Liprimar^® (Tablets) Instructions for Use

Marketing Authorization Holder

Viatris Specialty, LLC (USA)

Manufactured By

Pfizer Pharmaceuticals, LLC (Puerto Rico)

Packaging and Quality Control Release

PFIZER MANUFACTURING DEUTSCHLAND, GmbH (Germany)

Contact Information

VIATRIS LLC (Russia)

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN registered by WHO)

Dosage Forms

	Liprimar®	Film-coated tablets, 10 mg: 14, 28, 30, 35, 50, 56 or 100 pcs.
		Film-coated tablets, 20 mg: 14, 28, 30, 35, 50, 56 or 100 pcs.
		Film-coated tablets, 40 mg: 14, 28, 30, 35, 50, 56 or 100 pcs.
		Film-coated tablets, 80 mg: 14, 28, 30, 35, 50, 56 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, elliptical, engraved with “10” on one side and “PD 155” on the other side.

Excipients: calcium carbonate, microcrystalline cellulose (PH-101), lactose monohydrate, croscarmellose sodium, polysorbate 80, hypromellose (hydroxypropylcellulose), magnesium stearate.

Coating composition Opadry^® white YS-1-7040 (contains hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 8000), titanium dioxide, talc), simethicone emulsion (contains purified water, simethicone, polysorbate 65, methylcellulose, PEG 8 stearate, glyceryl stearate, xanthan gum, benzoic acid, sorbic acid, sulfuric acid), carnauba wax.

7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.
7 pcs. – blisters (5) – cardboard packs with first opening control.
7 pcs. – blisters (8) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Film-coated tablets white, elliptical, engraved with “20” on one side and “PD 156” on the other side.

Excipients: calcium carbonate, microcrystalline cellulose (PH-101), lactose monohydrate, croscarmellose sodium, polysorbate 80, hypromellose (hydroxypropylcellulose), magnesium stearate.

Coating composition Opadry^® white YS-1-7040 (contains hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 8000), titanium dioxide, talc), simethicone emulsion (contains purified water, simethicone, polysorbate 65, methylcellulose, PEG 8 stearate, glyceryl stearate, xanthan gum, benzoic acid, sorbic acid, sulfuric acid), carnauba wax.

7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.
7 pcs. – blisters (5) – cardboard packs with first opening control.
7 pcs. – blisters (8) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Film-coated tablets white, elliptical, engraved with “40” on one side and “PD 157” on the other side.

Excipients: calcium carbonate, microcrystalline cellulose (PH-101), lactose monohydrate, croscarmellose sodium, polysorbate 80, hypromellose (hydroxypropylcellulose), magnesium stearate.

Coating composition Opadry^® white YS-1-7040 (contains hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 8000), titanium dioxide, talc), simethicone emulsion (contains purified water, simethicone, polysorbate 65, methylcellulose, PEG 8 stearate, glyceryl stearate, xanthan gum, benzoic acid, sorbic acid, sulfuric acid), carnauba wax.

7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.
7 pcs. – blisters (5) – cardboard packs with first opening control.
7 pcs. – blisters (8) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Film-coated tablets white, elliptical, engraved with “80” on one side and “PD 158” on the other side.

Excipients: calcium carbonate, microcrystalline cellulose (PH-101), lactose monohydrate, croscarmellose sodium, polysorbate 80, hypromellose (hydroxypropylcellulose), magnesium stearate.

Coating composition Opadry^® white YS-1-7040 (contains hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol 8000), titanium dioxide, talc), simethicone emulsion (contains purified water, simethicone, polysorbate 65, methylcellulose, PEG 8 stearate, glyceryl stearate, xanthan gum, benzoic acid, sorbic acid, sulfuric acid).

7 pcs. – blisters (2) – cardboard packs with first opening control.
7 pcs. – blisters (4) – cardboard packs with first opening control.
7 pcs. – blisters (5) – cardboard packs with first opening control.
7 pcs. – blisters (8) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (5) – cardboard packs with first opening control.
10 pcs. – blisters (10) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor of steroids, including cholesterol. It is a synthetic hypolipidemic agent.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia, Atorvastatin reduces plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo-B), as well as very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG), and increases the concentration of high-density lipoprotein cholesterol (HDL-C).

Atorvastatin reduces plasma concentrations of TC and LDL-C by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, leading to enhanced uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles. It causes a pronounced and sustained increase in LDL receptor activity combined with favorable qualitative changes in LDL particles. It reduces LDL-C concentration in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Atorvastatin at doses of 10-80 mg reduces TC concentration by 30-46%, LDL-C by 41-61%, apo-B by 34-50%, and TG by 14-33%. The results of therapy are similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with type 2 diabetes mellitus.

In patients with isolated hypertriglyceridemia, Atorvastatin reduces the concentration of TC, LDL-C, VLDL-C, apo-B, and TG and increases HDL-C levels. In patients with dysbetalipoproteinemia, it reduces the content of intermediate-density lipoprotein cholesterol (IDL-C).

