INSTRUCTION

for medical use of the medicinal product

LIMISTIN 10

LIMISTIN 20

LIMISTIN 40

Composition:

Active substance: atorvastatin;

1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg or 20 mg, or 40 mg;

Inactive substances: calcium carbonate; cellulose microcrystalline; lactose, monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; hydroxypropyl methylcellulose; propylene glycol; polyethylene glycol-6000; talc; titanium dioxide (E 171) – tablets 10 mg and 20 mg;

calcium carbonate; cellulose microcrystalline; lactose, monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; crospovidone; sodium lauryl sulfate; hydroxypropyl methylcellulose; polyethylene glycol-6000; talc; titanium dioxide (E 171) – tablets 40 mg.

Pharmaceutical form. Film-coated tablets.

Basic physical and chemical properties:

• white or almost white capsule-like film-coated tablets with a scoring line on one side (tablets of 10 mg and 20 mg);
• white or almost white round biconvex film-coated tablets (tablets of 40 mg).

Pharmacotherapeutic group. Hipolipidemic agents, monocomponent. HMG-CoA reductase inhibitors.

ATC code: C10A A05.

Pharmacological properties.

Pharmacodynamics.

A selective competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A-reductase of the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, which is a precursor of sterols, including cholesterol. Atorvastatin lowers the level of cholesterol and lipoproteins of low density (LDL) in blood plasma through inhibiting 3-hydroxy-3-methylglutaryl coenzyme A-reductase and cholesterol synthesis in the liver. It also increases the amount of LDL receptors on the surface of hepatocytes, which leads to enhancement of the uptake and catabolism of LDL. Atorvastatin lowers the level of total cholesterol, LDLs, apolipoprotein B and triglycerides, causing the increase in the level of HDL-cholesterol and apolipoprotein A. Such results have been registered in patients with heterozygous familial hypercholesterolaemia and mixed hyperlipidemia, including the patients with insulin dependent diabetes mellitus.  

Pharmacokinetics.

After the intake, atorvastatin is rapidly absorbed; its maximum concentrations in blood plasma are achieved in 1-2 hours. The extent of absorption increases proportionally to the dose of atorvastatin. The bioavailability of the medicinal agent is 95-99%. The total bioavailability of atorvastatin is approximately 14%, and the systemic availability of its inhibiting activity of 3-hydroxy-3-methylglutaryl coenzyme A-reductase is almost 30%. The low systemic bioavailability is associated with a presystemic clearance in the mucous membrane of gastrointestinal tract and/or biotransformation at the first-pass hepatic metabolism. The average atorvastatin distribution is approximately 381 l. Atorvastatin binds to blood plasma proteins by more than 98%, and biotransforms under the action of cytochrome P450 3 A4, forming ortho- and para hydroxylated derivatives and other products of β-oxidation.

The effect of atorvastatin on 3-hydroxy-3methylglutaryl coenzyme A-reductase is determined approximately by 70% by the activity of circulating metabolites. The drug is excreted in the bile after hepatic or extrahepatic metabolism. The drug is not affected by enterohepatic circulation. The drug’s elimination half-life is almost 14 hours. Its inhibiting activity of HMG-CoA reductase lasts about 20-30 hours due to the presence of active metabolites. There are no data regarding the drug’s pharmacokinetics in children.    

Table 1.Effectofco-administeredmedicinalproductsonatorvastatinpharmacokinetics

^&          Data given as x-fold change represent a simple ratio between co-administration of the drugs and atorvastatin alone (thus 1-fold = unchanged). Data, given as % change represent % difference related to use of atorvastatin alone (thus 0% = unchanged). 

 ^#       For information about clinical significance, see sections “Precautions for use” and “Interaction with other medicinal products and other forms of interaction.”

