MERTENIL PILLS 5MG

Instructions for medical use

medicinal product

MERTENIL®

Tradename

Merten®

International non-proprietary name

Rosuvastatin

Active ingredient

One pill contains

active substance: rosuvastatin Calcium 5.2 mg (equivalent to 5.0 mg rosuvastatin), 10.4 mg (equivalent to 10.0 mg rosuvastatin), 20.8 mg (equivalent to 20.0 mg rosuvastatin), 41.6 mg (equivalent to 40.0 mg rozuvastatin),

Excipients: lactose monohydrate, microcrystalline cellulose 12, Magnesium hydroxide, crospovidone type A, magnesium stearate,

film coating composition: white opadry II: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc.

Pharmacological properties

Pharmacokinetics

Suction

The maximum concentration of Rosuvastatin in the blood plasma is reached 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is predominantly absorbed by the liver, which is the main site for the synthesis of cholesterol and clearance of cholesterol metabolism - low density lipoprotein (LDL). The volume of distribution of rosuvastatin is approximately 134 liters. 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Metabolism

Rosuvastatin undergoes a limited metabolism (approximately 10%), is not a substrate for metabolism by enzymes of the cytochrome P450 system.CYP2C9 is the major isoenzyme involved in metabolism, while isoenzymes CYP2C19, CYP3A4 and CYP2D6 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, 10% - by its metabolites.

Removal

Approximately 90% of the received dose of rosuvastatin is excreted unchanged from the body through the intestines (including absorbed and not absorbed rosuvastatin), and the rest is excreted unchanged by the kidneys. The half-life (T1 / 2) is 19 hours and does not change with increasing dose of the drug. The geometric mean plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other inhibitors of HMG-Coa reductase, membrane transport of organic anions (OATP-C) is involved in the hepatic capture process of rosuvastatin through the membranes transporter through rosuvastatin. This carrier plays a major role in the removal of rosuvastatin by the liver.

Linearity

The systemic effect of rosuvastatin increases in proportion to the dose of the drug. Changes in pharmacokinetic parameters when taking the drug several times a day is not observed.

Pharmacodynamics

Rosuvastatin, the active ingredient in Mertenil®, is a selective and competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutarycoenzyme A to mevalonate, which is a precursor of cholesterol.The main target of Merten® is the liver, where cholesterol (cholesterol) synthesis and low density lipoprotein catabolism (LDL) are performed.

Merten® increases the number of “liver” LDL receptors on the cell surface, increasing the uptake and catabolism of LDL.

It also inhibits the synthesis of very low density lipoprotein cholesterol (VLDL) in liver cells, thereby reducing the total content of LDL and VLDL.

Merten® reduces high cholesterol - LDL, total cholesterol and triglycerides (TG), increases cholesterol - high-density lipoprotein (HDL-C), and also reduces the content of apolipoprotein B (ApoB), cholesterol-HDLPA (total cholesterol minus levels HDL cholesterol, cholesterol-VLDL, TG-VLDL and increases the level of apolipoprotein AI (ApoA-I). Mertenil®, decreases the ratio of LDL / LDL / HDL / HCL, total cholesterol / HDL / HDL / LDL / ApoA-I.

The therapeutic effect can be achieved within one 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 the further intake of the drug.

Clinical efficacy

Merten® is effective in treating adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of their race, gender, or age, as well as in the treatment of a special category of patients with diabetes mellitus or the hereditary form of familial hypercholesterolemia.

The drug in a dose of 40 mg should be administered to patients with severe hypercholesterolemia and a high risk of developing cardiovascular diseases.

Indications

- primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet therapy, when diet and other non-drug therapies (eg exercise, weight loss) are insufficient

- familial homozygous hypercholesterolemia as an adjunct to diet therapy and other methods of lipid-lowering therapy (for example, LDL-apheresis) or in cases when this therapy is not effective enough

Dosage and administration

Before starting treatment, the patient should follow a standard diet with foods low in cholesterol, which should be continued during the entire period of treatment. Doses of the drug should be selected individually in accordance with the purpose of the treatment and the therapeutic response of the patient to the therapy, taking into account modern generally accepted recommendations on target lipid levels.