In patients with hyperlipoproteinemia type IIa and IIb according to the Fredrickson classification, the mean increase in HDL-C concentration during treatment with atorvastatin (10-80 mg), compared to baseline, is 5.1-8.7% and is dose-independent. There is a significant dose-dependent decrease in the ratios: total cholesterol/HDL-C and LDL-C/HDL-C by 29-44% and 37-55%, respectively.

Atorvastatin at a dose of 80 mg significantly reduces the risk of ischemic complications and mortality by 16% after a 16-week course, and the risk of rehospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26% (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study). In patients with different baseline LDL-C concentrations, Atorvastatin reduces the risk of ischemic complications and mortality (in patients with non-Q-wave myocardial infarction and unstable angina, men and women, patients younger and older than 65 years).

The reduction in plasma LDL-C concentration correlates better with the dose of atorvastatin than with its plasma concentration. The dose is selected taking into account the therapeutic effect (see section “Dosage Regimen”).

The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks, and persists throughout the entire therapy period.

Prevention of cardiovascular diseases

Atorvastatin at a dose of 10 mg reduces the relative risk of developing coronary complications (fatal CHD and non-fatal myocardial infarction (MI)) by 36%, total cardiovascular complications by 29%, fatal and non-fatal stroke by 26% (Atorvastatin in patients with Hypertension and Risk Factors (ASCOT LLA) study).

Diabetes mellitus

In patients with diabetes mellitus, therapy with atorvastatin reduces the relative risk of developing major cardiovascular complications (fatal and non-fatal MI, silent myocardial ischemia, fatal outcome due to exacerbation of CHD, unstable angina, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, revascularization procedures, stroke) by 37%, MI (fatal and non-fatal) by 42%, stroke (fatal and non-fatal) by 48% regardless of gender, patient age, or baseline LDL-C concentration (Collaborative Atorvastatin Diabetes Study (CARDS)).

Atherosclerosis

In patients with CHD, Atorvastatin at a dose of 80 mg/day leads to a reduction in total atheroma volume by 0.4% over 1.8 months of therapy (Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study).

Recurrent stroke

Atorvastatin at a dose of 80 mg/day reduces the risk of recurrent fatal or non-fatal stroke in patients who have had a stroke or transient ischemic attack (TIA) without a history of CHD (Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study), by 16% compared to placebo. This significantly reduces the risk of major cardiovascular complications and revascularization procedures. The reduction in the risk of cardiovascular disorders during therapy with atorvastatin is observed in all patient groups, except for the group that included patients with primary or recurrent hemorrhagic stroke.

Secondary prevention of cardiovascular complications

In patients with CHD, Atorvastatin at a dose of 80 mg, compared with 10 mg, significantly reduces the relative risk of developing major cardiovascular events by 22%, non-fatal MI (not associated with revascularization procedures) by 22%, fatal and non-fatal stroke by 25% (comparison of intensive atorvastatin therapy and moderate-intensity therapy in patients with CHD (according to the TNT study data)).

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration: the time to reach C_max is 1-2 hours. In women, the C_max of atorvastatin is 20% higher, and the AUC is 10% lower than in men. The extent of absorption and plasma concentrations of atorvastatin increase proportionally with the dose. The bioavailability of atorvastatin in tablet form is 95-99% compared to atorvastatin in solution. Absolute bioavailability is about 14%, and systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and/or during first-pass through the liver. Food intake somewhat reduces the rate and extent of absorption by approximately 25% and 9%, respectively (as evidenced by C_max and AUC determination results), but the reduction in LDL-C is similar to that when atorvastatin is taken on an empty stomach. Although plasma concentrations of atorvastatin after evening intake are lower (C_max and AUC approximately 30%) than after morning intake, the reduction in LDL-C does not depend on the time of day the drug is taken.

Distribution

The mean V_d of atorvastatin is about 381 L. Plasma protein binding is at least 98%. The erythrocyte/plasma concentration ratio of atorvastatin is about 0.25, i.e., Atorvastatin poorly penetrates erythrocytes.

Metabolism

Atorvastatin is extensively metabolized to form ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro, the ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% of the reduction in HMG-CoA reductase activity is due to the action of active circulating metabolites. Results of in vitro studies suggest that the hepatic isoenzyme CYP3A4 plays an important role in the metabolism of atorvastatin. This is supported by an increase in plasma concentrations of atorvastatin when co-administered with erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that Atorvastatin is a weak inhibitor of the CYP3A4 isoenzyme. Atorvastatin has no clinically significant effect on the plasma concentration of terfenadine, which is metabolized primarily by the CYP3A4 isoenzyme, so its significant effect on the pharmacokinetics of other substrates of the CYP3A4 isoenzyme is unlikely (see section “Drug Interactions”).