*       Higher increase in AUC (up to 2,5-fold) and/or C_max (up to 70%) was reported at excessive consumption of grapefruit juice (750 ml – 1,2 l or more per day)

 **    Single sample taken in 8-16 hours after the drug administration

      ^†     Due to rifampin’s dual mechanism of interaction, concomitant use of atorvastatin and rifampin is recommended, as studies showed that delay in atorvastatin use after administration of rifampin is associated with a significant decrease in atorvastatin plasma concentrations.

^‡        The dose of drug combination saquinavir + ritonavir in this study is not a clinically applied dose. The increased exposure of atorvastatin when used in clinical conditions might be higher than the one, which was observed in this study. Therefore, the drug should be used with caution in the lowest necessary dose.

Clinical particulars.

Indications.

Prevention of cardiovascular disease

For adults without clinically significant ischemic heart disease but with several risk factors for ischemic heart disease, such as age, smoking, arterial hypertension, low HDL levels or the presence of early ischemic heart disease in the family history, Limistin is indicated for:

• - reduction of the risk of myocardial infarction;
• - reduction of the risk of stroke;
• - reduction of the risk of revascularization procedures and stenocardia.

For patients with type II diabetes and without clinically significant ischemic heart disease but with several risk factors for ischemic heart disease such as retinopathy, albuminuria, smoking or arterial hypertension, Limistin is indicated for:

• - reduction of the risk of myocardial infarction;
• - reduction of the risk of stroke.

For patients with clinical ischemic heart disease, Limistin is indicated for:

• - reduction of the risk of non-fatal myocardial infarction;
• - reduction of the risk of non-fatal and fatal stroke;
• - reduction of the risk of revascularization procedures;
• - reduction of the risk of hospitalization due to congestive heart failure;
• - reduction of the risk of stenocardia.

Hyperlipidemia

• - As an adjunct to diet to reduce increased levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and to increase the level of HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-family) and mixed dyslipidemia (Types IIa and IIb by Fredrickson classification) .
• - As an adjunct to diet for the treatment of patients with increased levels of triglycerides in the blood serum (type IV by Fredrickson classification).
• - For the treatment of patients with primary dysbetalipoproteinemia (type III by Fredrickson classification) in case when the diet is not effective enough.
• - For reduction of total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatment (e.g. LDL apheresis) or if such methods of treatment are unavailable.
• - As an adjunct to diet to reduce levels of total cholesterol, LDL cholesterol and apolipoprotein B in boys and girls after the start of menstruation aged 10 to 17 years with heterozygous familial hypercholesterolemia if after the proper diet the test results are:

1. a) LDL cholesterol ³ 190 mg/dL or
2. b) LDL cholesterol ³ 160 mg/dL and:

• a family history has early cardiovascular disease or
• paediatric patients have two or more other risk factors for cardiovascular disease.

Contraindications.

Active liver disease, which may include a persistent increase of liver transaminase levels of unknown etiology.

Hypersensitivity to the active substance or to any of the excipients of this medicinal product.

Interaction with other medicinal products and other forms of interaction.

During the treatment with statins the risk of myopathy is increased in case of concomitant use of derivatives of fibric acid, lipidomodified doses of niacin, cyclosporin or potent CYP3A4 inhibitors (e.g. clarithromycin, HIV protease inhibitors and itraconazole) (see section "Precautions for use").

Potent CYP3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin and potent inhibitors of CYP 3A4 can lead to increased concentrations of atorvastatin in blood plasma (see. Table 1 and details below). The extent of interaction and potentiation depend on variability of effect on CYP 3A4. Co- administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided, if possible.In cases where co-administration of these medicinal products with atorvastatin cannot be avoided, lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient’s state is recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased atorvastatin exposure. Therefore, a lower maximum dose of atorvastatin should be considered, and appropriate clinical monitoring of the patient’s state is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or dose adjustments of the inhibitor.

Grapefruit juice. Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of atorvastatin, especially at excessive grapefruit juice consumption (>1.2 litres per day).

