The Order of Ministry of
Health of Ukraine
24.01.2019 № 192
for medical use
active substance: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin;
excipients: lactose monohydrate, microcrystalline cellulose, calcium carbonate, povidone K30, sodium сroscarmellose, colloidal anhydrous silica, magnesium stearate, Opadry 03F84827 pink*;
*Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E 172).
Pharmaceutical form. Coated tablets.
Main physico-chemical properties:
tablets coated with 10 mg, 20 mg: round biconvex tablets coated with pink color, debossed with "10" or "20" on one side;
tablets coated with 40 mg, 80 mg: round, biconvex coated with pink color, smooth on both sides.
Drugs that lower the cholesterol and triglycerides levels in blood serum.
HMG-CoA reductase inhibitors.CodeАТС C10A A05.
Atsat® 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 into mevalonate, a precursor of sterols, in particular cholesterol. Triglycerides (TG) and cholesterol in the liver are embedded in a very low density lipoprotein (VLDL) molecule, enter the blood plasma and are transported to peripheral tissues. Lipoprotein of low density (LDL) is formed from VLDL and catabolized mainly by interaction with high affinity LDL receptors (LDL-receptors).
Atorvastatin lowers cholesterol concentrations in blood plasma and lipoprotein in serum by inhibiting HMG-CoA reductase, and subsequently biosynthesis of cholesterol in the liver, and also increases the amount of liver LDL receptors on the cells’ surface, which leads to increased capture and catabolism of LDL.
Atorvastatin reduces the formation of LDL and the amount of LDL particles. Atorvastatin causes a pronounced and sustained increase in the activity of LDL-receptors, in combination with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol (CH) in patients with homozygous familial hypercholesterolemia, a group that has not responded to hypolipidemic therapy.
Apart from influencing plasma lipids, atorvastatin has other effects that potentize its antiatherosclerotic action. It suppresses the synthesis of isoprenoids - substances that act as growth factors on the proliferation of cells of smooth muscle of vessels, reduces plasma viscosity and activity of some factors of coagulation and aggregation. As a result of such action, it improves hemodynamics and helps to normalize blood coagulation. In addition, HMG-CoA-reductase inhibitors have an effect on the metabolism of macrophages and thus suppress their activation, which reduces the risk of rupture of atherosclerotic plaques.
It has been shown that atorvastatin reduces the concentration of total cholesterol (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%) and TG (14-33%), causing variable raising in LDL-C and apolipoprotein A in the study which investigated dose-dependence of its effect. These results are consistent with data on patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-independent diabetes.
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.
Atorvastatin is rapidly absorbed after oral administration and reaches maximum concentration in plasma after 1-2 hours. The level of absorption and concentration of atorvastatin in plasma depends on the dose of atorvastatin. The bioavailability of atorvastatin in the form of tablets, compared with a solution is 95 and 99% respectively. The absolute bioavailability of atorvastatin is approximately 14% and the systemic availability of inhibitory activity relative to HMG-CoA reductase is about 30%. The low systemic bioavailability is due to presystemic clearance in the mucous membrane of gastrointestinal tract and biotransformation during the initial passage through the liver. Food intake reduces the rate and extent of drug absorption by approximately 25% and 9% respectively, which is confirmed by the level of the maximum concentration and AUC (area under the "concentration-time" curve). Lowering LDL-C does not depend on the time of application. Atorvastatin concentration in plasma after aplication in the evening is lower than after aplication in the morning (exceeding maximum concentration levels and AUC by about 30%). Nevertheless, the reduction of LDL-C does not depend on the time of ingestion.
The average volume of distribution of atorvastatin is approximately 381 l. Binding to plasma proteins is > 98%. If the value of the ratio of erythrocytes/plasma is approximately 0.25, then it indicates to a low level penetration of preparation into erythrocytes. On the basis of observations in rats it is considered that atorvastatin is able to penetrate into breast milk (see. sections "Contraindications", "Use during pregnancy and breast feeding" and "Peculiarities of Use").
