Mertenil, 10 mg 30 pcs.

Mertenil is hypolipidemic.

Pharmacodynamics

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase – the enzyme that converts HMG-CoA to mevalonate, which is a precursor of cholesterol (CH). The main target of rosuvastatin action is the liver, where the synthesis of cholesterol and LDL catabolism take place.

Rosuvastatin increases the number of hepatic LDL receptors on the surface of cells, increasing the capture and catabolism of LDL.

It also inhibits the synthesis of LDL-C in liver cells, thereby reducing total LDL and LDL-C.

Rosuvastatin reduces elevated LDL, total cholesterol and triglycerides (TG), increases HDL, and decreases apolipoprotein B (apoB), non-HDL cholesterol (total cholesterol minus HDL cholesterol), LDL-C, TG-LDL and increases apolipoprotein A-I (apoA-I). Rosuvastatin decreases the ratio of LDL cholesterol/LDL cholesterol, total cholesterol/LDL cholesterol, non-LDL cholesterol/LDL cholesterol and apoB/apoA-I.

Therapeutic effect can be achieved within 1 week after the start of treatment, after 2 weeks 90% of the maximum possible effect is achieved. Usually the maximum possible therapeutic effect is achieved after 4 weeks and is maintained with continued use of the drug.

Clinical efficacy

Rosuvastatin is effective in treating adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia regardless of their race, sex or age as well as in treating a special category of patients, patients with diabetes or hereditary form of familial hypercholesterolemia.

Rosuvastatin is effective in treating patients with Fredrickson type IIa and IIb hypercholesterolemia (mean baseline LDL-C levels of about 4.8 mmol/L). In 80% of patients who received 10 mg of rosuvastatin the target values of LDL cholesterol levels established by the European Society for the Study of Atherosclerosis (less than 3 mmol/l) were achieved.

In patients with heterozygous familial hypercholesterolemia who received rosuvastatin in doses from 20 to 80 mg according to the scheme of forced dose titration, all doses taken had a significant impact on changes in parameters characterizing lipid content and on achieving the goal of therapy. As a result of titrating doses up to 40 mg/day (12 weeks of therapy), LDL cholesterol content decreased by 53%. In 33% of patients, LDL cholesterol values corresponding to the target norms (below 3 mmol/l) of the European Society for Atherosclerosis Research guidelines were achieved.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the mean reduction in LDL-C was 22%. In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who received rosuvastatin in doses of 5 to 40 mg/d for 6 weeks, plasma TG concentrations decreased significantly.

Additive effect is noted in combination with fenofibrate for TG content and nicotinic acid (more than 1 g/day) for HDL-C content.

The studies on the effect of rosuvastatin on the reduction of complications caused by lipid disorders such as coronary artery disease have not yet been completed.

. In patients with a low risk of CHD (defined as a Framingham risk of less than 10% over a period of more than 10 years), with a median LDL-C of 4 mmol/L (154,5 mg/dL) rosuvastatin at a dose of 40 mg/day significantly slowed the increase in the maximum value characterizing carotid wall thickening in 12 segments compared with placebo at a rate of -0.0145 mm/yr (95% confidence interval – CI – -0.0196 to -0.0093, with p

Pharmacokinetics

Absorption

T_max is 5 h after oral administration of the appropriate dose. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is absorbed primarily by the liver, which is the main site of HC synthesis and metabolism of LDL cholesterol. V_d of rosuvastatin is approximately 134 liters. 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism

It is subject to limited metabolism (approximately 10%). Rosuvastatin is a rather non-core substrate for metabolism by enzymes of cytochrome P450 system. CYP2C9 is the main isoenzyme involved in metabolism, while CYP2C19, CYP3A4 and CYP2D6 isoenzymes are less involved in metabolism. The main metabolite is N-desmethyl, which is 50% less active than rosuvastatin. Lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity on inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Elimination

Approximately 90% of the administered dose of rosuvastatin is excreted unchanged from the body through the intestine (including absorbed and unabsorbed rosuvastatin) and the remainder through the kidneys. T_1/2 is 19 h, does not change with increasing drug dose. Mean geometric plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves membrane transporter of CHC across membranes – transport protein with organic anions. This transporter plays a major role in the excretion of rosuvastatin by the liver.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. No changes in pharmacokinetic parameters are observed when taking the drug several times a day.

Age and sex

There is no clinically significant effect on pharmacokinetic parameters of rosuvastatin.

Ethnic groups

Comparative pharmacokinetic studies showed a two-fold increase in mean AUC and T_max values in patients of Asian origin (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to those of Caucasian race. Indians had about 1.3-fold higher mean AUC and C_max values. At the same time, analysis of pharmacokinetic parameters for the entire study population showed no clinically significant differences in pharmacokinetics of the drug among Caucasoid, Negroid, and Hispanic races.

