20–30 hours due to the presence of active metabolites. Less than 2% of the dose is excreted in urine after oral administration.
Atorvastatin is a substrate of hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also 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 (age > 65 years) are higher than in younger individuals, whereas the lipid-lowering effects are comparable to those observed in younger patients.
Children
Apparent oral clearance of atorvastatin in children was found to be similar to that in adults when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin, which included data from children with heterozygous familial hypercholesterolemia (aged 6 to 17 years).
Gender
Plasma concentrations of atorvastatin differ between women and men (peak plasma concentration (Cmax) is approximately 20% higher in women, while the area under the curve (AUC) is 10% lower). However, these differences are not clinically significant, and the lipid-lowering effect of the drug is nearly identical in men and women.
Renal impairment
Renal disease does not affect plasma concentrations or lipid-lowering effects of atorvastatin and its active metabolites.
Hemodialysis. Although clinical studies have not been conducted in patients with end-stage renal disease, hemodialysis is not considered to significantly enhance drug clearance, as atorvastatin is extensively bound to plasma proteins.
Hepatic impairment
Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values are four times 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 section «Contraindications»).
Clinical characteristics.
Indications.
Prevention of cardiovascular diseases
For adult patients without clinically evident ischemic heart disease (IHD), but with multiple risk factors for IHD such as advanced age, smoking, arterial hypertension, low HDL-C levels, or a family history of premature IHD, the drug is indicated for:
- reducing the risk of myocardial infarction;
- reducing the risk of stroke;
- reducing the risk of angina pectoris and the need for myocardial revascularization procedures.
For patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for IHD such as retinopathy, albuminuria, smoking, or arterial hypertension, the drug is indicated for:
- reducing the risk of myocardial infarction;
- reducing the risk of stroke.
For patients with clinically evident 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 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 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, as well as to increase high-density lipoprotein cholesterol (HDL-C) levels.
- Hypertriglyceridemia (type IV according to Fredrickson classification). As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels.
- Primary dysbetalipoproteinemia (type III according to Fredrickson classification). For treatment of patients when dietary measures are insufficiently effective.
- Homozygous familial hypercholesterolemia. To reduce total cholesterol and LDL-C as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.
- Heterozygous familial hypercholesterolemia in pediatric patients (aged 10–17 years). As an adjunct to diet to reduce levels of TC, LDL-C, and apolipoprotein B in adolescent boys and girls after onset of menstruation aged 10 to 17 years, if after appropriate dietary therapy laboratory results are as follows:
a) LDL-C remains ≥ 190 mg/dL (≥ 4.91 mmol/L), or
b) LDL-C ≥ 160 mg/dL (≥ 4.14 mmol/L) and:
- a family history of premature cardiovascular disease, or
- two or more other cardiovascular risk factors are present in the pediatric patient.
Contraindications.
- Hypersensitivity to any component of the medicinal product.
- Active liver disease or persistent elevations (of unknown etiology) in serum transaminase levels by three times or more the upper limit of normal.
- The drug is contraindicated in pregnant women, women who are breastfeeding, and women of reproductive potential who are not using appropriate contraceptive methods (see section "Use in pregnancy or breastfeeding").
- Concomitant use with the hepatitis C antiviral drugs glecaprevir/pibrentasvir.
Interaction with other medicinal products and other forms of interaction.
Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Plasma levels of atorvastatin may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Table 1 lists medicinal products that may increase exposure to the medicinal product Atoris® and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for managing and preventing such risks (see sections "Special precautions for use" and "Pharmacological properties").