Atorvastatin significantly metabolized, forming ortho- and parahydroxylated derivatives and various products of b-oxidation. In vitro, ortho- and parahydroxylated metabolites exhibit inhibitory activity against HMG-CoA reductase equivalent to the effect of atorvastatin. The inhibitory effect of the drug on HMG-CoA-reductase approximately by 70% is determined by the activity of circulating metabolites. In vitro studies confirm the importance of biotransformation of atorvastatin under the effect of cytochrome P450 3A4. Concomitant administration of atorvastatin and erythromycin, an inhibitor of cytochrome P450 3A4, leads to increased concentrations of atorvastatin in plasma. In vitro studies also confirm the fact that atorvastatin is a weak inhibitor of cytochrome P450 3A4. Concomitant administration of atorvastatin and terfenadine, which is mainly metabolized by cytochrome P450 3A4 system, the concentration of the latter in the blood plasma remains almost unchanged. Thus, it is unlikely that the use of cytochrome may significantly change the pharmacokinetics of other substrates of cytochrome P450 3A4. In animals, orthohydroxylated metabolite undergoes further glucuronidation.
Atorvastatin and its metabolites are mainly excreted with bile following hepatic and/or extrahepatic biotransformation, however, they do not undergo gastrohepatic recirculation. Mean half-life of atorvastatin in humans is approximately 14 hours. Inhibitory activity against HMG-CoA reductase persists for 20-30 hours due to the presence of active metabolites. After oral administration, less than 2% of atorvastatin are detectable in the urine.
Population of patients
The concentration of atorvastatin in blood plasma of healthy older people (age > 65 years) is higher than in younger people (about 40% of the maximum concentration and 30% of the AUC). The available data indicate that the effectiveness and safety in the elderly do not differ from those of the general population.
The apparent clearance in oral administration of atorvastatin in children was similar to the clearance of an adult when scaled alometrically by body weight, since body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 10 to 17 years old, n = 29) in an open 8-weeks study.
The concentration of atorvastatin in blood plasma in women differs from that in men (maximum concentration is higher by approximately 20% and AUC is less by 10%). However, these differences have no clinical significance, and hypolipidemic effect of the drug in men and women is almost identical.
Dosage and administration do not affect the concentration of atorvastatin in blood plasma and its hypolipidemic action. Thus, there is no need to adjust the dose.
No studies of the effect of atorvastatin in patients with kidney disease in the terminal stage have been carried out. Due to the fact that the drug is actively bound to plasma proteins, hemodialysis cannot significantly enhance atorvastatin clearance.
In patients with alcoholic cirrhosis, the concentration of atorvastatin in blood plasma is significantly increased (maximum concentration is about 16 times the value AUC – 11 times).
Patients with a polymorphism SLCO1B1 have an increased risk of atorvastatin exposure, which may increase the risk of developing rhabdomyolysis.
Prevention of cardiovascular diseases in adults
In adult patients without clinically significant ischemic heart disease, but with multiple risk factors of ischemic heart disease, such as age, tobacco smoking,arterial hypertension, low HDL or early heart disease in the family history, Atsat® is indicated to:
- reduce the risk of myocardial infarction;
- reduce the risk of stroke;
- reduce the risk for revascularization procedures and angina.
For patients with type II diabetes mellitus and without clinically significant ischemic heart disease, but with multiple risk factors of ischemic heart disease, such as retinopathy, albuminuria, tobacco smoking or arterial hypertension, Atsat® is indicated to:
- reduce the risk of myocardial infarction;
- reduce the risk of stroke.
For patients with clinical ischemic heart disease, Atsat® is indicated to:
- reduce the risk of non-lethal myocardial infarction;
- reduce the risk of lethal and non-lethal stroke;
- reduce the risk for revascularization procedures;
- reduce the risk of hospitalization due to congestive heart failure;
- reduce the risk of angina.
In adult patients
- As a dietary supplement to reduce the elevated total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides, and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-family) and mixed dyslipidemia (classified as Fredrickson types IIa and IIb).
- As a dietary supplement for the treatment of patients with increased levels of blood serum triglycerides (classified as Fredrickson type IV).