Renal failure

In patients with mild to moderate renal failure plasma concentrations of rosuvastatin or N-desmethyl metabolite do not change significantly. In patients with severe renal failure (creatinine Cl less than 30 ml/min) plasma concentration of rosuvastatin is 3 times higher, and concentration of N-desmethyl-metabolite is 9 times higher compared to healthy volunteers. Plasma concentrations of rosuvastatin were approximately 50% higher in patients on hemodialysis than in healthy volunteers.

Hepatic failure

Patients with varying degrees of hepatic failure with a Child-Pugh score of 7 or lower showed no increase in T_1/2 rosuvastatin. However, 2 patients with Child-Pugh scores of 8 and 9 showed prolongation of T_1/2, approximately 2 times greater than for patients with lower Child-Pugh scores. There is no experience with rosuvastatin in patients with a Child-Pugh score above 9.

Indications

Active ingredient

Composition

Active ingredient:

rosuvastatin calcium;

Associates:

MCC 12 – 21.55/43.1/86.2/172.4 mg;

Lactose monohydrate – 43.5/87/174/348 mg;

Magnesium hydroxide – 3.75/7.5/15/30 mg;

crospovidone (type A) – 0.25/0.5/1/2 mg;

magnesium stearate – 0.75/1.5/3/6 mg;

Cover film:

Opadry II white (talc – 0.444/0.74/1.48/2.96 mg, macrogol 3350 – 0.606/1.01/2.02/4.04 mg, titanium dioxide (E171) – 0.75/1.25/2.5/5 mg,

Polyvinyl alcohol 1.2/2/4/4/8 mg) – 3/5/10/20 mg;

How to take, the dosage

Over the body at any time of the day, regardless of meals, without chewing or crushing, swallowed whole with water.

Before treatment, the patient should follow a standard diet of low-cholesterol products, which should be continued throughout the treatment period. Doses should be adjusted individually according to the goal of treatment and the patient’s therapeutic response to therapy, taking into account current accepted recommendations for target lipid levels.

The recommended starting dose of the drug is 5 or 10 mg once daily for both patients who have not previously taken statins and for patients who are switched to this drug after therapy with other HMG-CoA reductase inhibitors.

When choosing the initial dose of the drug, the level of cholesterol in each individual patient should be considered, as well as the possible risk of cardiovascular complications and the potential risk of side effects. If necessary, a dose adjustment can be made after 4 weeks.

Because of the possible development of side effects when taking a dose of 40 mg compared to lower doses of the drug (see “Side Effects”) final titration to the maximum dose of 40 mg should only be performed in patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially patients with hereditary hypercholesterolemia), in whom the target cholesterol level was not achieved at the 20 mg dose and who will be under medical supervision. Close medical supervision is recommended when prescribing the 40 mg dose. The 40 mg dose is not recommended for patients who have not previously seen a physician.

Elderly patients

There is no need to adjust the dose due to age.

Patients with renal impairment

Patients with mild to moderate renal impairment do not require dose adjustment. The recommended starting dose of the drug is 5 mg for patients with moderate renal failure (creatinine Cl less than 60 ml/min). Administration of Mertenil® in any dose is contraindicated in patients with severe renal failure (see “Contraindications”). In patients with moderate renal insufficiency, administration of the drug in a dose of 40 mg is contraindicated.

Patients with hepatic impairment

Elevation of systemic concentration of rosuvastatin in patients with Child-Pugh score of 7 or lower has not been found. However, increased systemic drug concentrations were observed in patients with Child-Pugh scores of 8 and 9. Liver function should be monitored in such patients during therapy. There are no data on drug administration in patients with a Child-Pugh score above 9. Mertenil® is contraindicated in patients with active liver disease.

Ethnic groups

Asian patients may have increased systemic rosuvastatin concentrations. When doses of 10 and 20 mg are administered, the recommended starting dose of the drug in patients of Asian origin is 5 mg. The use of the drug in a dose of 40 mg in such patients is contraindicated (see “Contraindications”).

Patients with predisposition to myopathy

In prescribing doses of 10 and 20 mg, the recommended starting dose of the drug for patients with predisposition to myopathy is 5 mg. The use of the drug in a dose of 40 mg is contraindicated in such patients.

Interaction

Cyclosporine – concomitant administration of rosuvastatin and cyclosporine resulted in a 7-fold increase in the AUC of rosuvastatin compared to values obtained in healthy volunteers (see “Contraindications”). Concomitant use leads to an 11-fold increase in plasma concentrations of rosuvastatin. No changes in cyclosporine plasma concentrations have been detected when concomitant use of the drugs.