Clarithromycin. Atorvastatin AUC values are significantly increased in co-administration of atorvastatin 80 mg and clarithromycin (500 mg twice daily) compared with the use of atorvastatin alone. Therefore, Limistin at doses of more than 20 mg should be used with caution in patients treated with clarithromycin (see section "Precautions for use" and "Routes of Administration and Dosage").

The combination of protease inhibitors. Atorvastatin AUC values were ​​significantly increased at the co-administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with telaprevir, the inhibitor of hepatitis C virus protease, compared with the use of atorvastatin alone. Therefore, patients, treated with HIV protease inhibitor typranavir + ritonavir or protease inhibitor of hepatitis C virus telaprevir, should avoid co-administration of Limistin. The preparation should be prescribed with caution in patients treated with HIV protease inhibitor lopinavir + ritonavir and used in the lowest necessary dose. For the patients treated with HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the dose of Limistin should not exceed 20 mg and be used with caution (see section "Precautions for use" and "Routes of Administration and Dosage"). For the patients treated with HIV protease inhibitor nelfinavir or protease inhibitor of hepatitis C virus boceprevir, the dose of Limistin should not exceed 40 mg, and a close clinical monitoring of the patient’s state is recommended.

Itraconazole. Atorvastatin AUC values were increased at co-administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, patients, treated with itraconazole, should be careful if the dose of Limistin exceeds 20 mg (see section "Precautions for use" and "Routes of Administration and Dosage").

Cyclosporine. Atorvastatin and its metabolites are substrates of OATP1B1 transporter. OATP1B1 inhibitors (e.g. cyclosporine) may increase the bioavailability of atorvastatin. Atorvastatin AUC values are significantly increased at the co-administration of atorvastatin 10 mg and cyclosporine in the dose of 5.2 mg/kg/day compared to the use of atorvastatin alone. It is better to avoid the co-administration of Limistin and cyclosporine (see section "Precautions for use").

Medical recommendations for the interactions of medical products are summarized in Table 2 (see section "Precautions for use" and "Routes of Administration and Dosage").

Table 2.

Interactions of medicinal agents associated with the increased risk of myopathy/rhabdomyolysis

*Use with caution and in the lowest necessary dose.

Gemfibrozil. The co-administration of Limistin with gemfibrozil should be avoided due to the increased risk of myopathy/rhabdomyolysis at the co-administration of HMG-CoA reductase inhibitors and gemfibrozil (see section "Precautions for use").

Other fibrates. Since it is known that during the treatment with HMG-CoA reductase inhibitors, in concomitant use of other fibrates, the risk of myopathy is increased, so Limistin should be used with caution in concomitant use with other fibrates (see section "Precautions for use").

Niacin. The risk of adverse reactions in the skeletal muscles could be increased at co-administration of niacin. Therefore, in such circumstances the possibility of Limistin dose reduction should be considered (see section "Precautions for use").

Rifampin or other inducers of P450 3A4 cytochrome. The concomitant administration with inducers of P450 3A4 cytochrome (e.g. efavirenz, rifampin) can lead to unstable reduction of the blood plasma concentrations of atorvastatin. Because of rifampin’s dual mechanism of interaction, the concomitant administration of atorvastatin and rifampin is recommended. Studies showed that after rifampin introduction, the delay in use of atorvastatin is associated with a significant decrease in the blood plasma concentrations of atorvastatin.

Diltiazem hydrochloride. Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by increased blood plasma concentrations of atorvastatin.

Cimetidine. No features of interaction of atorvastatin and cimetidine were found.

Antacids. Simultaneous oral administration of atorvastatin and antacid suspension containing magnesium and aluminum hydroxide, is accompanied by a decrease in the plasma concentrations of atorvastatin approximately by 35%. The hypolipidemic effect of atorvastatin was unchanged.

Colestipol. Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol was co-administered with Atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were co-administered than when either medicinal product was administered alone.

Azithromycin. Concomitant administration of atorvastatin (10 mg once a day) and azithromycin (500 mg 1 once a day) was not accompanied by changes in the plasma concentrations of atorvastatin.