Table 1
Interaction of the medicinal product Atoris® with other medicinal products that increases the risk of myopathy and rhabdomyolysis with Atoris®.
| Cyclosporine or gemfibrozil |
|
| Clinical effect |
Plasma levels of atorvastatin were significantly increased when Atoris® was co-administered with cyclosporine, an inhibitor of CYP3A4 and OATP1B1 (see section "Pharmacological properties"). Monotherapy with gemfibrozil may cause myopathy. There is an increased risk of developing myopathy and rhabdomyolysis when cyclosporine or gemfibrozil are used concomitantly with Atoris®. |
| Actions |
Concomitant use of cyclosporine or gemfibrozil with Atoris® is not recommended. |
| Antiviral agents |
|
| Clinical effect |
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 "Pharmacological properties"). Cases of myopathy and rhabdomyolysis have been reported with concomitant use of the combination ledipasvir + sofosbuvir with Atoris®. |
| Actions |
|
| Examples |
Tipranavir + ritonavir, glecaprevir + pibrentasvir, lopinavir + ritonavir, simeprevir, saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir, nelfinavir, and ledipasvir + sofosbuvir. |
| Specific azole antifungals or macrolide antibiotics |
|
| Clinical effect |
Plasma levels of atorvastatin were significantly increased when Atoris® was co-administered with specific azole antifungals or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters (see section "Pharmacological properties"). |
| Actions |
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 specific azole antifungals or macrolide antibiotics with Atoris® should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the beginning of therapy and during dose escalation of any agent. |
| Examples |
Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. |
| Niacin |
|
| Clinical effect |
Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid-modifying doses of niacin (>1 g/day niacin) with Atoris®. |
| Actions |
Consider 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 use them concomitantly, monitor patients for signs and symptoms of myopathy, especially at the start of therapy and during dose escalation of either agent. |
| Fibrates (other than gemfibrozil) |
|
| Clinical effect |
Use of fibrates as monotherapy may cause myopathy. The risk of developing myopathy and rhabdomyolysis increases with concomitant use of fibrates and Atoris®. |
| Actions |
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 use them concomitantly, monitor patients for signs and symptoms of myopathy, especially at the start of therapy and during dose escalation of either agent. |
| Colchicine |
|
| Clinical effect |
Cases of myopathy and rhabdomyolysis have been observed during concomitant use of colchicine with Atoris®. |
| Actions |
The benefit/risk of concomitant use of colchicine with Atoris® should be considered. If a decision is made to use them concomitantly, monitor patients for signs and symptoms of myopathy, especially at the start of therapy and during dose escalation of either agent. |
| Grapefruit juice |
|
| Clinical effect |
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. |
| Actions |
Avoid consumption of large amounts of grapefruit juice (more than 1.2 liters per day) during treatment with Atoris®. |
Table 2
Interaction with medicinal products that may reduce exposure to the medicinal product Aторis®
| Rifampicin |
|
| Clinical effect |
Concomitant use of the medicinal product Atoris® with rifampicin, a cytochrome P450 3A4 inducer and OATP1B1 inhibitor, may lead to an unstable reduction in atorvastatin plasma concentration. Due to the dual interaction mechanism of rifampicin, delayed administration of Atoris® after rifampicin intake has been associated with a significant reduction in atorvastatin plasma concentration. |
| Precautions |
Concomitant administration of Atoris® and rifampicin is recommended. |
Table 3
Effect of the medicinal product Atoris® on other medicinal products
| Oral contraceptives |
|
| Clinical effect |
Concomitant use of the medicinal product Atoris® and oral contraceptives increased plasma concentrations of norethisterone and ethinylestradiol (see section "Pharmacological properties"). |
| Measures |
This fact should be taken into account when selecting an oral contraceptive for patients taking Atoris®. |
| Digoxin |
|
| Clinical effect |
When multiple doses of the medicinal product Atoris® and digoxin were used concomitantly, steady-state plasma concentrations of digoxin increased (see section "Pharmacological properties"). |
| Measures |
Patients taking digoxin should be appropriately monitored. |
Diltiazem hydrochloride.
Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is associated with increased plasma concentration of atorvastatin.
Cimetidine.
No evidence of interaction between atorvastatin and cimetidine has been observed in clinical studies.
Antacids.
Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminium hydroxide results in approximately 35 % reduction in atorvastatin plasma concentration. However, the hypolipidemic effect of atorvastatin remains unchanged.
Azithromycin.
Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentration.
Inhibitors of transporter proteins.
Inhibitors of transporter proteins may increase systemic exposure to atorvastatin (see Table 1). Cyclosporine and letermovir are inhibitors of transporters involved in atorvastatin distribution, including OATP1B1/1B3, P-gp, and BCRP, leading to increased systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transporter proteins on atorvastatin exposure in hepatocytes is unknown. If concomitant administration cannot be avoided, dose reduction of atorvastatin and clinical monitoring of efficacy are recommended (see Table 1).
Concomitant use of atorvastatin with letermovir and cyclosporine is not recommended (see section "Special precautions for use").
Gemfibrozil/fibrinic acid derivatives.
Fibrates used as monotherapy have been associated with muscle-related adverse effects, including rhabdomyolysis. The risk of such events may be increased when fibrinic acid derivatives are used concomitantly with atorvastatin. If concomitant use cannot be avoided, the lowest dose of atorvastatin necessary to achieve therapeutic goals should be used, and patients should be appropriately monitored (see section "Special precautions for use").
Ezetimibe.
Ezetimibe used as monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of such events may be increased when ezetimibe is used concomitantly with atorvastatin. Appropriate clinical monitoring of such patients is recommended.
Colestipol.
Plasma concentration of atorvastatin was lower (by approximately 25 %) when colestipol was administered concomitantly. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved with either agent alone.
Fusidic acid.
Drug interaction studies between atorvastatin and fusidic acid have not been conducted. However, as with other statins, cases of muscle-related adverse effects (including rhabdomyolysis) have been reported during post-marketing use when fusidic acid was administered concomitantly with atorvastatin. The mechanism of this interaction remains unknown. Patients require close monitoring, and temporary discontinuation of atorvastatin therapy may be necessary.
Colchicine.
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine. Therefore, atorvastatin should be administered with caution when used together with colchicine.
Daptomycin.
Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions for use").
Effect of atorvastatin on concomitantly administered medicinal products
Digoxin.
When multiple doses of atorvastatin and digoxin are administered concomitantly, steady-state digoxin plasma concentrations increase by approximately 20 %. Patients receiving digoxin should be appropriately monitored.
Oral contraceptives.
Concomitant use of atorvastatin with oral contraceptives increases plasma concentrations of norethisterone and ethinylestradiol. These increases should be taken into account when selecting an oral contraceptive for women taking atorvastatin.
Warfarin.
In a clinical study of patients on long-term warfarin therapy, concomitant administration of 80 mg atorvastatin daily with warfarin resulted in a small decrease (approximately 1.7 seconds) in prothrombin time during the first 4 days of therapy; however, this parameter returned to baseline within the next 15 days of atorvastatin treatment. Although clinically significant anticoagulant interactions have been reported only very rarely, prothrombin time should be monitored carefully when initiating atorvastatin therapy in patients taking coumarin anticoagulants. Prothrombin time should be determined frequently at the start of therapy to confirm the absence of any significant change. Once a stable prothrombin time has been established, monitoring can continue at intervals typically recommended for patients on coumarin anticoagulants. This monitoring should be repeated if atorvastatin therapy is discontinued or the dose changed. In patients not taking anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.
Special precautions for use.
Myopathy and rhabdomyolysis
The medicinal product may cause myopathy (muscle pain, tenderness or weakness in combination with elevated creatine kinase (CK) more than 10 times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure due to myoglobinuria). Rare fatal cases of rhabdomyolysis have been reported with statins, including Atoris®.
Myopathy risk factors
Risk factors for developing myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other medications, and use of higher doses of Atoris® (see section "Interaction with other medicinal products and other forms of interaction").
