Liprimar, 10 mg, film-coated tablets, 30 pcs.

Liprimar

Synthetic lipid-lowering drug. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into mevalonate, a precursor of steroids, including cholesterol.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the content of total cholesterol (C), LDL-C and apolipoprotein B (apo-B) in the blood plasma, as well as the content of VLDL-C and TG, causing unstable increase in HDL-C levels.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles. Causes a pronounced and persistent increase in the activity of LDL receptors, combined with favorable qualitative changes in LDL particles. Reduces the level of LDL-C in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Atorvastatin in doses of 10-80 mg reduces total cholesterol by 30-46%, LDL-C by 41-61%, apo-B by 34-50% and TG by 14-33%. Treatment results are similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, incl. in patients with non-insulin-dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia, atorvastatin reduces the levels of total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases the level of HDL-C. In patients with dysbetalipoproteinemia, it reduces the level of intermediate-density lipoprotein cholesterol.

In patients with hyperlipoproteinemia types IIa and IIb according to the Fredrickson classification, the average increase in HDL-C levels during treatment with atorvastatin (10-80 mg), compared with the baseline value, is 5.1-8.7% and is independent of dose. 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.

Liprimar® at a dose of 80 mg significantly reduces the risk of ischemic complications and mortality rate by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26%. In patients with different initial levels of LDL-C, Liprimar® causes a reduction in the risk of ischemic complications and death (in patients with myocardial infarction without a Q wave and unstable angina, men and women, patients under and over 65 years of age).

A decrease in plasma LDL cholesterol levels correlates better with the dose of the drug than with its concentration in the blood plasma.

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

Prevention of cardiovascular diseases

In the Anglo-Scandinavian study of cardiovascular complications, lipid-lowering branch (ASCOT-LLA), the effect of atorvastatin on fatal and non-fatal outcomes of coronary artery disease found that the effect of treatment with atorvastatin at a dose of 10 mg significantly exceeded the effect of placebo, and therefore it was decided to early termination of the study after 3.3 years instead of the expected 5 years.

Atorvastatin significantly reduced the development of the following complications:

There were no significant reductions in overall mortality and mortality from cardiovascular causes, although positive trends were observed.

Diabetes

The pooled study of the effects of atorvastatin in patients with type 2 diabetes (CARDS) on fatal and non-fatal cardiovascular disease outcomes showed that atorvastatin therapy, regardless of patient gender, age or baseline LDL-C level, reduced the risk of developing the following cardiovascular events :

Atherosclerosis

The Reversal of Coronary Atherosclerosis with Intensive Lipid-Lowering Therapy (REVERSAL) study with atorvastatin 80 mg in patients with coronary artery disease found that the average reduction in total atheroma volume (the primary outcome measure) from the start of the study was 0.4%.

Recurrent stroke

The Intensive Reduction in Cholesterol Levels (SPARCL) program found that atorvastatin 80 mg/day reduced the risk of recurrent fatal or nonfatal stroke in patients with a history of stroke or transient ischemic attack without a history of coronary artery disease by 15% compared with placebo. At the same time, the risk of major cardiovascular complications and revascularization procedures was significantly reduced. A reduction in the risk of cardiovascular events during atorvastatin therapy was observed in all groups except the one that included patients with primary or recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group).

Hemorrhagic stroke

In patients treated with atorvastatin 80 mg, the incidence of hemorrhagic or ischemic stroke (265 versus 311) or coronary artery disease (123 versus 204) was lower than in the control group.

Secondary prevention of cardiovascular complications

The Treatment of the New Targeted Trial (TNT) compared the effect of atorvastatin at doses of 80 mg/day and 10 mg/day on the risk of cardiovascular events in patients with clinically confirmed coronary artery disease.