Inhibitors of transport proteins. Inhibitors of transport proteins (e.g. cyclosporine) can increase the level of systemic exposure of atorvastatin (see Table 1). The effect of cumulative transport proteins inhibition on concentration of atorvastatin in liver cells is unknown. If it is impossible to avoid the concomitant prescription of these preparations, the reduction of the dose and clinical monitoring of the effectiveness of atorvastatin are recommended (see Table 1).

Ezetimibe. The use of ezetimibe as monotherapy is associated with the development of phenomena in the musculoskeletal system, including rhabdomyolysis. Thus, during the concomitant use of ezetimibe and atorvastatin, the risk of these events is increased. It is recommended to carry out a proper clinical monitoring of the state of these patients.

Fusidic acid. Interaction studies of atorvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with atorvastatin and fusidic acid administered concurrently. The mechanism of this interaction remains unknown. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate.

Digoxin. At the concomitant administration of high doses of atorvastatin and digoxin, the balanced levels of plasma concentrations of digoxin are increased approximately by 20%. The state of the patients taking digoxin should be monitored appropriately.

Oral contraceptives. Concomitant administration of atorvastatin with oral contraceptives increased the AUC values for ethinylestradiol and norethisterone. These increases should be considered when selecting an oral contraceptive for a woman who takes atorvastatin.

Warfarin. Atorvastatin had no clinically significant effect on prothrombin time in patients who had long-term warfarin treatment.

Colchicine. The cases of myopathy, including rhabdomyolysis were reported at the concomitant administration of atorvastatin and colchicine, so atorvastatin and colchicine should be used with caution.

Other medicines

Clinical studies show that concomitant use of atorvastatin and antihypertensive agents and its use in the oestrogen-replacement therapy are not accompanied by clinically significant side effects. There were no studies regarding the interaction with other preparations.

Precautions for use.

Skeletal muscles

There are rare cases of rhabdomyolysis with acute renal failure caused by myoglobinuria at the administration of atorvastatin and other drugs of this class. The history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients need closer monitoring to detect disorders of the skeletal muscles. Sometimes Limistin, like other statins, causes myopathy, defined as muscle pain or muscle weakness, combined with increased levels of creatine phosphokinase (CPK) 10 times more than the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and potent inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole and HIV protease inhibitors) increases the risk of myopathy / rhabdomyolysis.

The use of atorvastatin may cause immunologically mediated necrotizing myopathy (IONM) - autoimmune myopathy associated with the use of statins. IONM is characterized by the following features: proximal muscle weakness and increased levels of creatine kinase in the blood serum, which remain despite the discontinuance of statins; muscle biopsy shows necrotizing myopathy without significant inflammation; the use of immunosuppressive agents shows positive dynamics.

The possibility of myopathy should be considered in any patient with diffuse myalgias, muscle pain or weakness, and/or a significant increase of CPK. Patients should be advised to immediately inform the doctor about muscle pain, muscle weakness or pain of unknown etiology, especially if it is accompanied by a feeling of malaise or fever, or if signs and symptoms remain even after discontinuance of atorvastatin therapy. Treatment should be discontinued if CPK is significantly increased or myopathy is diagnosed or suspected.

During the treatment with the agents of this class, the risk of myopathy is increased at co-administration of cyclosporine, derivatives of fibric acid, erythromycin, clarithromycin, protease inhibitors of hepatitis C virus telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, typranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or azole antimycotics group. Physicians considering combined therapy of atorvastatin and derivatives of fibric acid, erythromycin, clarithromycin, combinations of saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, antimycotics of azoles or lipidomodified doses of niacin, should reconsider the potential benefits and risks and monitor the state of patients for any signs or symptoms of pain or weakness in muscles, especially during the initial months of therapy and any periods of dose titration towards the increase of any of the drugs. It is necessary to consider the possibility of use of low initial and maintenance doses of atorvastatin in concomitant use of the abovementioned preparations (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, the possibility of periodic determination of CPK may be considered, but there is no assurance that such monitoring will prevent the cases of severe myopathy.