Excretion

Atorvastatin and its metabolites are excreted mainly in bile after hepatic and/or extrahepatic metabolism (Atorvastatin does not undergo significant enterohepatic recirculation). T_1/2 is about 14 hours, and the inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and persists for about 20-30 hours due to their presence. After oral administration, less than 2% of the administered dose of the drug is found in urine.

Atorvastatin is a substrate for liver enzyme transporters, OATP1B1 and OATP1B3 transporters. Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters MDR1 and breast cancer resistance protein, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Pharmacokinetics in special patient groups

Elderly patients. The plasma concentration of atorvastatin in patients over 65 years of age is higher (C_max approximately 40%, AUC approximately 30%) than in young adult patients. No differences in safety, efficacy, or achievement of hypolipidemic therapy goals were found in elderly patients compared to the general population.

Children. In an 8-week open-label study, children (aged 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C ≥4 mmol/L received therapy with atorvastatin as chewable tablets 5 mg or 10 mg or film-coated tablets at a dose of 10 mg or 20 mg once daily, respectively. The only significant covariate in the population pharmacokinetic model receiving Atorvastatin was body weight. The apparent clearance of atorvastatin in children did not differ from that in adult patients with allometric scaling by body weight. A consistent reduction in LDL-C and TC was observed over the range of atorvastatin and o-hydroxyatorvastatin exposure.

Gender. Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C_max and 10% lower for AUC). However, no clinically significant differences in lipid effects between men and women were observed.

Renal impairment. Renal impairment does not affect the plasma concentration of atorvastatin or its effect on lipid metabolism parameters. Therefore, no dose adjustment is required in patients with renal impairment (see section “Dosage Regimen”). No studies have been conducted on the use of atorvastatin in patients with end-stage renal disease. Atorvastatin is not removed by hemodialysis due to extensive binding to plasma proteins.

Hepatic impairment. The concentration of atorvastatin is significantly increased (C_max approximately 16 times, AUC approximately 11 times) in patients with alcoholic liver cirrhosis (Child-Pugh class B) (see section “Contraindications”).

SLCO1B1 polymorphism

Hepatic uptake of all HMG-CoA reductase inhibitors, including Atorvastatin, occurs with the participation of the OATP1B1 transporter. Patients with SLCO1B1 genetic polymorphism are at risk of increased atorvastatin exposure, which may lead to an increased risk of rhabdomyolysis. Polymorphism of the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold increase in atorvastatin exposure (AUC) compared to patients without this genotypic change (c.521TT). Impaired hepatic uptake of atorvastatin associated with genetic disorders may also occur in such patients. Possible consequences for efficacy are unknown.

Drug interaction studies

Atorvastatin is a substrate of the hepatic transport proteins OATP1B1 and OATP1B3. Atorvastatin metabolites are substrates of OATP1B1. It has also been established that Atorvastatin is a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary excretion of atorvastatin.

Liprimar^® did not have a clinically significant effect on prothrombin time in patients receiving long-term warfarin therapy.

Indications

Hypercholesterolemia

• As an adjunct to diet to reduce elevated total cholesterol, LDL-C, apo-B, and triglycerides in adults, adolescents, and children aged 10 years or older with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (corresponding to types IIa and IIb according to the Fredrickson classification), when the response to diet and other non-pharmacological treatments is insufficient;
• To reduce elevated total cholesterol and LDL-C in adults with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Prevention of Cardiovascular Diseases

• Prevention of cardiovascular events in adult patients at high risk of developing primary cardiovascular events, as an adjunct to the correction of other risk factors;
• Secondary prevention of cardiovascular complications in patients with coronary artery disease to reduce mortality, myocardial infarctions, strokes, rehospitalizations for angina, and the need for revascularization.

ICD codes

Dosage Regimen

The drug is taken orally at any time of the day, regardless of meals.

Before starting treatment with Liprimar^®, an attempt should be made to control hypercholesterolemia through diet, physical exercise, and weight reduction in obese patients, as well as treatment of the underlying disease.

When prescribing the drug, the patient should be recommended a standard hypocholesterolemic diet, which they must adhere to throughout the entire therapy period.

The drug dose varies from 10 mg to 80 mg once daily and is titrated based on LDL-C concentration, therapy goals, and individual response to the treatment.

The maximum daily dose of the drug is 80 mg.

At the start of treatment and/or during dose increase of Liprimar^®, plasma lipid concentrations should be monitored every 2-4 weeks, and the drug dose should be adjusted accordingly.

For primary hypercholesterolemia and combined (mixed) hyperlipidemia, the recommended dose of Liprimar^® for most patients is 10 mg once daily. The therapeutic effect occurs within 2 weeks and usually reaches its maximum after 4 weeks. The effect is maintained during long-term treatment.

For homozygous familial hypercholesterolemia, the drug is prescribed in most cases at a dose of 80 mg once daily (reduction in LDL-C concentration by 18-45%).

For heterozygous familial hypercholesterolemia, the initial dose is 10 mg/day. The dose should be individually selected and the appropriateness of the dose assessed every 4 weeks, with a possible increase to 40 mg/day. Then, the dose can either be increased to the maximum of 80 mg/day, or bile acid sequestrants can be combined with atorvastatin at a dose of 40 mg/day.