- For the treatment of patients with primary dysbetalipoproteinemia (type III Fredrickson classification) when diet is not effective.
- To reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia in addition to other hypolipidemic methods of treatment (e.g. LDL apheresis) or if such treatments are not available.
- As a dietary supplement to reduce the levels of total cholesterol, LDL cholesterol and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after an appropriate diet test results are as follows:
a) LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or
b) LDL cholesterol ≥ 160 mg/dL (4.14 mmol/L) and:
there are early cardiovascular diseases in a family history or
two or more other cardiovascular risk factors are present in the pediatric patient.
- Acute phase of liver disease, which may include a persistent increase of liver transaminases of unknown etiology.
- Hypersensitivity to any component of this drug.
Interaction with other medicinal products and other forms of interaction.
The risk of myopathy during treatment with statins is increased with simultaneous administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) (see sect. “Administration details” and “Pharmacological properties”).
Strong Inhibitors of CYP 3A4. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in blood plasma concentrations of atorvastatin (see detailed information, given below). The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. If possible, avoid the simultaneous administration with potent inhibitors of CYP3A4 (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir). If the simultaneous administration of these drugs with atorvastatin is impossible to be avoided, the possibility of using smaller initial dose and maximal dose of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended (see table 1).
Moderate inhibitors of CYP3A4 (such as erythromycin, diltiazem, verapamil and fluconazole) may increase the blood plasma concentration of atorvastatin. Simultaneous administration of erythromycin and statins are associated with an increased risk of myopathy. Studies of drugs interaction for assessment the effects of amiodarone or verapamil were not conducted. It is known that amiodarone and verapamil inhibit the activity of CYP3A4, and, therefore co-administration of these drugs with atorvastatin may increase the exposure of atorvastatin. Thus,atorvastatin and these moderate inhibitors of CYP 3A4 should be considered when administering atorvastatin at lower doses. It is also recommended to conduct clinical monitoring of the patient. It is recommended to conduct clinical monitoring of the patient after starting treatment with inhibitor or after the dose adjustment.
Contains one or more components that inhibit CYP 3A4 and can increase blood plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (more than 1.2 liters per day).
Clarithromycin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg and clarithromycin (500 mg twice daily) compared to that of atorvastatin alone (see sect. “Pharmacological properties”). Therefore, in patients taking clarithromycin, caution should be used when the atorvastatine dose exceeds 20 mg (see sect. “Administration details” and “Dosage and administration”).
Combination of protease inhibitors. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with inhibitor of hepatitis C virus protease inhibitor telaprevir, compared to that of atorvastatin alone (see sect. “Pharmacological properties”). Therefore, in patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C protease inhibitor telaprevir, concomitant use of Atsat® should be avoided. In patients taking the HIV protease inhibitor lopinavir + ritonavir, caution should be used when prescribing the drug and the necessary lowest dose should be used. In patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the dose of atorvastatin should not exceed 20 mg and it should be used with caution (see sect “Administration details” and “Dosage and administration”). In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin should not exceed 40 mg. Close clinical monitoring of patients is also recommended.
Itraconazole. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin at the dosage of 40 mg and itraconazole at the dosage of 200 mg (see sect. “Pharmacological properties”). Therefore, patients taking itraconazole should be careful when the atorvastatin dose exceeds 20 mg (see sect. “Administration details” and “Dosage and administration”).
Cyclosporine. Atorvastatin and its metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone (see sect. “Pharmacological properties”). The co-administration of atorvastatin with cyclosporine should be avoided (see sect. “Administration details”).
Medical recommendations for administration of drugs that interact are summarized in Table 1 (see sect. “Dosage and administration”, “Administration details”, “Pharmacological properties”).
Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin with gemfibrozil should be avoided (see sect. “Administration details”).
Other fibrates. As it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant administration of other fibrates, atorvastatin should be administered with caution when used simultaneously with other fibrates (see sect. “Administration details”).
Niacin. The risk of skeletal muscle adverse reactions may be increased when the drug is used in combination with niacin, thus a reduction of atorvastatin dosage should be considered in these circumstances (see sect. “Administration details”).