During the treatment with atorvastatin, rare cases of myopathy were observed, including rhabdomyolysis at concomitant use of atorvastatin and colchicine. That is why colchicine and atorvastatin should be prescribed to patients with caution (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with Limistin should be discontinued temporarily or completely stopped in any patient with acute serious condition that indicates the development of myopathy, or the presence of risk factors for renal failure development due to rhabdomyolysis (e.g. severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures).

Liver dysfunction

Studies showed that statins, like some other lipid-lowering therapeutic agents, were associated with deviation from the normal biochemical parameters of liver function. Steady increase (3 times higher than the upper limit of the normal range, which occurred 2 times or more) of the levels of serum transaminases was observed in 0.7% of patients treated with atorvastatin. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 2.3% for doses of 10, 20, 40 and 80 mg, respectively.

There are data that one patient treated with the preparation developed jaundice. In the other patients the increased indicators of liver function tests (LFT) were not associated with jaundice or other clinical signs and symptoms. After a dose reduction, a break in the drug administration or discontinuance of the drug administration, the transaminase levels were returned to pre-treatment levels or about those without residual effects. 18 out of 30 patients with persistent increase of liver function indicators continued the treatment with atorvastatin in smaller doses.

Before starting therapy with Limistin, it is recommended to get the test results of liver enzymes indicators and to retest the samples if there is a clinical necessity. There were rare postregistration reports of lethal and non-lethal liver failure in patients treated with preparations of statins, including atorvastatin. The treatment should be stopped immediately in case of severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurrence during the atorvastatin therapy. If there is no alternative etiology, the drug treatment should not be re-started.

Limistin should be used with caution in patients who have alcohol abuse and/or have a history of liver disease. Limistin is contraindicated for patients with active liver disease or stable elevation of liver transaminases of unknown etiology (see section "Contraindications").

Endocrine function

The increase of HbA1c levels and glucose concentration in blood serum were reported during the administration of inhibitors of HMG-CoA reductase inhibitors, including atorvastatin.

Statins prevent cholesterol synthesis and theoretically might reduce the secretion of adrenals and/or gonadal steroids. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentrations and does not damage the adrenal reserve. Effect of statins on the ability of sperm fertilization was not studied in the sufficient number of patients.

It is unknown how the preparation affects the system of "sex glands-hypophysis-hypothalamus" in women in premenopausal period. Be careful in co-administration of the preparation of statin group and other medical products that can reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

The use in patients with recent cases of stroke or transient ischemic attack.

During the therapy with atorvastatin (80 mg dose) in patients without ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, a higher incidence rate of haemorrhagic stroke was observed.

Among patients treated with atorvastatin, aged 65-75 years, no general difference in safety and efficacy of this preparation between these patients and younger patients was observed. There were also no differences in response to the treatment between elderly and younger patients but we cannot exclude an increased sensitivity of some older patients. Since the elderly age (65 years) is the factor of predisposition to myopathy, Limistin should be prescribed with caution to elderly people.

Liver failure

Limistin is contraindicated for patients with active liver disease, including persistent increase of liver transaminases of unknown etiology (see section "Contraindications").

Before the treatment

Limistin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations:

• - Renal failure;
• - Hypothyroidism;
• - Personal or familial history of hereditary muscular disorders;
• - Previous history of muscular toxicity caused by statins or fibrates;
• - Previous history of liver disease and/or consumption of alcohol in large quantities

In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.

An increase of the drug levels in blood plasma may occur in case of interactions and treatment of special populations including genetic subpopulations.

In such situations, the possible risks should be considered in relation to possible benefits, and clinical monitoring is recommended. If CK levels are significantly elevated (> 5 times ULN) at the beginning of the treatment, treatment should not be started.