Measures to avoid or reduce the risk of myopathy and rhabdomyolysis
Exposure to Atoris® may increase due to 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]), increasing the risk of myopathy and rhabdomyolysis. Concomitant use of Atoris® with cyclosporine, gemfibrozil, or the combination of tipranavir + ritonavir or glecaprevir + pibrentasvir is not recommended. Dose modification of Atoris® is recommended for patients taking certain antiviral agents, azole antifungals, or macrolide antibiotics (see section "Posology and method of administration"). Cases of myopathy/rhabdomyolysis have been reported with concomitant use of atorvastatin and lipid-modifying doses (>1 g/day) of niacin, fibrates, colchicine, or the combination of ledipasvir + sofosbuvir. The benefit of using these agents should be weighed against the increased risk of myopathy and rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant consumption of large quantities of grapefruit juice (more than 1.2 liters per day) is not recommended in patients taking Atoris® (see section "Interaction with other medicinal products and other forms of interaction").
Discontinue Atoris® if markedly elevated CK levels are observed or if 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 renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disturbances; uncontrolled epilepsy).
Patients should be informed about the risk of developing myopathy and rhabdomyolysis at the beginning of treatment or when increasing the dose of Atoris®. 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 certain statins. Clinically, IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological testing may be required. Immunosuppressive therapy may be needed. The risk of IMNM should be carefully considered before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.
Hepatic function
Liver enzyme tests should be obtained before starting therapy and periodically thereafter. Patients who develop symptoms suggestive of liver injury should have liver function tests performed. Patients with elevated transaminase levels should have liver function monitored until abnormalities resolve. If persistent elevations of serum transaminases occur at 3 times or more above the upper limit of normal (ULN), discontinuation of the medicinal product is recommended (see section "Undesirable effects").
Atorvastatin should be administered with caution in patients who consume alcohol excessively and/or have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
Post hoc analysis of stroke subtypes in patients without ischemic heart disease (IHD) who recently experienced a stroke or transient ischemic attack (TIA) showed a higher incidence of hemorrhagic stroke with atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarction at study entry. The risk-benefit balance of atorvastatin 80 mg in patients with prior hemorrhagic stroke or lacunar infarction is not established; therefore, the potential risk of hemorrhagic stroke should be carefully evaluated before initiating treatment.
Skeletal muscle
Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare cases 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) (>10 times normal), myoglobinemia, and myoglobinuria, which may lead to renal failure.
Before starting treatment
Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Prior to initiating statin therapy in patients predisposed to rhabdomyolysis, CK levels should be measured in the following cases:
- Renal impairment;
- Hypothyroidism;
- Personal or family history of hereditary muscle disorders;
- Previous episodes of statin or fibrate-induced myotoxicity;
- Previous liver disease and/or alcohol abuse.
When treating elderly patients (over 70 years), the need for these measures should be assessed considering other risk factors for rhabdomyolysis.
Increased plasma concentrations of the drug may occur, particularly due to drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in specific patient groups, including patients with hereditary disorders (see section "Pharmacokinetics").
In such cases, risk-benefit assessment of treatment and clinical monitoring of patients are recommended.
If CK levels are markedly elevated (more than 5 times the upper limit of normal) before starting treatment, therapy should not be initiated.
Measurement of creatine kinase levels
CK levels should not be measured after intense physical exertion or in the presence of any other possible alternative causes of elevated CK, as this may complicate interpretation of results. If baseline CK levels are significantly elevated (exceeding ULN by more than 5 times), repeat measurement should be performed after 5–7 days to confirm the result.
During treatment
- Patients should be informed about the need to immediately report muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.
- If these symptoms occur during atorvastatin treatment, CK levels should be measured. If CK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should be discontinued.
- Discontinuation of treatment should also be considered if CK elevation does not reach fivefold ULN but muscle symptoms are severe and cause daily discomfort.
- After resolution of symptoms and normalization of CK levels, resumption of atorvastatin therapy or initiation of an alternative statin may be considered, using the lowest possible dose and under close monitoring.