Rifampin or other inducers of cytochrome CYP3A4. Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in blood plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous administration of Atsat® with rifampin is recommended, as delayed administration of the drug after administration of rifampin has been associated with a significant reduction in atorvastatin blood plasma concentrations.
Diltiazem hydrochloride. Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is followed by increasing of blood plasma atorvastatin concentration.
Cimetidine. According to researching results, the interaction of atorvastatin and cimetidine was not determined.
Antacids. Simultaneous oral administration of atorvastatin and antacid suspension that contains magnesium and aluminum hydroxide is followed by decrease of blood plasma concentration of atorvastatin by approximately 35%. Upon that, hypolipidemic action of atorvastatin has not been changed.
Colestipol. The concentration of atorvastatin in the blood plasma was lower (ratio of atorvastatin concentration: 0.74) with concomitant administration of atorvastatin and colestipol. In this case, the hypolipidemic effect of the combination of atorvastatin and coltispol exceeds the effect that gives each of these drugs separately.
Simultaneous institution of atorvastatin (10 mg 1 time per day) and azithromycin (500 mg once daily) was not accompanied with changes in blood plasma concentration of atorvastatin.
Inhibitors of transport proteins. Inhibitors of transport proteins (e.g. cyclosporine) can increase the level of systemic exposure of atorvastatin. Effect from inhibition of accumulative transport proteins on the atorvastatin concentration in liver cells is unknown. If simultaneous administration of these drugs is impossible to be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended.
Ezetimibe. Administration of ezetimibe as monotherapy is associated with the development of the muscular system events, including rhabdomyolysis. Thus, simultaneous administration of ezetimibe and atorvastatin increases the risk of these events. An appropriate clinical monitoring of these patients is recommended.
Fusidic acid.Simultaneous application of fusidic acid with statins may increase the risk of developing myopathy, including rhabdomyolysis. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both at the same time) is still unknown. Rhabdomyolysis cases (including those with fatal outcome) have been reported in patients who received a combination of these drugs. If systemic use of fusidic acid is required, the use of atorvastatin should be discontinued for the entire duration of fusidic acid use (see section "Administration details").
Digoxin. Simultaneous administration ofmultiple doses of atorvastatin and digoxin, equilibrium concentrations of digoxin in plasma are increased by about 20%. Patients, who are taking digoxin, should be under proper supervision.
Oral contraceptives. Simultaneousadministration of atorvastatin and oral contraceptives increases AUC for norethisterone and ethinylestradiol (see sect. “Pharmacological properties”). This fact must be taken into account in per oral contraceptives choice for a woman, who uses Atsat®.
Warfarin. Atorvastatin had no clinically significant effect on prothrombin time, when administered to patients who underwent long-term treatment with warfarin.
Colchicine. Itwas reported about cases of myopathy and rhabdomyolysis, induced by simultaneous administration of atorvastatin and colchicine, thus atorvastatin and colchicine should be carefully prescribed.
Clinical studies have shown that concomitant use of atorvastatin and antihypertensive drugs and its use during estrogen replacement therapy was not accompanied by clinically significant side effects. Interaction studies with other drugs have not been conducted.
Drug interactions associated with increased risk of myopathy/rhabdomyolysis
Recommendations for medical use
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C protease inhibitor (telaprevir)
Avoid atorvastatin administration
HIV protease inhibitor (lopinavir + ritonavir)
Administer with caution and the lowest necessary dose
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily
* Use with caution and with the lowest necessary dose.
Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria when using atorvastatin and other medicines of this class have been reported. The presence of a history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require more careful monitoring to detect skeletal muscle disorders.
Atorvastatin, like other drugs of statins group, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values above 10 times upper limit of normal (ULN). The simultaneous administration of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; administration of immunosuppressive means shows positive trend.