Creatine kinase level measurement

Creatine kinase (CK) level should not be measured following strenuous exercise or in the presence of any plausible alternative causes of CK increase, as this makes the value interpretation difficult. If CK levels are significantly elevated at the baseline (> 5 times ULN), levels should be re-measured within the following 5 to 7 days to confirm the results.

During the treatment

Patients must be advised to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.

If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), the treatment should be stopped.

If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.

If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring of the patient’s state.

Atorvastatin treatment must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Concomitant treatment with other medicinal products

Risk of rhabdomyolysis development is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the blood plasma concentrations of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins: ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc. The risk of myopathy may also be increased at the concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting with atorvastatin) therapies should be considered instead of these medicinal products.

In cases where co-administration of these medicinal products with atorvastatin is necessary, the possible benefits and risks of such concurrent treatment should be carefully considered. When patients administer medicinal products that increase the plasma concentrations of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended.

The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin may be considered during fusidic acid therapy.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially at long-term therapy. This disease manifestations can include dyspnoea, non- productive cough and deterioration in general health (fatigue, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Excipients

Limistin includes lactose. This preparation should not be used in patients with rare hereditary diseases associated with intolerance to galactose, Lapp lactase deficiency or disturbance of glucose-galactose malabsorption. Lipidomodified drug therapy should be one of the components of complex therapy for patients with a significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.

Drug therapy is recommended as a diet adjunct, when the results of the diet, which limits consumption of saturated fats and cholesterol, as well as the results of other non-drug measures were not efficient enough. The intake of Limistin may be started simultaneously along with the diet for patients with ischemic heart disease or several risk factors for ischemic heart disease.

Limitations of use

Atorvastatin was not studied in the conditions where the main deviation from the norm of the lipoprotein is increase of chylomicrons (types I and V by Fredrickson classification).

Pregnancy and lactation.

Limistin is contraindicated for women who are pregnant, trying to become pregnant or suspect they are pregnant. Statins can cause a fatal damage to a fetus. Limistin may be used in women of childbearing age only if there is certainty that such patient does not become pregnant, and they were informed about potential risk factors. Women of childbearing age should take appropriate contraceptive measures. If during the treatment the patient decides to become pregnant, she should stop taking the drug no later than a month before a planned pregnancy. If a woman has become pregnant during the treatment with Limistin, the administration of the drug should immediately be discontinued, and the patient should be re-consulted about the potential risks for the fetus and the absence of known clinical benefits of administration of the drug during pregnancy.

During normal pregnancy, the levels of serum cholesterol and triglycerides are increased. The intake of lipid-lowering drugs during pregnancy will have no beneficial effects, since cholesterol and its derivatives are necessary for normal development of the fetus. Atherosclerosis is a chronic process, and therefore a break in taking lipid-lowering drugs during pregnancy should not have a significant effect on the long-term treatment of primary hypercholesterolemia. Adequate and well-controlled studies of atorvastatin use during pregnancy have not been carried out. There are data of congenital anomalies after intrauterine exposure to statins. In pregnant women who were treated with other statin agents, the incidence of congenital abnormalities of the fetus, miscarriage and intrauterine death/dead born child did not exceed the rate expected for the general population. However, in 89% of these cases, the drug treatment was started before pregnancy and it was stopped during the first trimester after pregnancy discovery.

It is not known whether atorvastatin is excreted in human milk, but it is known that a small amount of another medical product of the same class is excreted in breast milk.  Because of the potential ability of statins to cause serious adverse reactions, women taking Limistin should not breast-feed their infants (see section "Contraindications").

Effects on reaction rates while driving vehicles and operating machinery.

Haslittleeffectonreactionratewhiledrivingoroperatingmachinery.

Routes of administration and dosage.