Vitamin K antagonists – as with other HMG-CoA reductase inhibitors, starting therapy with rosuvastatin or increasing the dose of the drug in patients receiving simultaneously vitamin K antagonists (such as warfarin or other coumarin anticoagulants) may lead to increased MHO. Cancellation or reduction of the dose of rosuvastatin may cause a decrease in MHO. In such cases, MHO should be monitored.

Ezetimibe – There is no change inAUC or Cmax of both drugs when taking rosuvastatin and ezetimibe concomitantly. However, pharmacodynamic interaction between rosuvastatin and ezetimibe that may cause adverse events cannot be excluded.

Gemfibrozil and other lipid-lowering agents – concomitant administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see “Special Precautions”).

Based on specific interaction studies, no corresponding pharmacokinetic interaction with fenofibrates is expected, but a pharmacodynamic interaction is possible. Hemfibrozil, fenofibrate, other fibrates and nicotinic acid at lipid-lowering doses (1 g or more per day) when concomitantly taken with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can also cause myopathy when taken in monotherapy. Concomitant administration of 40 mg of rosuvastatin and fibrates is contraindicated (see “Special Precautions” and “Contraindications”). When concomitant administration with gemfibrozil and other lipid-lowering agents, the initial dose of Mertenil® should not exceed 5 mg.

Protease inhibitors – Although the exact mechanism of interaction is unknown, concomitant administration of rosuvastatin with protease inhibitors may result in prolongation of T1/2 rosuvastatin. In a pharmacokinetic study, concomitant administration of 20 mg rosuvastatin and a combination drug containing two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers showed a 2-fold increase in AUC0-24 and 5-fold increase in Cmax rosuvastatin respectively. Therefore, it is not recommended to simultaneously prescribe rosuvastatin and protease inhibitors during therapy of patients with HIV.

Antacids – concomitant administration of rosuvastatin and antacids in suspension containing aluminum or magnesium hydroxide may lead to a decrease in plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 h after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Eritromycin – concomitant administration of rosuvastatin and erythromycin may decrease AUC0-t rosuvastatin by 20% and Cmax rosuvastatin by 30%. This relationship may be due to increased intestinal motility caused by taking erythromycin.

Peroral contraceptives/hormone replacement therapy – concomitant administration of rosuvastatin and oral contraceptives may increase AUC of etinylestradiol and norgestrel by 26% and 34%, respectively. This increase in plasma concentrations should be considered when choosing a dose of oral contraceptives. Pharmacokinetic data on concomitant use of rosuvastatin and hormone replacement therapy drugs are not available, so we cannot rule out a similar effect when using this combination. However, this combination of drugs was quite widely used by women in clinical trials and was well tolerated.

Other drugs – no clinically significant interaction is expected with concomitant administration of rosuvastatin and digoxin.

Cytochrome P450 isoenzymes – the results of in vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a rather weak substrate for these enzymes. There was not revealed clinically significant interaction between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzymes inhibitor) or ketoconazole (CYP2A6 and CYP3A4 isoenzymes inhibitor). Co-administration of itraconazole (CYP3A4 isoenzyme inhibitor) and rosuvastatin increases the AUC of rosuvastatin by 28% (clinically not significant). Therefore, no interaction of drugs related to cytochrome P450 metabolism is expected.

Special Instructions

Pediatric use. Efficacy and safety of the drug administration in children under 18 years old have not been established. The experience of using the drug in pediatric practice is limited to a small number of children (8 years and older) with familial homozygous hypercholesterolemia. Currently, Mertenil® is not recommended for use in children under 18 years of age.

Kidney effects. Proteinuria, predominantly of tubular origin, has been noted in patients taking high doses of Mertenil®, particularly 40 mg, but has been intermittent or transient in most cases. Such proteinuria has not been shown to imply the occurrence of acute or progressive existing renal disease. The incidence of serious renal function abnormalities is increased when taking 40 mg of rosuvastatin. It is recommended to monitor renal function parameters during therapy with Mertenil®.

Motor system. Myalgia, myopathy and, rarely, rhabdomyolysis have been observed with Mertenil® at all doses, and particularly with doses greater than 20 mg. Rhabdomyolysis occurred very rarely when concomitant administration of ezetimibe and HMG-CoA reductase inhibitors. In this case, pharmacological interaction of the drugs cannot be excluded, therefore Mertenil® and ezetimibe should be used with caution (see “Interaction”). The incidence of rhabdomyolysis is increased when taking 40 mg of rosuvastatin.

The determination of CPK. Determination of CPK activity should not be performed after strenuous physical activity that causes an increase in CPK, because this may complicate the interpretation of the results. If CPK activity before the start of therapy rises more than 5 times the ULN, a repeat measurement should be performed after 5-7 days. If re-measurement confirms the baseline CPK value (5 times the ULN), therapy with Mertenil® should not be started.