The possibility of development of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Atsat®. Drug therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration 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, and also niacin, or azole antifungals. Physicians considering combined therapy with Atsat® and fibric acid derivatives, erythromycin, clarithromycin, a combination of 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 should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken simultaneously with the above mentioned drugs (see sect. “Interaction with other medicinal products and other forms of interaction”). Periodic CPK determinations may be considered in such situations, but there are no guaranties that such monitoring will prevent the occurrence of severe myopathy.
Cases of myopathy, including rhabdomyolysis, have been reported while atorvastatin is co-administered with colchicine, so atorvastatin with colchicine should be prescribed to patients with caution (see section "Interaction with other drugs and other types of interactions").
The treatment with Atsat® should be temporarily or fully discontinued in patients with a severe, serious condition which indicates on myopathy, or in the presence of a risk factor for renal failure due to rhabdomyolysis (e.g. severe acute infection, arterial hypotension, surgical intervention, trauma, severe metabolic, endocrine and electrolytic disorders, as well as uncontrolled seizures).
Statinsas well as some other hypolipidemic therapies, associated with biochemical abnormalities of liver function have been observed. After dose reduction, atorvastatin interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequela. It is recommended that liver enzyme tests be obtained prior to initiating therapy with Atsat® and repeated as clinically indicated. There are rare reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Atsat®, promptly discontinue therapy. If an alternate etiology of liver injury is not found, do not restart the application with statins treatment.
Atsat® should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the Atsat® administration (see sect. “Contraindications”).
Increases in HbA1c level and fasting blood serum glucose concentration have been reported with HMG-CoA reductase inhibitors administration, including atorvastatin.
Statins interfere with cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Atorvastatin does not reduce basal blood plasma cortisol concentration and does not damage the adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The drug effects, if any, on the gonadal-pituitary hypothalamic axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Atorvastatin in dosage of 80 mg therapy in patients without cardiovascular disease, which for 6 months or less before the start of treatment had a stroke or transient ischemic attack, increases the incidence of hemorrhagic stroke. Patients who have a hemorrhagic stroke developed at the beginning of therapy have increased the risk of recurrent hemorrhagic stroke. Atorvastatin 80 mg dose reduces the total number of stroke and the number of cardiovascular diseases.
Elderly patients (over 65 years).
No overall differences in safety and effectiveness of the drug were observed between the elderly and younger patients, but greater sensitivity of some older adults cannot be excluded. Since older age (over 65 years) is a predisposing factor for myopathy, Atsat® should be prescribed with caution in the elderly patients.
Before starting treatment.
Atorvastatin should be administered with cautionto patients with factors inducing rhabdomyolysis. A CPK level must be determined before the treatment with statins in the following cases: renal failure, hypothyroidism, inherited muscular disorders in individual or family anamnesis; with muscle toxicity observed after the treatment with statins or fibrates; if a patient suffered from hepatic disorders and/or consumes alcohol; in patients of advanced age (aged over 70) the need for the conduct of the present study is determined by the presence of other factors inducing rhabdomyolysis; in cases of the possible increase of the atorvastatin concentration in the blood plasma, for example, during the interaction with medicinal products and in special groups of patients, including genetic subpopulations (see sect. “Pharmacokinetics”).
It is advisable to carefully assess the benefit-risk of the treatment in such situations. A thorough clinical monitoring is highly recommended. In case of a significant increase of the initial CPK level (more than 5 times in comparison to ULN), the treatment with this product does not start.
Determination of the level of CPK.
The level of CPK should not be performed after intense physical activity, or in the presence of any other factors that may increase the level of CPK, as this may lead to inaccurate results. With a significant increase in the initial level of CPK (more than 5 times compared to the ULN), it is recommended that the study be re-conducted within 5-7 days to confirm the results.
- Patients should immediately inform the doctor about all cases of muscle aches, seizures or weakness, especially if followed by malaise and fever;
- if similar symptoms occur during treatment with atorvastatin, CPK values should be measured. In case of significant CPK elevation (exceeding five times ULN), treatment should be discontinued;
- if muscle symptoms are severe or cause valuable discomfort, discontinuation of treatment should be considered, even though CPK values are not over five times ULN;
- if symptoms disappear and CPK values become normal, treatment with atorvastatin or another statin group can be considered by decreasing its dosage; the patient should be under constant supervision of the doctor;
- if significant elevation of CPK values (exceeding ten times ULN) or in case of diagnosed rhabdomyolysis or suspicion of its occurrence.