Homozygous familial and non-familial hyperlipidemia and mixed dyslipidemia (types IIa and IIb by Fredrickson classification)

The recommended initial dose of Limistin is 10 or 20 mg once a day. For patients requiring a significant reduction of LDL-C levels (by more than 45%), the therapy may be started from the dose of 40 mg once a day. Limistin dose range is between 10 to 80 mg once a day. The preparation can be taken as a single dose any time regardless of the meal. Initial and maintenance doses of Limistin should be adjusted individually, according to the goals of the treatment and patient’s response. After starting the treatment and/or after the titration of Limistin dose, the lipid levels should be analyzed within a period of 2 to 4 weeks and the dose should be adjusted accordingly.

Heterozygous familial hypercholesterolemia in paediatric practice (10 – 17-years old patients). It is recommended to use Limistin at the initial dose of 10 mg once a day. The maximum recommended dose is 20 mg once a day (doses exceeding 20 mg were not studied in this age group of patients). Doses may be individualised according to the goals of the therapy and adjusted every 4 weeks.

Homozygous familial hypercholesterolaemia. The dose of Limistin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily that provides a reduction of LDL-C by more than 15% (18-45%). Limistin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Concurrent lipid-lowering therapy

Limistin can be used with bile acid sequestrants. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should be used with caution (see section "Precautions for use", "Interaction with other medicinal products and other forms of interaction").

Dosage for patients with renal failure

Renal failure does not affect either the drug blood plasma concentrations or reduction of LDL-C level at administration of Limistin, thus, no dose adjustment for patients with renal failure is needed (see sections “Precautions for use,” “Pharmacokinetics”).

The dosage for patients treated with cyclosporine, clarithromycin, itraconazole or certain protease inhibitors

You should avoid treatment with atorvastatin in patients treated with cyclosporine or HIV protease inhibitors (typranavir + ritonavir) or protease inhibitor of hepatitis C virus (telaprevir). Limistin should be used with caution in patients with HIV, who are treated with lopinavir + ritonavir, and to be used in the lowest necessary dose. In patients treated with clarithromycin, itraconazole or in patients with HIV treated in a combination with saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of Limistin should be limited to the dose of 20 mg, and it is recommended to conduct the proper clinical examinations to ensure the application of the lowest necessary dose of Limistin. In patients treated with protease inhibitor of HIV, nelfinavir, or protease inhibitor of HCV, boceprevir, treatment with Limistin should be limited to the dose of 40 mg, and it is recommended to conduct proper clinical examinations to ensure the application of the lowest necessary dose of Limistin (see sections "Precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Children.

Atorvastatin was reported to be safe and effective for patients aged 10-17 years with heterozygous familial hypercholesterolemia, namely for adolescent boys and girls after the beginning of their menstruation period. Patients treated with atorvastatin had a similar profile of adverse reactions as patients receiving placebo. Infectious diseases were the most often reported adverse reactions observed in both groups despite the causal link to the drug administration. Patients did not receive the drug at doses of more than 20 mg. The study showed no significant effect of the drug on growth or sexual maturation in boys or duration of menstrual cycle in girls (see sections “Adverse reactions,” “Routes of administration and dosage.”). Adolescent girls should be informed about the appropriate methods of contraception during the treatment with Limistin (see section “Pregnancy and lactation”).

Efficacy and safety of atorvastatin treatment in adolescent patients or children under 10-years old have not been studied.

Clinical efficacy of atorvastatin at doses of 80 mg/day during 1 year in patients with homozygous familial hypercholesterolemia, including 8 paediatric patients, have been studied (see section “Homozygous familial hypercholesterolemia”).

Overdose.

Specific treatment is not available for atorvastatin overdose. In case an overdose occurs, the patient should be treated symptomatically and, if necessary, supportive measures should be initiated. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.

Adverse reactions.

Limistin is generally well-tolerated.