The recommended initial dose of the drug is 5 mg or 10 mg 1 time per day, both for patients who have not previously taken statins, and for patients who have been transferred to this drug after therapy with other HMG-CoA reductase inhibitors.

Choosing the initial dose of the drug, you should consider the level of cholesterol in each particular patient, as well as the possible risk of cardiovascular complications and the potential risk of side effects.If necessary, after 4 weeks you can adjust the dose.

Titration of the drug to a maximum dose of 40 mg should be carried out only in patients with severe hypercholesterolemia and a high risk of cardiovascular diseases (in particular, with familial hypercholesterolemia) in whom the target cholesterol level has not been reached with a dose of 20 mg under medical supervision. At purpose of a dose of 40 mg careful supervision over patients is recommended. It is not recommended to prescribe a dose of 40 mg in patients who have not previously taken the drug. Merten® can be taken at any time of day, inside, regardless of food intake, do not chew or chop, swallow whole, washed down with water.

Use in elderly patients

For patients over the age of 70 years, the prescription of the drug in the initial dose of 5 mg is recommended. Dose adjustment due to age is not required.

Use in patients with renal failure

In patients with renal insufficiency, mild or moderate severity does not require dose adjustment. The recommended initial dose of the drug is 5 mg for patients with moderate renal insufficiency (CC less than 60 ml / min.).

Use in patients predisposed to myopathy

The recommended initial daily dose in patients with predisposing factors for the development of myopathy is 5 mg.

Adverse effects

Often (> 1/100 to <1/10)

- dizziness, headache

- myalgia

- asthenia

- nausea, constipation, abdominal pain

Infrequently (> 1/1 000 to <1/100)

- itch, rash, urticaria

Rarely (> 1/10 000 to <1/1 000)

- hypersensitivity reactions (including angioedema)

- pancreatitis

- myositis, rhabdomyolysis

- increased activity of liver transaminases

- proteinuria

Very rare (<1/1 000)

- polyneuropathy, memory loss

- jaundice, hepatitis

- arthralgia

- hematuria

- sleep disorders, including insomnia and nightmares

- depression

- sexual dysfunction

- isolated cases - interstitial lung diseases.

Contraindications

For tablets 5, 10, 20 mg

- hypersensitivity to rosuvastatin or any of the components of the drug

- liver diseases in the active phase, including a persistent increase in the activity of “liver” transaminases, as well as any increase in serum transaminase activity by more than 3 times compared with the upper limit of normal

- liver failure with a score above 9 on the Childe Pugh scale

- pronounced renal dysfunction (creatinine clearance less than 30 ml / min);

- myopathy

- simultaneous reception of cyclosporine

- predisposition to the development of myotoxic complications

- myotoxicity against the background of taking other HMG-CoA reductase inhibitors or a history of fibrates

- congenital lactose intolerance, lactase deficiency or glucose-galactose malabsorption

- pregnancy and lactation

- children's and teenage age up to 18 years

For 40 mg tablets

- hypersensitivity to rosuvastatin or any of the components of the drug

- liver diseases in the active phase, including a persistent increase in the activity of “liver” transaminases, as well as any increase in serum transaminase activity by more than 3 times compared with the upper limit of normal

- - liver failure with a score above 9 on the Childe Pugh scale

- pronounced renal dysfunction (creatinine clearance less than 60 ml / min);

- myopathy

- simultaneous reception of cyclosporine

- hypothyroidism

- personal or family history of muscular diseases

- predisposition to the development of myotoxic complications

- myotoxicity against the background of taking other HMG-CoA reductase inhibitors or a history of fibrates

- simultaneous reception of fibrates

- excessive use of alcohol

- conditions that can lead to increased plasma concentrations of rosuvastatin

- Asian patients

- congenital lactose intolerance, lactase deficiency or glucose-galactose malabsorption

- pregnancy and lactation

- children's and teenage age up to 18 years

Drug interactions

Cyclosporin: while taking drugs, there is no change in the concentration of cyclosporine in the blood plasma, but it leads to an increase in the concentration of rosuvastatin in the blood plasma 11 times.