Atorvastatin at a dose of 80 mg significantly reduced the development of the following complications:

Pharmacokinetics

Suction

Atorvastatin is rapidly absorbed after oral administration; Cmax is reached after 1-2 hours. The degree of absorption and plasma concentrations of atorvastatin increase in proportion to the dose. The absolute bioavailability of atorvastatin is about 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to first-pass metabolism in the gastrointestinal mucosa and/or during the “first pass” through the liver. Food reduces the rate and extent of absorption by approximately 25% and 9%, respectively (as evidenced by Cmax and AUC), but the reduction in LDL-C is similar to that observed with fasting atorvastatin. Despite the fact that after taking atorvastatin in the evening, its plasma concentration is lower (Cmax and AUC by approximately 30%) than after taking it in the morning, the decrease in LDL-C does not depend on the time of day at which the drug is taken.

Distribution

The average Vd of atorvastatin is about 381 l. The binding of atorvastatin to plasma proteins is at least 98%. The ratio of atorvastatin content in red blood cells/blood plasma is about 0.25, i.e. Atorvastatin penetrates red blood cells poorly.

Metabolism

Atorvastatin is extensively metabolized to form ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% of the decrease in HMG-CoA reductase activity is due to the activity of circulating metabolites. The results of in vitro studies suggest that the CYP3A4 isoenzyme plays an important role in the metabolism of atorvastatin. This is confirmed by an increase in the concentration of atorvastatin in human plasma while taking 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 does not have a clinically significant effect on the plasma concentration of terfenadine, which is metabolized mainly by the CYP3A4 isoenzyme; therefore, a significant effect of atorvastatin on the pharmacokinetics of other substrates of the CYP3A4 isoenzyme is unlikely.

Removal

Atorvastatin and its metabolites are excreted mainly in bile after hepatic and/or extrahepatic metabolism (atorvastatin does not undergo significant enterohepatic recirculation). T1/2 is about 14 hours, while 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 atorvastatin dose is found in the urine.

Pharmacokinetics in special clinical situations

Plasma concentrations of atorvastatin in patients over 65 years of age are higher (Cmax approximately 40%, AUC approximately 30%) than in younger adult patients. There were no differences in the safety, effectiveness, or achievement of lipid-lowering treatment goals in elderly patients compared with the general population.

Pharmacokinetic studies of the drug have not been conducted in children.

Plasma concentrations of atorvastatin in women differ (Cmax is approximately 20% higher and AUC is 10% lower) from those in men.

Impaired renal function does not affect the plasma concentration of atorvastatin or its effect on lipid metabolism. In this regard, no dose changes are required in patients with impaired renal function.

Atorvastatin is not excreted during hemodialysis due to intense binding to plasma proteins.

Atorvastatin concentrations are significantly increased (Cmax and AUC approximately 16-fold and 11-fold, respectively) in patients with alcoholic cirrhosis (Child-Pugh class B).

Liprimar, 10 mg, film-coated tablets, 30 pcs.

Atorvastatin

- a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into mevalonate, a precursor of steroids, including cholesterol, a synthetic lipid-lowering agent.

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the plasma levels of total cholesterol (C), LDL-C and apolipoprotein B (apo-B), as well as VLDL-C and triglycerides (TG), causes an unstable increase in HDL-C levels.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL-C.

Atorvastatin reduces the formation of LDL-C and the number of LDL particles, causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable qualitative changes in LDL particles, and also reduces the level of LDL-C in patients with homozygous hereditary familial hypercholesterolemia, resistant to therapy with other lipid-lowering drugs means.

Atorvastatin in doses from 10 to 80 mg reduces total cholesterol by 30–46%, LDL-C by 41–61%, apolipoprotein 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, incl. in patients with non-insulin-dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia, atorvastatin reduces total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases HDL-C levels.

In patients with dysbetalipoproteinemia, atorvastatin reduces the level of intermediate-density lipoprotein cholesterol.

In patients with Frederickson type IIa and IIb hyperlipoproteinemia, the mean increase in HDL-C levels during treatment with atorvastatin (10–80 mg) compared to baseline is 5.1–8.7% and is independent of dose. 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.

Liprimar® at a dose of 80 mg significantly reduces the risk of ischemic complications and mortality rate by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia by 26%. In patients with different initial concentrations of LDL-C, Liprimar® causes a reduction in the risk of ischemic complications and mortality (in patients with myocardial infarction without a Q wave and unstable angina, regardless of the patient’s gender and age).