The adverse reactions are:

- General disorders: chest pain, facial oedema, fever, asthenia, rigid neck, fatigue, photosensitivity reactions, generalized oedema, pyrexia, peripheral oedema;

- Nervous system disorders: insomnia, dizziness, paraesthesia, drowsiness, amnesia, sleep disturbance, nightmares, decreased libido, emotional lability, incoordination, peripheral neuropathy, torticollis, facial nerve paralysis, hyperkinesia, depression, hypoesthesia, hypertension, headache, dysgeusia;

- Gastrointestinal disorders: gastroenteritis, liver dysfunction, colitis, vomiting, nausea, gastritis, dry mouth, rectum haemorrhage, esophagitis, glossitis, mouth ulcers, anorexia, increased appetite, stomatitis, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, bleeding gums, gastric ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, diarrhoea, abdominal pain, dyspepsia, constipation, meteorism, epigastrium discomfort, belching, cholestasis;

- Musculoskeletal and connective tissue disorders: arthritis, myopathy, myalgia, myositis, muscle cramps; bursitis, tendosynovitis, myasthenia gravis, tendon contracture, musculoskeletal pain, muscle spasms, increased muscle fatigue, neck pain, swollen joints, tendonopathy (sometimes complicated by a tendon rupture), joint pain, back pain;

- Metabolism and nutrition disorders: peripheral oedema, hyperglycemia, increase of creatine phosphokinase, gout, weight gain, hypoglycemia, anorexia, increased transaminase levels, abnormal liver function tests, increased alkaline phosphatase levels;

- Hepatobiliary disorders: liver failure;

- Skin and subcutaneous tissue disorders: alopecia, pruritus, contact dermatitis, dry skin, increased sweating, acne, urticaria, eczema, seborrhea, skin ulcers, skin rash, angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis;

- Respiratory, thoracic and mediastinal disorders: sore throat and larynx, bronchitis, rhinitis, pneumonia, dyspnoea, asthma, epistaxis, nasopharyngitis;

- Blood and lymphatic system disorders: ecchymosis, anaemia, lymphadenopathy, thrombocytopenia, petechiae;

- Immune system disorders: allergic reactions; anaphylaxis;

- Sense organs disorders: amblyopia, parosmia, loss of taste, perverted appetite;

- Eye disorders: blurred vision, visual disturbance, dry eyes, refraction disturbance, cataract, eye haemorrhage, glaucoma;

- Ear and labyrinth disorders: tinnitus, hearing loss;

- Reproductive and urinary system disorders: urinary tract infection, haematuria, albuminuria, frequent urinary, cystitis, dysuria, urolithiasis, nocturia, epididymitis, mastopathy, vaginal haemorrhage, uterine bleeding, increase of breasts, metrorrhagia, nephritis, urinary incontinence, urinary retention, acute urinary retention, impotence, ejaculation disturbance, leukocyturia, gynecomastia;

- Cardiovascular disorders: palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina, hypotension;

- Changes of laboratory test results: common: false results of liver function tests, increased blood creatine kinase level; uncommon: positive white blood cells urine test.

Paediatric Population (10-17 years-old). Patients, treated with atorvastatin, have noted that adverse reactions are similar to those in patients of the placebo group. The most common adverse reaction, observed in both groups, regardless causal relationship, was infections.

In the post-marketing period, there were adverse reactions, such as: thrombocytopenia; allergic reactions (including anaphylaxis); angioneurotic edema, weight gain; hypoesthesia, amnesia, dizziness, tinnitus; Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rash, urticaria; rhabdomyolysis, tendon rupture, arthralgia, back pain; chest pain, peripheral oedema, malaise, fatigue, dysgeusia, headache, abdominal pain, tinnitus, peripheral oedema, increased activity of alanine aminotransferase, increase of blood creatine phosphokinase activity.

Storage life. 2 years.

Storage conditions.

Store in the original package at temperature not exceeding 30 °С.

Keep out of reach of children.

Package.  10 tablets in a blister, 3 blisters in a box.

Terms of dispensing. On prescription.

Manufacturer.

Marksans Pharma Ltd.

Manufacturer’s registered address.

Plot no. L-82, L-83, Verna Industrial Estate, Verna, Goa - 403722, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

 Date of last review. 24.02.16.