Prevention of cardiovascular diseases: in primary prevention studies, the atorvastatin dose was 10 mg/day. A dose increase may be necessary to achieve LDL-C values consistent with current guidelines.

Use in children aged 10 to 18 years with heterozygous familial hypercholesterolemia: the recommended initial dose is 10 mg once daily. The dose can be increased to 80 mg/day depending on the clinical effect and tolerability. The drug dose must be titrated according to the goal of lipid-lowering therapy. Dose adjustment should be performed at intervals of once every 4 weeks or longer.

In hepatic insufficiency, the dose of Liprimar^® should be reduced with regular monitoring of liver transaminase activity: AST and ALT.

Renal impairment does not affect the plasma concentration of atorvastatin or the degree of LDL-C reduction, therefore dose adjustment of the drug is not required.

When using the drug in elderly patients, no differences in therapeutic efficacy and safety compared to the general population were found; dose adjustment is not required (see section “Pharmacokinetics”).

Use in combination with other medicinal products

When concomitant use with cyclosporine, telaprevir, or the combination tipranavir/ritonavir or glecaprevir/pibrentasvir is necessary, the dose of Liprimar^® should not exceed 10 mg/day.

Atorvastatin is not recommended for patients receiving letermovir therapy concomitantly with cyclosporine.

Pharmacokinetic drug interaction leading to increased systemic plasma concentration of atorvastatin has also been noted with other HIV protease inhibitors (lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir, and nelfinavir), hepatitis C protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin, itraconazole, and letermovir. Caution should be exercised when co-administering with atorvastatin. Appropriate clinical assessment is recommended, and the lowest effective dose of atorvastatin should be used (see sections “Special Precautions” and “Drug Interactions”).

Adverse Reactions

Liprimar^® is usually well tolerated. Adverse reactions are generally mild and transient.

Adverse reactions are distributed by frequency according to the following classification: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), unknown - cannot be estimated from the available data. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations common – nasopharyngitis.

Blood and lymphatic system disorders rare – thrombocytopenia.

Immune system disorders: common – allergic reactions; very rare – anaphylaxis.

Metabolism and nutrition disorders common – hyperglycemia; uncommon – hypoglycemia, weight increase, anorexia; unknown – diabetes mellitus: frequency of development depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated TG levels, history of arterial hypertension).

Psychiatric disorders uncommon – nightmare, insomnia; unknown – depression.

Nervous system disorders common – headache; uncommon – dizziness, paresthesia, hypoesthesia, taste perversion, amnesia; rare – peripheral neuropathy; unknown – memory loss or impairment.

Eye disorders uncommon – visual blurring; rare – visual disturbance.

Ear and labyrinth disorders: uncommon – tinnitus; very rare – hearing loss.

Respiratory, thoracic and mediastinal disorders common – pharyngolaryngeal pain, epistaxis; unknown – isolated cases of interstitial lung disease (usually with long-term use).

Gastrointestinal disorders common – constipation, flatulence, dyspepsia, nausea, diarrhea; uncommon – vomiting, abdominal pain, eructation, pancreatitis, abdominal discomfort.

Hepatobiliary disorders uncommon – hepatitis; rare – cholestasis; very rare – hepatic failure.

Skin and subcutaneous tissue disorders uncommon – urticaria, pruritus, skin rash, alopecia; rare – angioedema, bullous rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Musculoskeletal and connective tissue disorders common – myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain, musculoskeletal pain; uncommon – neck pain, muscle weakness; rare – myopathy, myositis, rhabdomyolysis, tendinopathy (in some cases with tendon rupture); unknown – immune-mediated necrotizing myopathy.

Reproductive system and breast disorders uncommon – impotence; very rare – gynecomastia.

General disorders and administration site conditions uncommon – malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia.

Investigations common – abnormal liver function tests (AST and ALT), increased blood creatine phosphokinase; uncommon – leukocyturia; unknown – increased glycosylated hemoglobin (Hb_A1) concentration.

Children

The number of adverse reactions associated with Liprimar^® intake did not differ from the number of reactions with placebo. The most frequent reactions, regardless of causality assessment, were infections.

Children and adolescents aged 10 to 17 years who were treated with atorvastatin had an adverse event profile that was comparable to that of patients receiving placebo. The most common adverse effects observed, regardless of causality assessment in both groups, were infections. During a 3-year study evaluating overall maturation and development, Tanner stage, and measurements of height and weight, no clinically significant effect on growth and puberty was observed. The safety and tolerability profile in children and adolescents was generally consistent with the known safety profile of atorvastatin in adult patients.

The clinical safety database also includes data from 520 pediatric patients who received Atorvastatin. Of these: 7 patients were younger than 6 years, 121 patients were aged 6 to 9 years, and 392 patients were aged 10 to 17 years. Based on the available data, the frequency, type, and severity of adverse effects in children are similar to those in adults.