Concomitant use with other drugs.
The risk of rhabdomyolysis is increased by concurrent use of atorvastatin with some medicinal products such as 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 administration of gemfibrozil with other fibric acid derivatives, boecerevir, erythromycin, niacin and ezetimibe, telaprevir or combinations of telaprevir/ritonavir also increases the risk of myopathy. If possible, use other drugs (which do not interact with atorvastatin) instead of the above mentioned.
If simultaneous treatment with atorvastatin and mentioned drugs is necessary, weight the benefits and risks.If drugs that increase the blood plasma atorvastatin concentration are administered to patients, then minimization of atorvastatin dose is recommended.In addition, in the case of strong CYP3A4 inhibitors administration, a lower starting dose of atorvastatin should be considered to administer. Also an appropriate clinical monitoring of these patients is recommended.
Atorvastatin should not be used concurrently with systemic administration of fusidic acid, or within 7 days after discontinuation of treatment with fusidic acid. In patients in whom systemic use of fusidic acid is considered necessary, statin treatment should be stopped for the entire period of fusidic acid use. Rhabdomyolysis cases (including lethal) have been reported in patients receiving fusidic acid and statins in the combination (see section "Interaction with other medicinal products and other forms of interaction"). The patient should be advised to seek medical attention immediately in the event of any symptoms of weakness, pain or painful sensation in the muscles.
Statin therapy can be continued 7 days after the last dose of fusidic acid.
In exceptional circumstances, when long-term systemic use of fusidic acid is required, for example, for the treatment of severe infections, the need for simultaneous use of the Atsat® and fusidic acid should only be considered individually and under close medical supervision.
Interstitial lung disease.
During the treatment of some statins (especially during long-term treatment), exceptional cases of interstitial lung disease development were described. Symptoms may include dyspnea, unproductive cough, general deterioration of well-being (fatigue, weight loss, fever). In case of suspicion of interstitial lung disease, statin treatment should be discontinued.
Limitation of administration.
Atorvastatin under conditions where the main deviation from the norm from the side of the lipoproteins was an increase in the level of chylomicrons have not been studied (Fredrickson classification types I and V).
Excipients. The drug contains lactose. If you have intolerance to some sugars, consult your doctor before taking this medicine.
Administration during pregnancy or breast feeding.
Atorvastatin is contraindicated in pregnant women, since the safety of its use in pregnant women is not established and there is no obvious benefit of lipid-lowering drugs during pregnancy. Since inhibitors of HMG-CoA-reductase reduce cholesterol synthesis and possibly the synthesis of other biologically active substances that are cholesterol derivatives, atorvastatin may have a detrimental effect on the fetus. Atsat® should be discontinued as soon as the pregnancy is established (see section "Contraindications").
The estimated background risk for significant congenital malformations and miscarriages for this population is unknown. In the overall US population, the estimated background risk for significant congenital malformations and miscarriages in clinically recognized pregnancies is between 2-4% and 15-20%, respectively.
Atorvastatin can harm the fetus when used by a pregnant woman. Women of reproductive age should be informed about the need for effective contraception during treatment with this drug.
Limited published data from observational studies, meta-analyzes, and clinical trials on the use of atorvastatin calcium did not indicate an increased risk of severe congenital malformations or miscarriages.
There were rare reports of congenital anomalies after intrauterine exposure of other HMG-CoA reductase inhibitors. A prospective observation of approximately 100 cases of pregnancy in women treated with simvastatin or lovastatin showed that the incidence of congenital fetal abnormalities, miscarriages, and fetal death / stillbirths did not exceed the frequency expected for the general population. The number of cases is sufficient to exclude ≥ 3-4 fold increase in congenital abnormalities of fetal development versus background frequency. In 89% of pregnant women, who were prospectively monitored, drug treatment began before pregnancy and stopped during the first trimester after pregnancy.
Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfeeding child or on lactation. It is not known whether atorvastatin penetrates into breast milk, but it has been shown that another drug of this class penetrates into breast milk, atorvastatin is present in milk of rats. Since statins are potentially capable of causing serious adverse reactions in children who are breast-feeding, women who need treatment with Atsat® should not breast-feed their children (see section "Contraindications").
Effects on ability to drive and use machines.
Atorvastatin has slight impact on the ability to drive and use machines, but it is recommended that caution be taken when performing the above actions.
Dosage and administration.
Hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb)
Recommended initial dose of Atsat® is 10 or 20 mg 1 time per day. For patients who require a significant reduction in LDL cholesterol (over 45%), therapy may be initiated with a dosage of 40 mg 1 time per day. Dose range of Atsat® is from 10 to 80 mg 1 time per day. The single drug dose can be administered regardless of the meal and time. Initial and maintenance doses of Atsat® should be selected individually, depending on the treatment goals and response. After the initiation of treatment and/or after Atsat® dose titration, lipid levels should be analyzed over a period of 2 to 4 weeks and adjust dose accordingly.
Heterozygous familial hypercholesterolemia in pediatric patients (10–17 years of age).
The recommended starting dose of Atsat® is 10 mg/day;the usual dose range is 10 to 20 mg orally once a day. Doses should be individualized according to the recommended goal of therapy. Dose adjustments should be made at intervals of 4 weeks or more.
Homozygous familial hypercholesterolemia.
The dosage of Atsat® in patients with homozygous familial hypercholesterolemia is from 10 to 80 mg daily. The drug should be administered as an adjunct to other hypolipidemic methods of treatment (e.g., LDL apheresis) or if lipid-lowering treatment methods are unavailable.
Simultaneous hypolipidemic therapy.
Atsat® may be used with bile acid resin. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sect. “Administration details”, “Interaction with other medicinal products and other forms of interaction”).
Dosage in patients with renal impairment
Renal disease does not affect the blood plasma concentrations nor LDL-C reduction of Atsat® administration. Thus, dosage adjustment in patients with renal dysfunction is not necessary (see sect. “Administration details”).
Dosage in patients taking cyclosporine, clarithromycin, itraconazole or certain protease inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir + ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with Atsat® should be avoided. In patients with HIV taking lopinavir + ritonavir, caution should be used when prescribing Atsat® and the lowest dose necessary administered. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, therapy with Atsat® should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atsat® is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with Atsat® should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see sect. “Administration details”, “Interaction with other medicinal products and other forms of interaction”).
Heterozygous familial hypercholesterolemia
The safety and efficacy of atorvastatin have been indicated in children aged 10 to 17 years with heterozygous familial hypercholesterolemia as a supplement to the diet to lower total cholesterol, LDL levels and apolipoprotein B levels when, after an adequate dietary intervention, there are:
• LDL cholesterol ≥ 190 mg/dl (4.91 mmol/l) or
• LDL cholesterol ≥ 160 mg/dL (4.14 mmol/l) and
o family anamnesis of family cholesterol or early cardiovascular disease in relatives of the first or second degree or
o there are two or more other risk factors for cardiovascular disease.
Indications for the use of atorvastatin have been confirmed on the basis of studies:
A 6-month placebo-controlled clinical trial involving 187 boys and girls after menstruation from 10 to 17 years of age. Patients treated with atorvastatin at the dosage of 10 mg or 20 mg every day had a similar profile of undesirable reactions to such in patients receiving placebo. No significant effect of the drug on growth or puberty of the boys or on the duration of the menstrual cycle in the girls in this narrow, controlled study, was detected.
A three-year, open, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia for which a dose has been prescribed to achieve a target LDL-C level of < 130 mg/dl (3.36 mmol/l). The safety and efficacy of atorvastatin with lowering LDL cholesterol are generally consistent with those observed in adult patients, despite limiting the uncontrolled study plan.
It is necessary to consults girls after menstruation about contraception, if appropriate for the patient.