- Atorvastatin treatment must be discontinued if clinically significant elevation of CK (exceeding ULN by more than 10 times) is observed or if rhabdomyolysis is diagnosed or suspected.
Concomitant use with other medicinal products
The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentrations, such as strong CYP3A4 inhibitors or transporter proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, lopinavir, 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 fibrinic acid derivatives, antiviral agents for hepatitis C (HCV) (e.g., boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. Alternative (non-interacting) treatment options should be considered when possible.
If concomitant therapy with atorvastatin and these agents is necessary, the benefits and risks should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma concentrations, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using strong CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered, with appropriate clinical monitoring (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 after discontinuation of fusidic acid. In patients for whom fusidic acid treatment is considered essential, statin therapy should be discontinued throughout the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should seek immediate medical attention if symptoms of muscle weakness, pain, or tenderness occur.
Statin therapy may be resumed 7 days after the last dose of fusidic acid.
In exceptional cases where prolonged fusidic acid therapy is required, e.g., for the treatment of severe infections, the possibility of concomitant use of atorvastatin and fusidic acid should be evaluated on a case-by-case basis and under continuous medical supervision.
The risk of developing myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily discontinuing Atoris® in patients receiving daptomycin unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.
Interstitial lung disease
Rare cases of interstitial lung disease have been reported with some statins, particularly with long-term treatment (see section "Undesirable effects"). Clinical manifestations may include dyspnea, dry cough, and deterioration in general health (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Paediatric population
In a three-year study assessing overall development using the Tanner scale and measurements of height and body weight, no clinically significant effect on overall and sexual development was observed (see section "Undesirable effects").
Diabetes mellitus
Some data suggest that statins as a class may increase HbA1c and fasting glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in cardiovascular risk associated with statin use and therefore should not be a reason to discontinue statin therapy. According to national guidelines, clinical and biochemical monitoring of at-risk patients (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) is recommended.
Myasthenia gravis
In isolated cases, statins have been reported to induce de novo myasthenia gravis or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Undesirable effects"). If symptoms worsen, atorvastatin should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.
Excipients
The product contains lactose; therefore, it should not be used in patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.
Use during pregnancy or breastfeeding.
Women of childbearing potential
Women of childbearing potential should use appropriate contraceptive methods during treatment (see section "Contraindications"). If a patient intends to become pregnant during treatment with atorvastatin, she should discontinue the drug no later than one month before planned conception.
Pregnancy
Atoris® is contraindicated during pregnancy, as safety has not been established and there are no controlled studies on the use of atorvastatin in pregnant women. Rare cases of congenital anomalies have been reported following in utero exposure to HMG-CoA reductase inhibitors. Animal studies have shown toxic effects on reproductive function.
Atorvastatin treatment may reduce intrauterine mevalonate levels, necessary for cholesterol biosynthesis. Atherosclerosis is a chronic process; therefore, interruption of lipid-lowering therapy during pregnancy is not expected to significantly affect long-term outcomes of primary hypercholesterolemia treatment.
Therefore, atorvastatin should not be used in pregnant women or in women planning or suspecting pregnancy. Treatment with Atoris® should be discontinued during pregnancy or if pregnancy is confirmed (see section "Contraindications").
Period of breastfeeding
It is unknown whether atorvastatin and its metabolites are excreted in human breast milk, but it is known that a small amount of atorvastatin or its metabolites passes into rat milk. Due to the potential risk of serious adverse effects, women taking Atoris® should discontinue breastfeeding (see section "Contraindications").
Atorvastatin is contraindicated during breastfeeding (see section "Contraindications").
Fertility
In animal studies, atorvastatin did not affect fertility in males or females.
Ability to influence reaction speed when driving or operating machinery.
There are no reports of atorvastatin affecting the ability to drive or operate machinery. However, some patients may experience dizziness and muscle cramps during treatment. Therefore, caution should be exercised when driving or operating machinery during therapy.