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, initiating Merten® therapy, or increasing the dose of a drug in patients receiving vitamin K antagonists (such as Warfarin or other coumarin anticoagulants), may lead to an increase in the international normalized ratio (INR).Canceling or lowering the dose of Merten® can cause a decrease in INR. In such cases, an INR should be monitored.

Ezetimibe: simultaneous administration of Merten® and ezetimibe did not lead to changes in the AUC or Cmax of any of the active ingredients. Gemfibrozil and other lipid-lowering agents: simultaneous administration of Merten® and gemfibrozil resulted in a 2-fold increase in Rosmaxastin's C max and AUC.

Based on data from individual studies of drug interactions, pharmacokinetic interactions with fenofibrate are not expected, however, pharmacodynamic interaction of drugs is possible. Gemfibrozil, fenofibrate, other fibrates and doses of niacin (nicotinic acid) in lipid-lowering doses (1 g or more per day) increase the risk of developing myopathy while being administered with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when taken in monotherapy.

Protease inhibitors: at the same time, it is not recommended to prescribe Mertenil® and protease inhibitors in the treatment of patients with HIV, prolongation of the half-life of rosuvastatin is possible.

Antacids: simultaneous administration of Merten® and antacids in a suspension containing aluminum and magnesium hydroxide may result in a decrease in the concentration of Merten® in the blood plasma by about 50%. This effect is less pronounced if antacids are applied 2 hours after taking Merten®.

Erythromycin: simultaneous administration of Mertenil and Erythromycin resulted in a 20% decrease in AUC (0-t) and 30% Cmax of rosuvastatin.This relationship may be caused by increased intestinal motility, caused by taking erythromycin.

Oral contraceptives / hormone replacement therapy (HRT): simultaneous use of Merten® and oral contraceptives resulted in an increase in AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. When selecting doses of oral contraceptives, it is necessary to consider the possibility of increasing plasma concentrations.

Cytochrome P450 isoenzymes: Mertenil® is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. It is a fairly weak substrate for these enzymes. There were no clinically significant interactions between Merten® and Fluconazole (CYP2C9 and CYP3A4 inhibitor) or Ketoconazole (CYP2A6 and CYP3A4 inhibitor). The simultaneous administration of itraconazole (a CYP3A4 inhibitor) and Merten® resulted in a 28% increase in Rosuvastatin AUC.

Other drugs: no clinically significant interaction is expected when co-administered with Merten® and Digoxin .

special instructions

Impact on the kidneys

Proteinuria, predominantly of tubular origin, was observed in patients when taking high doses of Merten®, especially 40 mg, but in most cases it was intermittent or short-term. It is shown that such proteinuria does not mean the occurrence of acute or progression of existing kidney disease. The frequency of serious impairment of kidney function is increased when taking 40 mg of rosuvastatin.It is recommended to monitor indicators of renal function during therapy with Mertenil®.

At appointment of a dose less than 40 mg it is necessary to be careful.

Effect on skeletal muscle

When using Merten® in all dosages, and especially when taking the drug in a dose of more than 20 mg, myalgia, myopathy and, in rare cases, rhabdomyolysis were detected. Very rarely did rhabdomyolysis occur while taking ezetimibe and HMG-CoA reductase inhibitors. In this case, pharmacological interaction of drugs cannot be excluded, therefore Merten® and ezetimibe should be used with caution together. The incidence of rhabdomyolysis when taking 40 mg of rosuvastatin is increased.

Assessment of the activity of creatine phosphokinase (CPK)

Determination of CPK activity should not be carried out after intense physical exertion causing an increase in CPK, as this may make interpretation of results difficult. With an increase in CPK before therapy is more than 5 times higher than the upper limit of normal, after 5-7 days should be re-measured. If repeated measurement confirms the baseline CPK (5 times higher than the upper limit of the norm), Merten® therapy should not be started.