The following undesirable adverse effects have been observed with the use of certain statins

• Sexual dysfunction;
• Depression;
• In exceptional cases, especially during long-term therapy, interstitial lung disease (see section “Special Precautions”);
• Diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m², elevated TG levels, existing arterial hypertension).

Contraindications

• Hypersensitivity to atorvastatin or to any of the components of the drug;
• Active liver disease or unexplained persistent elevation of plasma hepatic transaminases more than 3 times the upper limit of normal (ULN);
• Pregnancy;
• Breastfeeding period;
• Women of childbearing potential not using adequate contraceptive methods;
• Age under 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group), except for heterozygous familial hypercholesterolemia (use is contraindicated in children under 10 years of age);
• Concomitant use with fusidic acid;
• Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

In patients who abuse alcohol; in patients with a history of liver disease.

In patients with risk factors for rhabdomyolysis (renal impairment, hypothyroidism, personal or family history of hereditary muscle disorders, previous toxic effect of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue, history of liver disease and/or patients who consume significant amounts of alcohol, age over 70 years, situations where an increase in plasma atorvastatin concentration is expected (e.g., interaction with other drugs)).

Use in Pregnancy and Lactation

Women of childbearing potential

Women of childbearing age should use appropriate contraceptive methods during treatment (see section “Contraindications”).

Pregnancy

Liprimar^® is contraindicated during pregnancy (see section “Contraindications”). Safety during pregnancy has not been established. No controlled clinical studies with atorvastatin have been conducted in pregnant women. Rare cases of congenital anomalies have been reported following intrauterine exposure to HMG-CoA reductase inhibitors (statins). Studies in animals have shown reproductive toxicity.

When atorvastatin is taken by a pregnant woman, a decrease in mevalonate levels in the fetus is possible, as mevalonate is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy generally has only a minor impact on the long-term risk associated with primary hypercholesterolemia.

Therefore, Liprimar^® should not be prescribed to pregnant women, women planning pregnancy, or if pregnancy is suspected. Liprimar^® should be discontinued during pregnancy or until pregnancy is ruled out (see section “Contraindications”).

Breastfeeding period

It is not known whether Atorvastatin or its metabolites are excreted in human breast milk. In rat studies, plasma concentrations of atorvastatin and its active metabolites were similar to those in milk. Due to the risk of serious adverse effects, women taking Liprimar^® should not breastfeed their children. The use of Liprimar^® is contraindicated during breastfeeding (see section “Contraindications”).

Fertility

In animal studies, Atorvastatin had no effect on fertility in males or females.

Use in Hepatic Impairment

Contraindicated in active liver disease or unexplained persistent elevation of plasma hepatic transaminases more than 3 times the ULN.

Should be used with caution in patients with a history of liver disease.

Use in Renal Impairment

Renal impairment does not affect the plasma concentration of atorvastatin or the degree of LDL-C reduction, therefore no dose adjustment of the drug is required.

Pediatric Use

Contraindicated under the age of 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group), except for heterozygous familial hypercholesterolemia (use is contraindicated in children under 10 years of age).

Geriatric Use

The drug should be prescribed with caution to patients over 70 years of age.

Special Precautions

Effect on the liver

As with other hypolipidemic agents of this class, moderate elevations (more than 3 times the ULN) in liver transaminases AST and ALT have been observed with the use of Liprimar^®. Persistent elevation of serum hepatic transaminases (more than 3 times the ULN) was observed in 0.7% of patients receiving Liprimar^®. The frequency of such changes when using the drug at doses of 10 mg, 20 mg, 40 mg, and 80 mg was 0.2%, 0.2%, 0.6%, and 2.3%, respectively. Elevation of liver transaminases was usually not accompanied by jaundice or other clinical manifestations. When the dose of Liprimar^® was reduced, temporarily interrupted, or completely discontinued, liver transaminase activity returned to baseline. Most patients continued taking Liprimar^® at a reduced dose without any clinical consequences.

Liver function tests should be performed before starting therapy, 6 weeks and 12 weeks after starting Liprimar^® or after increasing its dose. Liver function should also be monitored if clinical signs of liver damage appear. In case of elevated liver transaminases, ALT and AST should be monitored until they normalize. If the elevation of AST or ALT more than 3 times the ULN persists, a reduction in dose or discontinuation of Liprimar^® is recommended (see section “Adverse Reactions”).

Liprimar^® should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or persistently elevated plasma hepatic transaminases of unclear etiology are contraindications for the use of Liprimar^® (see section “Contraindications”).