Method of Administration and Dosage
Dosage
Before initiating treatment with Atoris®, the degree of hypercholesterolemia should be determined, and adherence to an appropriate diet, physical exercise, weight reduction in obese patients, and treatment of other underlying medical conditions should be ensured. During treatment with Atoris®, the patient should follow a standard cholesterol-lowering diet.
Hyperlipidemia and mixed dyslipidemia
The recommended initial dose of atorvastatin is 10 mg or 20 mg once daily. For patients requiring substantial LDL-C reduction (more than 45%), therapy may be initiated with a dose of 40 mg once daily.
The dosage range of the medicinal product is from 10 mg to 80 mg once daily. The drug can be administered as a single dose at any time of day, regardless of food intake. Initial and maintenance doses should be individually adjusted based on LDL-C levels, treatment goals, and patient response. Lipid levels should be monitored 2–4 weeks after initiating treatment and/or dose titration, and the dose should be adjusted accordingly.
Heterozygous familial hypercholesterolemia in pediatric patients (aged 10 to 17 years)
The recommended initial dose of atorvastatin is 10 mg/day. The usual dosage range is 10 mg to 20 mg orally once daily. Doses should be individually adjusted according to the recommended treatment goal. Therapeutic response occurs within 2–4 weeks and is maintained during long-term therapy. Dose adjustments should be made at intervals of 4 weeks or longer.
Homozygous familial hypercholesterolemia
The atorvastatin dosage for patients with homozygous familial hypercholesterolemia ranges from 10 mg to 80 mg daily (see section "Pharmacodynamics"). Atorvastatin should be used as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.
Concomitant lipid-lowering therapy
Atoris® may be coadministered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").
Renal impairment
Renal disease does not affect plasma concentrations or LDL-C reduction with the drug; therefore, dose adjustment in patients with renal impairment is not required (see sections "Special precautions", "Pharmacokinetics").
Hepatic insufficiency
Atoris® should be administered with caution to patients with hepatic impairment (see sections "Special precautions", "Pharmacokinetics"). Atoris® is contraindicated in patients with active liver disease (see section "Contraindications").
Combination use with other medicinal products
Treatment with the drug should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Use with caution is recommended in HIV patients receiving lopinavir + ritonavir, and the lowest necessary dose should be used. For patients taking clarithromycin, itraconazole, or HIV patients receiving combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of the drug should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest effective dose. For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, treatment with the drug should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest effective dose (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
Elderly patients
For patients over 70 years of age, the efficacy and safety of atorvastatin at recommended doses should be evaluated considering the presence of other risk factors predisposing to rhabdomyolysis.
Concomitant use with other medicinal products
In patients receiving the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus infection prophylaxis, the atorvastatin dose should not exceed 20 mg/day (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").
Concomitant use of atorvastatin is not recommended in patients receiving letermovir together with cyclosporine (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").
Children
Heterozygous familial hypercholesterolemia
For patients aged 10 years and older with heterozygous familial hypercholesterolemia, the recommended initial dose of atorvastatin is 10 mg per day (see section "Pharmacodynamics"). The dose may be increased up to 80 mg per day according to response and tolerability. Doses should be individually adjusted according to the treatment goal. Dose adjustments should be made at intervals of 4 weeks or longer. Titration to a dose of 80 mg per day is supported by data from studies in adults and limited clinical data in children with heterozygous familial hypercholesterolemia (see sections "Adverse reactions" and "Pharmacodynamics").
Safety and efficacy data in children aged 6 to 10 years with heterozygous familial hypercholesterolemia are derived from open-label studies. Atorvastatin should not be used for treatment in patients under 10 years of age (see sections "Adverse reactions", "Pharmacodynamics", and "Pharmacokinetics"). For patients in this age group, another pharmaceutical form or dosage strength may be more appropriate.
Clinical efficacy of atorvastatin at doses up to 80 mg/day for one year has been reported in patients with homozygous familial hypercholesterolemia, including 8 pediatric patients (see section "Homozygous familial hypercholesterolemia").