A decrease in plasma LDL cholesterol levels correlates better with the dose of the drug than with its concentration in the blood plasma. The dose is selected taking into account the therapeutic effect (see section “Method of administration and dosage”).

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

Prevention of cardiovascular complications

In the Anglo-Scandinavian study of cardiovascular complications (lipid-lowering branch (ASCOT-LLA) of the effect of atorvastatin on fatal and non-fatal outcomes of coronary artery disease, it was found that the effect of treatment with atorvastatin at a dose of 10 mg significantly exceeded the effect of placebo, and therefore a decision was made to early ending the study after 3.3 years instead of the expected 5 years.

Atorvastatin significantly reduced the risk of developing the following complications (see Table 1).

Table 1

There were no significant reductions in overall mortality and mortality from cardiovascular causes, although positive trends were observed.

Diabetes

The pooled study of the effect of atorvastatin on fatal and nonfatal cardiovascular events in type 2 diabetes mellitus (CARDS) showed that treatment with atorvastatin reduced the risk of developing the following cardiovascular events, regardless of patient sex, age, or baseline LDL-C level (see Table 2).

table 2

Atherosclerosis

The Reversal of Coronary Atherosclerosis with Intensive Lipid-Lowering Therapy (REVERSAL) study with atorvastatin 80 mg in patients with coronary artery disease found that the mean reduction in total atheroma volume (the primary outcome measure) from the start of the study was 0.4%.

Recurrent stroke

The Intensive Lowering Cholesterol Levels (SPARCL) program found that atorvastatin 80 mg/day reduced the risk of recurrent fatal or nonfatal stroke in patients who had a stroke or transient ischemic attack (TIA) without a history of CAD by 15% compared with placebo. At the same time, the risk of major cardiovascular complications and revascularization procedures was significantly reduced. A reduction in the risk of cardiovascular events during atorvastatin therapy was observed in all groups except the one that included patients with primary or recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group).

Hemorrhagic stroke

In patients treated with atorvastatin 80 mg, the incidence of hemorrhagic or ischemic stroke (265 versus 311) or coronary artery disease (123 versus 204) was lower than in the control group.

Secondary prevention of cardiovascular complications

The New Targeted Trial (TNT) compared the effect of atorvastatin 80 and 10 mg/day on the risk of cardiovascular events in patients with clinically documented CAD. Atorvastatin at a dose of 80 mg significantly reduced the development of the following complications (see Table 3).

Table 3

Liprimar®

From the nervous system:

> 1%
—
insomnia, dizziness; <1% - headache, asthenia, malaise, drowsiness, nightmares, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial paralysis, hyperkinesis, migraine, depression, hypoesthesia, loss of consciousness.

From the senses:

<1% - amblyopia, ringing in the ears, dry conjunctiva, impaired accommodation, retinal hemorrhage, deafness, glaucoma, parosmia, loss of taste, taste perversion.

From the cardiovascular system:

> 1% - chest pain; <1% - palpitations, symptoms of vasodilation, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.

From the hematopoietic system:

<1% - anemia, lymphadenopathy, thrombocytopenia.

From the respiratory system:

> 1% - bronchitis, rhinitis; <1% - pneumonia, dyspnea, exacerbation of bronchial asthma, nosebleeds.

From the digestive system:

> 1% - nausea; <1% - heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, decreased or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, bleeding gums, tenesmus.

From the musculoskeletal system:

> 1% - arthritis; <1% - leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonicity, joint contractures, joint swelling, tendinopathy (in some cases with tendon rupture).

From the genitourinary system:

> 1% - urogenital infections, peripheral edema; <1% - dysuria (including pollakiuria, nocturia, urinary incontinence or urinary retention, urinary urgency), leukocyturia, nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, impaired ejaculation.

Dermatological reactions:

> 1% - alopecia, xeroderma, photosensitivity, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

From the endocrine system:

<1% - gynecomastia, mastodynia.

From the side of metabolism:

<1% - weight gain, exacerbation of gout.

Allergic reactions:

<1% - itching, skin rash, contact dermatitis, rarely - urticaria, angioedema, facial swelling, anaphylaxis, erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Laboratory indicators:

<1% - hyperglycemia, hypoglycemia, increased serum CPK, albuminuria.