Rosuvastatin - instructions for use, dose, side effects, contraindications

Pharmacodynamics:A hypolipidemic agent from the group of statins, an inhibitor of HMG-CoA reductase. According to the principle of competitive antagonism, the statin molecule binds to that part of the coenzyme A receptor where this enzyme is attached. Another part of the statin molecule inhibits the conversion of hydroxymethylglutarate to mevalonate, an intermediate in the synthesis of the cholesterol molecule. Inhibition of HMG-CoA reductase activity results in a decrease in intracellular cholesterol content. This leads to activation of the synthesis of LDL receptors in hepatocytes and an increase in the capture of LDL from the blood plasma.
The hypolipidemic effect of statins is associated with a decrease in the level of total cholesterol due to Xc-LDL. The decrease in LDL is dose-dependent and has a non-linear, but an exponential nature.
In addition to lipid-lowering effects, statins have a positive effect on endothelial dysfunction (preclinical signs of early atherosclerosis), on the vascular wall, atheroma state, improve the rheological properties of blood, and possess antioxidant, antiproliferative properties.
Therapeutic effect is manifested within 1 week. after the start of therapy and after 2 weeks of treatment it is 90% of the maximum possible effect, which is usually achieved by 4 weeks and after that remains constant.

Pharmacokinetics:

After oral administration of Cmax, rosuvastatin in blood plasma is reached after approximately 5 hours. Bioavailability is approximately 20%.

Rosuvastatin accumulates in the liver. Vd - about 134 liters. Binding to plasma proteins (predominantly with albumin) is approximately 90%.

Biotransformed to a small extent (about 10%), being a non-core substrate for cytochrome P450 isoenzymes. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.

About 90% of the dose of rosuvastatin is excreted unchanged with feces.The remainder is excreted in the urine. The plasma half-life is approximately 19 hours. The half-life does not change with increasing dose. The average value of plasma clearance is approximately 50 l / h (coefficient of variation of 21.7%).

The systemic exposure of rosuvastatin increases in proportion to the dose.

In patients with severe renal failure (CC <30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-dimethyl is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

In patients with hepatic insufficiency, the extent of which was 8 and 9 on the Child-Pugh scale, an increase in the half-life of at least 2-fold was noted.

Indications:

Hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-medicamentous treatments (eg exercise, weight loss) are insufficient.

Family homozygous hypercholesterolemia as an adjunctto a diet and other cholesterol-lowering therapy or in cases when such therapy is not suitable for the patient.

ICD-10

IV.E70-E90.E78.0 Pure hypercholesterolemia

IV.E70-E90.E78.2 Mixed hyperlipidemia

Contraindications:

Diseases of the liver in the active phase (including persistent increase in hepatic transaminase activity or any increase in transaminase activity more than 3 times in comparison with IGN), expressed renal dysfunction (CK <30 ml / min), myopathy, simultaneous administration of cyclosporine, pregnancy, lactation (breastfeeding), women of reproductive age who do not use adequate methods of contraception, children and adolescents under 18 years (because efficacy and safety are not established), increased sensitivity to rosuvastatin.

Carefully:Use with caution in the presence of risk factors for rhabdomyolysis (including renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates), chronic alcoholism, in patients over 65 years,with liver diseases in history, sepsis, arterial hypotension, during extensive surgical interventions, traumas, severe metabolic, endocrine or electrolyte disturbances, with uncontrolled epilepsy, in Asian people (Chinese, Japanese).

Pregnancy and lactation:

Contraindicated in pregnancy and lactation.

Do not use in women of reproductive age who do not use reliable methods of contraception.

FDA recommendation category X.

Dosing and Administration:

Accepted inwards. The recommended initial dose is 10 mg 1 time / day. If necessary, the dose can be increased to 20 mg after 4 weeks. A dose increase of up to 40 mg is possible only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) with insufficient efficacy at a dose of 20 mg and under the condition of a doctor's control.