Pre-therapy. Mertenil®, like other HMG-CoA reductase inhibitors, should be administered with particular caution to patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

– renal impairment;

– hypothyroidism (for 40 mg dose see “Contraindications”);

– own or family history of muscle disease (for 40 mg dose see

– a history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates (for 40 mg dose, see “Contraindications”);

– a history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates (for 40 mg dose, see “Contraindications”). “

– abuse of alcohol (for 40 mg dose, see “Contraindications”);

– age over 65 years;

– conditions accompanied by an increase in plasma concentrations of the drug (see “Interactions. “Interactions, for the dose of 40 mg see “Contraindications”);

– concomitant administration of fibrates (for the dose of 40 mg see “Contraindications”).

In such patients, the risk/benefit ratio of therapy should be evaluated and clinical monitoring should be performed throughout the course of therapy.

In therapy. Patients should be informed of the need to promptly inform the physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially in conjunction with malaise or fever.

In these patients, CPK activity should always be monitored. Treatment should be discontinued if CPK activity is more than 5 times the ULN or if muscle symptoms are severe and cause daily discomfort throughout the day (even if CPK activity is 5 times less than ULN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Mertenil® or prescribing an alternative HMG-CoA reductase inhibitor at a lower dose with close monitoring of the patient. Regular monitoring of CPK activity in patients without symptoms of rhabdomyolysis is unnecessary.

Contraindications

Side effects

Immune system disorders: rare – hypersensitivity reactions, including angioedema.

Endocrine system disorders: often – diabetes mellitus type 2.

CNS disorders: often – headache, dizziness.

The digestive system: often – constipation, abdominal pain, nausea; rarely – pancreatitis.

Skin and subcutaneous fatty tissue: infrequent – skin itching, rash, urticaria.

Muscular system and connective tissue: often – myalgia; rarely – myopathy (including myositis), rhabdomyolysis.

Others: often – asthenic syndrome.

As with other HMG-CoA reductase inhibitors, the incidence of side effects is dose-dependent.

The incidence of rhabdomyolysis, significant renal and hepatic adverse events increases in patients when taking rosuvastatin at a dose of 40 mg.

Renal and urinary tract side effects: proteinuria, predominantly of tubular origin, has been observed while taking rosuvastatin. Changes in urinary protein content (from no or trace amounts to ++ and higher) were found in less than 1% of patients taking 10 and 20 mg rosuvastatin, and in approximately 3% of patients taking 40 mg doses.

The minimal change in the amount of protein in the urine, expressed as a change from zero or trace levels to a + level, was observed when taking the drug at the 20 mg dose. In most cases, proteinuria decreased and passed on its own during treatment. When analyzing data from clinical studies, no causal relationship between proteinuria and acute or progressive kidney disease was found.

A number of patients treated with rosuvastatin had hematuria, but data from clinical studies have shown that the incidence of these cases is very low.

Musculoskeletal disorders: effects on skeletal muscles, causing myalgia, myopathy (including myositis) and in rare cases rhabdomyolysis with or without acute renal failure, have been observed in patients taking any dose of rosuvastatin, especially a dose above 20 mg. Elevation of CPK activity depending on the dose taken was detected in patients taking rosuvastatin, but in most cases these manifestations were insignificant, asymptomatic and temporary. If CPK activity is 5-fold greater than VHF, treatment should be discontinued (see “Special Precautions”).

Hepatic disorders: As with other HMG-CoA reductase inhibitors, a dose-dependent increase in hepatic transaminase activity has been detected in a small number of patients taking rosuvastatin. However, in most cases this increase was moderate, asymptomatic and transient.

Laboratory parameters: increased concentration of glucose, bilirubin, GGTP activity, ALP, thyroid dysfunction.

Postmarketing use

Digestive system disorders: very rare – jaundice, hepatitis; rare – increased liver transaminase activity; unspecified frequency – diarrhea.

Musculoskeletal system: very rare – arthralgia.

CNS disorders: very rare – polyneuropathy, memory loss.

Respiratory system: unspecified frequency – cough, shortness of breath.

Renal and urinary tract disorders: very rare – hematuria.

Skin and subcutaneous fat: unspecified frequency – Stevens-Johnson syndrome

Others: unspecified frequency – peripheral edema.

The following side effects have been reported with some statins – depression, sleep disturbances, including insomnia and nightmares, sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with long-term use of the drugs.

Pregnancy use

Mertenil® is contraindicated during pregnancy and lactation.

Women of childbearing age should use reliable and appropriate contraception.

Because cholesterol and products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefits of its use in pregnancy.

In case of pregnancy, the drug should be discontinued immediately. There are no data on excretion of rosuvastatin with breast milk. If it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued.

Similarities