Overdose
There is no specific antidote for overdose. In case of overdose, symptomatic and supportive treatment should be administered as needed. Liver function tests should be performed and serum CK levels monitored. Due to the high degree of plasma protein binding of the drug, significant increases in drug clearance by hemodialysis are not expected.
Adverse Reactions
Because clinical trials are conducted under varying conditions, the incidence rates of adverse reactions observed in clinical trials of a drug cannot be directly compared with those from clinical trials of another drug, and may not reflect the rates observed in clinical practice.
According to data from clinical trials, the most common adverse reactions leading to discontinuation of the drug in patients treated with atorvastatin, occurring at a higher frequency (> 2%) than in the placebo group, were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).
The most frequently reported adverse reactions (≥ 2% compared to placebo), regardless of causal relationship, in patients receiving placebo in the studies (n = 8755), were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infection (5.7%).
Table 4
Clinical adverse reactions occurring in 2% or more of patients treated with any dose of atorvastatin and at a higher frequency than in the placebo group, regardless of causal relationship (% of patients).
| Adverse reaction |
Any dose N=8755 |
10 mg N=3908 |
20 mg N=188 |
40 mg N=604 |
80 mg N=4055 |
Placebo N=7311 |
||||||
| Nasopharyngitis |
8.3 |
12.9 |
5.3 |
7 |
4.2 |
8.2 |
||||||
| Arthralgia |
6.9 |
8.9 |
11.7 |
10.6 |
4.3 |
6.5 |
||||||
| Diarrhea |
6.8 |
7.3 |
6.4 |
14.1 |
5.2 |
6.3 |
||||||
| Limb pain |
6 |
8.5 |
3.7 |
9.3 |
3.1 |
5.9 |
||||||
| Urinary tract infection |
5.7 |
6.9 |
6.4 |
8 |
4.1 |
5.6 |
||||||
| Dyspepsia |
4.7 |
5.9 |
3.2 |
6 |
3.3 |
4.3 |
||||||
| Nausea |
4 |
3.7 |
3.7 |
7.1 |
3.8 |
3.5 |
||||||
| Musculoskeletal pain |
3.8 |
5.2 |
3.2 |
5.1 |
2.3 |
3.6 |
||||||
| Muscle spasms |
3.6 |
4.6 |
4.8 |
5.1 |
2.4 |
3 |
||||||
| Myalgia |
3.5 |
3.6 |
5.9 |
8.4 |
2.7 |
3.1 |
||||||
| Insomnia |
3 |
2.8 |
1.1 |
5.3 |
2.8 |
2.9 |
||||||
| Pharyngolaryngeal pain |
2.3 |
3.9 |
1.6 |
2.8 |
0.7 |
2.1 |
||||||
Other adverse reactions reported during placebo-controlled studies include:
General disorders: malaise, pyrexia;
Gastrointestinal disorders: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis;
Musculoskeletal system disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture);
Metabolism and nutrition disorders: increased transaminases, abnormal liver function tests, increased blood alkaline phosphatase, increased creatine phosphokinase activity, hyperglycemia;
Nervous system disorders: nightmares;
Respiratory system disorders: epistaxis;
Skin and appendages disorders: urticaria;
Eye disorders: blurred vision, visual disturbance;
Ear and labyrinth disorders: tinnitus;
Vascular disorders: vasculitis;
Renal and urinary system disorders: leukocyturia;
Reproductive system and breast disorders: gynecomastia.
The frequency of adverse reactions was defined as follows: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000).
Nervous system disorders: common: headache; uncommon: dizziness, paresthesia, hypoaesthesia, dysgeusia, amnesia; rare: peripheral neuropathies; frequency not known: myasthenia gravis.
Eye disorders: frequency not known: ocular myasthenia.
Gastrointestinal disorders: common: constipation; uncommon: pancreatitis, vomiting.