Effect on skeletal muscle

Myalgia has been reported in patients receiving Liprimar^® (see section “Adverse Reactions”). Myopathy should be considered in patients with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK (more than 10 times the ULN). Therapy with Liprimar^® should be discontinued if a marked elevation in CPK occurs, or if myopathy is diagnosed or suspected. The risk of myopathy was increased with the concomitant use of drugs that increase the systemic concentration of atorvastatin (see sections “Drug Interactions” and “Pharmacokinetics”). Many of these drugs inhibit metabolism mediated by the CYP3A4 isoenzyme and/or drug transport. The CYP3A4 isoenzyme is known to be the primary hepatic isoenzyme involved in the biotransformation of atorvastatin. When using Liprimar^® in combination with fibrates, erythromycin, immunosuppressants, azole antifungals, HIV/HCV protease inhibitors, hepatitis C non-structural protein inhibitors (NS5A/NS5B), letermovir, or niacin in lipid-lowering doses (>1 g/day), the physician must carefully weigh the expected benefit of treatment against the possible risk. Patients should be regularly monitored for signs of muscle pain or weakness, especially during the first months of therapy and during dose escalation of any of these agents. If combination therapy is necessary, the possibility of using lower initial and maintenance doses of the aforementioned agents should be considered (see section “Dosage Regimen”). Concomitant use of atorvastatin and fusidic acid is not recommended, so temporary discontinuation of atorvastatin is advised during treatment with fusidic acid. In such situations, periodic monitoring of CPK activity can be recommended, although such monitoring may not prevent the development of severe myopathy (see section “Drug Interactions”).

Before starting treatment

Atorvastatin should be prescribed with caution to patients with factors predisposing to the development of rhabdomyolysis. Control of CPK activity should be performed in the following cases before starting atorvastatin therapy

• Impaired renal function;
• Hypothyroidism;
• Hereditary muscle disorders in the patient’s history or family history;
• Previously experienced toxic effects of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue;
• History of liver disease and/or patients who consume significant amounts of alcohol;
• In patients over 70 years of age, the need for CPK control should be assessed, considering that these patients already have factors predisposing to the development of rhabdomyolysis;
• Situations in which an increase in the plasma concentration of atorvastatin is expected, such as interactions with other drugs (see the “Drug Interactions” section).

In such situations, the risk/benefit ratio should be assessed and medical monitoring of the patient’s condition should be carried out.

In case of a significant increase in CPK activity (more than 5 times the ULN), atorvastatin therapy should not be started.

When using Liprimar^®, as well as other HMG-CoA reductase inhibitors, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described. A risk factor for the development of rhabdomyolysis may be pre-existing renal impairment. Such patients should be provided with more careful monitoring of the musculoskeletal system. If symptoms of possible myopathy occur or if there are risk factors for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, major surgery, trauma, metabolic, endocrine and water-electrolyte imbalances, uncontrolled seizures), therapy with Liprimar^® should be temporarily discontinued or completely withdrawn.

Attention! Patients should be warned that they should immediately consult a doctor if unexplained pain or muscle weakness appears, especially if they are accompanied by malaise or fever.

Hemorrhagic stroke

A special analysis of a clinical study involving 4731 patients without coronary artery disease who had a stroke or TIA within the previous 6 months and were prescribed Atorvastatin 80 mg/day revealed a higher incidence of hemorrhagic strokes in the atorvastatin 80 mg group compared to the placebo group (55 in the atorvastatin group versus 33 in the placebo group). Patients with a hemorrhagic stroke at the time of inclusion in the study had a higher risk of recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group). However, patients receiving Atorvastatin at a dose of 80 mg/day had fewer strokes of any type (265 versus 311) and fewer cardiovascular events (123 versus 204) (see the “Pharmacological action” section).

Diabetes mellitus

Some evidence suggests that HMG-CoA reductase inhibitors (statins), as a class, may lead to an increase in plasma glucose concentration, and in some patients at high risk of developing diabetes mellitus, a state of hyperglycemia requiring correction as in diabetes mellitus may develop. However, this risk does not outweigh the benefit of HMG-CoA reductase inhibitor (statin) therapy in terms of vascular risks, so this cannot be a reason to discontinue therapy. Patients at risk (fasting blood glucose concentration from 5.6 to 6.9 mmol/L, BMI >30 kg/m², elevated plasma TG concentration, arterial hypertension) should be under medical supervision, including monitoring of blood biochemical parameters, in accordance with local guidelines.

Interstitial lung disease

During therapy with some HMG-CoA reductase inhibitors (statins), especially during long-term therapy, isolated cases of interstitial lung disease have been noted. Dyspnea, non-productive cough and deterioration in general health (fatigue, weight loss and fever) may be observed. If interstitial lung disease is suspected in a patient, atorvastatin therapy should be discontinued.

Endocrine function

When using HMG-CoA reductase inhibitors (statins), including atorvastatin, cases of increased glycosylated hemoglobin (Hb_A1) and fasting plasma glucose concentration have been noted. However, the risk of hyperglycemia is lower than the degree of reduction in the risk of vascular complications while taking HMG-CoA reductase inhibitors (statins).

Excipients

Liprimar^® contains lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome should not take Liprimar^®.