Long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
The safety and efficacy of atorvastatin therapy is not established for children under the age of 10 with heterozygous familial hypercholesterolemia.
Homozygous familial hypercholesterolemia
Clinical efficacy of the drug at doses up to 80 mg/day during 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, which included 8 children.
There is no specific treatment; conduct supporting therapy. It is necessary to conduct functional tests of the liver and to monitor the blood serum CKP level. As atorvastatin binds with plasma proteins hemodialysis is ineffective.
Infectious and parasitic diseases: nasopharyngitis, infections.
Blood and lymphatic system: thrombocytopenia.
Immune system: allergic reactions, anaphylactic reactions (including anaphylactic shock), anaphylaxis.
Metabolism: hyperglycemia, hypoglycemia, weight gain, loss of appetite (anorexia), diabetes mellitus.
Mental: depression, sleep disorders, including insomnia terrible dreams and nightmares.
Nervous system: head ache, dizziness, paresthesia, hypoesthesia, change in taste (dysgeusia), peripheral neuropathy, cognitive impairment (for example, memory loss, memory, amnesia, memory impairment, confusion) associated with the use of statins, stroke.
Visual organs: eclipse view, blurred vision, impaired vision.
Acoustic organ and labyrinth:sonitus, tinnitus, hearing loss.
Genito-urinary system:leukocyturia, urinary tract infections.
Respiratory system, the chest and mediastinum: nasal bleeding, interstitial lung disease, sore throat and larynx (pharyngolaryngeal pain).
GIT: constipation, flatulence, dyspepsia, nausea, lacrimation, diarrhea, vomiting, gastrointestinal discomfort, pain in the upper and lower abdomen, stomach pain, abdominal pain, pancreatitis.
Liver and gallbladder: hepatitis, cholestasis, cholestatic jaundice, liver failure including lethal.
Skin and subcutaneous tissue: urticaria, skin rash, itching, alopecia, angioneurotic edema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal system and connective tissue:muscle pain (myalgia), joint pain (arthralgia), limb pain, muscle spasm, convulsions, swelling of the joints, musculoskeletal pain, back pain, neck pain, muscle tiredness, muscle weakness, myopathy, including immunologically mediated necrotizing myopathy, myositis, increased fatigue of the muscles, rhabdomyolysis, tendopatiya (sometimes complicated by the rupture of the tendon);
Reproductive system and mammary gland: gynecomastia, sexual dysfunction, impotence.
General disorders and disorders at the injection site: feeling sickness, discomfort, asthenia, fatigue, chest pain, peripheral edema, increased fatigue, high fever (pirexia).
Laboratory and instrumental data: serum transaminases increasing that does not require discontinuation of treatment, activity of alanine aminotransferase increasing, blood creatine phosphokinase activity increasing, liver function tests changing, increased blood creatine kinase, the presence of leukocytes in the urine, and alkaline phosphatase levels increasing in the blood.
Adverse reactions during clinical trials on the use of atorvastatin in children
During a 26-week controlled trial in boys and girls after menstruation with heterozygous familial hypercholesterolemia (aged 10 to 17 years) (n = 140, 31% female; 92% are european race, 1.6% are representatives of the Negroid race, 1.6% are representatives of the Mongoloid race and 4.8% are representatives of other ethnic groups) safety profile and tolerability of atorvastatin in a dose of 10 mg to 20 mg per day as a supplement to the diet to lower total cholesterol, cholesterol levels LDL and apolipoprotein B levels were similar profile to placebo.
Store in the original package at a temperature NMT 25 ºС.
Keep it out of reach of children.
14 tablets are in blisters; 2 or 4 or 6 blisters are in a carton box.
Conditions of supply.
“KUSUM PHARM” LLC.
40020, Ukraine, Sumy Oblast, Sumy, Skryabina Str., 54.
Last revision date.
24.01.2019 № 192
1 film coated tablet contains Atorvastatin calcium which is equivalent to 10 mg or 20 mg of Atorvastatin; Drugs for reducing the level of cholesterol and triglyceride in blood serum. HMG-CoA reductaseinhibitors.
|View instructions||Dounload instruction|