Musculoskeletal and connective tissue disorders: common: arthralgia, back pain; rare: myopathy, myositis, rhabdomyolysis and red-brown discoloration of urine.
General disorders: uncommon: asthenia, chest pain, peripheral edema, fatigue.
Metabolism and nutrition disorders: uncommon: hypoglycemia, weight gain, anorexia.
Hepatobiliary disorders: very rare: hepatic failure.
Skin and connective tissue disorders: uncommon: skin rashes, pruritus, alopecia; rare: angioneurotic edema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis, drug-induced lichenoid reaction.
Respiratory, thoracic and mediastinal disorders: common: throat and laryngeal pain.
Blood and lymphatic system disorders: rare: thrombocytopenia.
Immune system disorders: common: allergic reactions; very rare: anaphylaxis.
Eye disorders: uncommon: blurred vision.
Laboratory test abnormalities: common: abnormal liver function tests, increased blood creatine phosphokinase activity; uncommon: positive test for leukocytes in urine.
As with other HMG-CoA reductase inhibitors, elevated serum transaminase activity has been observed in patients treated with atorvastatin. These changes were generally mild, transient, and did not require discontinuation or treatment. Clinically significant elevations in serum transaminase activity (more than three times the upper limit of normal) were observed in 0.8% of patients treated with atorvastatin. This increase was dose-dependent and reversible in all patients.
Elevated serum creatine kinase activity more than three times the upper limit of normal was observed in 2.5% of patients treated with atorvastatin. This is consistent with observations during clinical studies with other HMG-CoA reductase inhibitors. Serum levels more than ten times the upper limit of normal were observed in 0.4% of patients receiving atorvastatin.
Adverse reactions observed during clinical trials: urinary tract infection, diabetes mellitus, stroke, increased serum transaminase activity (dose-dependent and reversible in all patients), increased serum creatine kinase activity, diabetes mellitus.
Post-marketing experience
The following adverse reactions have been identified during post-marketing use of atorvastatin. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with atorvastatin treatment and reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy and pancreatitis.
Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions").
Rare post-marketing reports of cognitive disorders (e.g., partial memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders have been reported with all statins. Overall, these reactions were not considered serious adverse reactions and were reversible after discontinuation of statin therapy, with variable time to onset (from 1 day to several years) and resolution (median duration of 3 weeks).
With the use of some statins, the following adverse events have been described: sexual dysfunction; rare cases of interstitial lung disease, particularly during long-term treatment.
The following adverse reactions have been reported during post-marketing surveillance.
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).
Metabolism and nutrition disorders: weight gain.
Nervous system disorders: headache, hypoaesthesia, dysgeusia.
Gastrointestinal disorders: abdominal pain.
Ear and labyrinth disorders: tinnitus.
Skin and subcutaneous tissue disorders: urticaria.
Musculoskeletal and connective tissue disorders: arthralgia, back pain, lupus-like syndrome, muscle rupture.
General disorders: chest pain, peripheral edema, malaise, fatigue.
Laboratory test abnormalities: increased alanine aminotransferase activity, increased blood creatine phosphokinase activity.
Pediatric population
Pediatric patients aged 10 to 17 years receiving atorvastatin had an overall adverse reaction profile generally similar to that of placebo-treated patients. In a three-year study assessing overall development by Tanner staging and measurements of height and body weight, no clinically significant effect on overall or sexual development was observed. The safety and tolerability profile in pediatric patients was similar to the known safety profile of atorvastatin in adult patients.
The clinical safety database includes safety data from 520 pediatric patients treated with atorvastatin, including 7 patients under 6 years of age, 121 patients aged 6 to 9 years, and 392 patients aged 10 to 17 years. Based on available data, the frequency, type, and severity of adverse reactions in children are similar to those in adults.
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach and sight of children.
Packaging.
10 mg, 20 mg: 10 tablets in a blister; 3 or 9 blisters in a cardboard box.
40 mg: 10 tablets in a blister; 1, 3, or 9 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and site of operation.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.