Liprimar^® contains sodium. The 10 mg and 20 mg tablets contain less than 1 mmol (23 mg) of sodium, i.e., the preparation is essentially sodium-free. The 40 mg and 80 mg tablets contain more than 1 mmol (23 mg) of sodium, so this information must be taken into account for patients on a sodium-restricted diet.

Effect on ability to drive vehicles and mechanisms

There are no data on the effect of Liprimar^® on the ability to drive vehicles and engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. However, given the possibility of dizziness, caution should be exercised when performing these types of activities.

Overdose

Treatment There is no specific antidote. If necessary, symptomatic therapy is carried out. Liver function tests should be performed and CPK activity should be monitored. Since the drug is actively bound to plasma proteins, hemodialysis is ineffective.

Drug Interactions

During treatment with HMG-CoA reductase inhibitors, when used concomitantly with cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (>1 g/day) or inhibitors of the CYP3A4 isoenzyme/transport protein (for example, erythromycin, clarithromycin, antifungal agents – azole derivatives), the risk of myopathy increases (see the “Dosage regimen” and “Special instructions” sections).

Inhibitors of the CYP3A4 isoenzyme

Since Atorvastatin is metabolized by the CYP3A4 isoenzyme, concomitant use of atorvastatin with inhibitors of the CYP3A4 isoenzyme may lead to an increase in the plasma concentration of atorvastatin. The degree of interaction and potentiation effect is determined by the variability of the effect on the CYP3A4 isoenzyme.

It has been established that potent inhibitors of the CYP3A4 isoenzyme lead to a significant increase in the plasma concentration of atorvastatin. Concomitant use of potent inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir and others) should be avoided if possible. If concomitant use of these drugs is necessary, the possibility of starting therapy with the minimum dose should be considered, and the possibility of reducing the maximum dose of atorvastatin should be assessed.

Moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, diltiazem, verapamil and fluconazole) may lead to an increase in the plasma concentration of atorvastatin. An increased risk of myopathy has been noted with the concomitant use of HMG-CoA reductase inhibitors (statins) and erythromycin. Interaction studies of amiodarone or verapamil and atorvastatin have not been conducted. It is known that both amiodarone and verapamil inhibit the activity of the CYP3A4 isoenzyme and concomitant use of these drugs with atorvastatin may lead to an increase in atorvastatin exposure. In this regard, it is recommended to reduce the maximum dose of atorvastatin and conduct appropriate monitoring of the patient’s condition when used concomitantly with moderate inhibitors of the CYP3A4 isoenzyme. Monitoring should be carried out after the start of therapy and when changing the dose of the inhibitor.

Gemfibrozil/fibrates

During monotherapy with fibrates, adverse reactions, including rhabdomyolysis, related to the musculoskeletal system have been periodically noted. The risk of such reactions increases with the concomitant use of fibrates and atorvastatin. If concomitant use of these drugs cannot be avoided, the minimum effective dose of atorvastatin should be used, and regular monitoring of patients should be carried out.

Ezetimibe

The use of ezetimibe is associated with the development of adverse reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with the concomitant use of ezetimibe and atorvastatin. Careful monitoring is recommended for such patients.

Erythromycin/clarithromycin

With concomitant use of atorvastatin and erythromycin (500 mg 4 times/day) or clarithromycin (500 mg 2 times/day), inhibitors of CYP3A4, an increase in the plasma concentration of atorvastatin was observed (see the “Special instructions” and “Pharmacokinetics” sections).

Protease inhibitors

Concomitant use of atorvastatin with protease inhibitors, known as CYP3A4 inhibitors, is accompanied by an increase in the plasma concentration of atorvastatin.

Diltiazem

Concomitant use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the plasma concentration of atorvastatin (see the “Pharmacokinetics” section).

Cimetidine

No clinically significant interaction between atorvastatin and cimetidine was found (see the “Pharmacokinetics” section).

Itraconazole

Concomitant use of atorvastatin at doses from 20 mg to 40 mg and itraconazole at a dose of 200 mg led to an increase in the AUC value of atorvastatin (see the “Pharmacokinetics” section).

Grapefruit juice

Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, its excessive consumption (more than 1.2 l/day) can cause an increase in the plasma concentration of atorvastatin (see the “Pharmacokinetics” section).

Transport protein inhibitors

Atorvastatin is a substrate of liver enzyme transporters (see the “Pharmacokinetics” section).

Concomitant use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day led to an increase in atorvastatin exposure (AUC ratio: 8.7) (see the “Pharmacokinetics” section). Cyclosporine is an inhibitor of the organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, multidrug resistance-associated protein 1 (MDR1) and breast cancer resistance protein, as well as CYP3A4, therefore it increases atorvastatin exposure. The daily dose of atorvastatin should not exceed 10 mg (see the “Dosage regimen” section).

Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein, therefore they increase atorvastatin exposure. The daily dose of atorvastatin should not exceed 10 mg (see the “Dosage regimen” section).