Side effects:

From the side of the central nervous system: often - headache, dizziness, asthenic syndrome; possibly - anxiety, depression, insomnia, neuralgia, paresthesia.

From the digestive system: often - constipation, nausea, abdominal pain; possible - reversible transient dose-dependent increase in hepatic transaminase activity, dyspepsia (including diarrhea, flatulence, vomiting), gastritis, gastroenteritis.

From the respiratory system: often pharyngitis; possibly - rhinitis, sinusitis, bronchial asthma, bronchitis, cough, dyspnea, pneumonia.

From the cardiovascular system: possibly - angina pectoris, increased blood pressure, palpitations, vasodilation.

From the musculoskeletal system: often - myalgia; possible - arthralgia, arthritis, muscle hypertonia, back pain, pathological limb fracture (without damage); rarely - myopathy, rhabdomyolysis (simultaneously with impaired renal function, against the background of taking the drug at a dose of 40 mg).

From the urinary system: tubular proteinuria (in less than 1% of cases - for doses of 10 and 20 mg, 3% for doses of 40 mg); possible peripheral edema (arms, legs, ankles, lower legs), pain in the lower abdomen, infection of the urinary system.

Allergic reactions: possible - skin rash, itchy skin; rarely - angioedema.

From the laboratory indicators: a transient dose-dependent increase in the activity of CKK (with an increase in the activity of CK more than 5 times compared with VGN therapy should be temporarily suspended).

Other: often - asthenic syndrome; possibly - accidental trauma, anemia, chest pain, diabetes, ecchymosis, flu-like syndrome, periodontal abscess.

Overdose:No data.

Interaction:

The beginning of rosuvastatin therapy or an increase in the dose of the drug in patients receiving simultaneously vitamin K antagonists (for example, warfarin), may lead to an increase in prothrombin time and INR, and cancellation of rosuvastatin or a decrease in dose may result in a decrease in INR (in such cases, monitoring of INR is recommended).

The combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax in the blood plasma and AUC of rosuvastatin.

The simultaneous use of rosuvastatin and erythromycin leads to a 20% decrease in AUC of rosuvastatin and 20% in rosuvastatin Cmax, and probably by a 30% increase in motility of the intestine caused by erythromycin.

The simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinylestradiol and AUC norgestrel by 26% and 34%, respectively. It is impossible to exclude such interaction with simultaneous application of rosuvastatin and hormone replacement therapy.

Gemfibrozil, other fibrates and hypolipidemic doses of nicotinic acid (≥1 g / day) increased the risk of myopathy when used with other HMG-CoA reductase inhibitors, possibly because they can cause myopathy and when used as monotherapy.

Special instructions:

Therapy should be discontinued if the level of CK is significantly increased (more than 5 times in comparison with VGN), or if the muscle symptoms are pronounced and cause daily discomfort (even if the level of CK is 5 times lower compared to VGN).

When using rosuvastatin in a dose of 40 mg, it is recommended to monitor the indicators of kidney function.

In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset or progression of an existing kidney disease.

An increase in the incidence of myositis and myopathy in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives (including gemfibrozil) has been reported; ciclosporin, nicotinic acid, azole antifungal agents, protease inhibitors and macrolide antibiotics.Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, the simultaneous administration of rosuvastatin and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully weighed against the combined use of rosuvastatin and fibrates or niacin.

It is recommended to perform the determination of liver function indices before the start of therapy and 3 months after the initiation of therapy. The use of rosuvastatin should stop or reduce the dose, if the level of activity of transaminases in the serum is 3 times higher than VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the treatment of underlying diseases should be performed prior to the initiation of treatment with rosuvastatin.

Impact on the ability to drive vehicles and manage mechanisms

When dealing with potentially hazardous activities, patients should be aware that dizziness may occur during therapy.

Instructions

Rosuvastatin (Rosuvastatinum)