Mertenil®, like other HMG-CoA reductase inhibitors, should be used with extreme caution in patients with myopathy / rhabdomyolysis risk factors. These factors include:

- renal failure

- hypothyroidism

- own or family history of muscular diseases (for a dose of 40 mg)

- the presence of a history of myotoxicity while taking other HMG-CoA reductase inhibitors or fibrates (for a dose of 40 mg)

- alcohol abuse (for a dose of 40 mg)

- age over 70 years

- conditions accompanied by an increase in the concentration of the drug in the blood plasma (for a dose of 40 mg)

- simultaneous reception of fibrates (for a dose of 40 mg)

In such patients, the ratio of risk to potential benefit of therapy should be assessed and clinical observation should be carried out throughout the course of therapy.

During treatment

It is recommended to inform patients about the need to immediately report to the doctor about cases of sudden onset of muscle pain, muscle weakness or spasms, especially in combination with indisposition or fever.

In such patients, the activity of CPK should be monitored. Treatment should be stopped if the level of CPK is more than 5 times higher than the upper limit of the norm, or if the muscular symptoms are pronounced and cause daily discomfort (even if the activity of CPK is 5 times less than the upper limit of the norm). If symptoms disappear and CPK activity returns to a normal level, consideration should be given to re-administering Merten® or prescribing an alternate inhibitor of HMG-CoA reductase at lower doses while carefully monitoring the patient. Regular monitoring of CPK activity in patients in the absence of clinical manifestations is impractical.

However, an increase in the incidence of myositis and myopathy was found in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses, antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy in combination with some inhibitors of HMG-CoA reductase. Therefore, the concomitant use of rosuvastatin and gemfibrozil is not recommended. The ratio of risk and potential benefit should be carefully evaluated when rosuvastatin is used together with fibrates or nicotinic acid in lipid-lowering doses (more than 1 g).

Mertenil® should not be prescribed to patients with acute, severe diseases, suggesting myopathy or with the possible development of secondary renal failure associated with rhabdomyolysis (for example: sepsis, arterial hypotension, surgery, trauma, severe metabolic, endocrine, electrolyte disturbances, uncontrolled convulsions seizures).

Effect on liver

Like other HMG-CoA reductase inhibitors, Mertenil® should be given with particular caution to patients who abuse alcohol and / or have a history of liver disease.

It is recommended to carry out the determination of liver function parameters before and 3 months after the start of treatment.If the activity of “liver” transaminases in the serum is 3 times higher than the upper limit of normal, you should stop taking Merten® or reduce the dose taken. The frequency of pronounced abnormal liver function (associated mainly with an increase in the activity of "liver" transaminases), increases when taking 40 mg of the drug.

In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome, the treatment of the underlying disease must be carried out before starting treatment with Merten®.

Interstitial lung disease

Extremely rare cases of the development of interstitial lung disease have been described when taking individual statins, especially long-term ones. Clinical manifestations may include shortness of breath, dry cough, and worsening of the general condition (general weakness, weight loss, and fever). If a patient is suspected of developing interstitial lung disease, statin therapy should be discontinued.

Diabetes

In patients whose glucose level was 5.6–6.9 mmol / l on an empty stomach, taking rosuvastatin was associated with an increased risk of diabetes.

In the course of pharmacokinetic studies, an increase in the systemic concentration of rosuvastatin among patients of Asian origin was detected in comparison with the data obtained among patients - representatives of the European race.

Features of the effect of the drug on the ability to drive a vehicle and potentially dangerous machinery

Studies studying the effect of Merten® on the ability to drive a car and control mechanisms have not been conducted. However, when driving a vehicle or other mechanisms, it must be borne in mind that dizziness may occur during treatment.

Overdose

Symptoms: severity of symptoms of side effects.

Treatment: symptomatic. Liver function and degree of CPK activity should be monitored. There is no specific treatment for overdose.

Storage conditions

Store in original packaging in a dark place at a temperature of from 15 ° C to 30 ° C,

Keep out of the reach of children!