Concomitant use of atorvastatin at a dose of 20 mg and letermovir at a dose of 480 mg/day led to an increase in atorvastatin exposure (AUC ratio: 3.29) (see the “Pharmacokinetics” section). Letermovir is an inhibitor of Pgp, BCRP, MRP2, OAT2 transporters and the hepatic transporter OATP1B1/1B3, thus it enhances atorvastatin exposure. The daily dose of atorvastatin should not exceed 20 mg (see the “Dosage regimen” section).

The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interaction on the concomitant use of drugs may differ when letermovir is co-administered with cyclosporine. Atorvastatin is not recommended for patients receiving letermovir therapy concomitantly with cyclosporine.

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein, therefore they increase atorvastatin exposure. They should be used with caution and at the lowest necessary dose (see the “Dosage regimen” section).

Inducers of the cytochrome CYP3A4 isoenzyme

Concomitant use of atorvastatin with inducers of the cytochrome CYP3A4 isoenzyme (for example, efavirenz or rifampicin or preparations of St. John’s wort) may lead to a decrease in the plasma concentration of atorvastatin. Due to the dual mechanism of interaction with rifampicin (an inducer of the cytochrome CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), concomitant use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after rifampicin intake leads to a significant decrease in the plasma concentration of atorvastatin (see the “Pharmacokinetics” section). However, the effect of rifampicin on the concentration of atorvastatin in hepatocytes is unknown, and if concomitant use cannot be avoided, the effectiveness of such a combination should be carefully monitored during therapy.

Antacids

Concomitant oral administration of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the plasma concentration of atorvastatin (AUC change: 0.66), but the degree of reduction in LDL-C concentration did not change.

Phenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

Colestipol

With concomitant use of colestipol, the plasma concentration of atorvastatin decreased (AUC change: 0.74); however, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug separately.

Digoxin

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, the concentration of digoxin increased (AUC change: 1.15). Patients receiving digoxin in combination with atorvastatin require clinical monitoring.

Azithromycin

With concomitant use of atorvastatin at a dose of 10 mg once/day and azithromycin at a dose of 500 mg once/day, the plasma concentration of atorvastatin did not change.

Oral contraceptives

With concomitant use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, an increase in the concentration of norethisterone (AUC change: 1.28) and ethinyl estradiol (AUC change: 1.19) was observed. This effect should be taken into account when choosing an oral contraceptive for a woman taking Atorvastatin.

Terfenadine

With concomitant use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine were found.

Warfarin

In a clinical study in patients regularly receiving warfarin therapy, concomitant use of atorvastatin at a dose of 80 mg/day led to a slight increase in prothrombin time by approximately 1.7 sec during the first 4 days of therapy. The indicator returned to normal within 15 days of atorvastatin therapy. Although significant interaction affecting anticoagulant function has been noted only in rare cases, prothrombin time should be determined before starting atorvastatin therapy in patients receiving coumarin anticoagulants and frequently enough during therapy to prevent significant changes in prothrombin time. Once the prothrombin time value has stabilized, its control can be carried out as recommended for patients receiving coumarin anticoagulants. When changing the dose of atorvastatin or discontinuing therapy, prothrombin time control should be carried out according to the same principles described above. Atorvastatin therapy was not associated with the development of bleeding or changes in prothrombin time in patients who were not receiving anticoagulant treatment.

Colchicine

Although studies of the concomitant use of colchicine and atorvastatin have not been conducted, there are reports of the development of myopathy with the use of this combination. Caution should be exercised when using atorvastatin and colchicine concomitantly.

Amlodipine

In a drug interaction study in healthy subjects, concomitant use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg led to a clinically insignificant increase in atorvastatin concentration (AUC change: 1.18).

Fusidic acid

During post-marketing studies, cases of rhabdomyolysis have been reported in patients taking statins, including Atorvastatin, and fusidic acid concomitantly. The mechanism of this interaction is unknown. In patients for whom the use of fusidic acid is considered necessary, statin treatment should be discontinued for the entire period of fusidic acid use. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases, where prolonged systemic therapy with fusidic acid is necessary, for example, for the treatment of severe infections, the need for concomitant use of atorvastatin and fusidic acid should be considered in each specific case and under strict medical supervision. The patient should immediately seek medical attention if symptoms of muscle weakness, tenderness or pain appear.

Other concomitant therapy

In clinical studies, Atorvastatin was used in combination with antihypertensive agents and estrogens as part of hormone replacement therapy. No signs of clinically significant undesirable interaction were noted; interaction studies with specific drugs have not been conducted.

In addition, an increase in atorvastatin concentration was noted with concomitant use with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir), clarithromycin and itraconazole. Caution should be exercised when using these drugs concomitantly, and the lowest effective dose of atorvastatin should be used.

Effect of other drugs on the pharmacokinetics of atorvastatin

^&The ratio of therapy types is presented (co-administration of the drug with atorvastatin compared to the use of atorvastatin alone).

Children

Interaction studies have been conducted only in adult patients.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.