ROSUVASTATIN PILLS 40MG

Active substance

Rosuvastatin

Composition

Rosuvastatin 40 mg.

pharmachologic effect

Pharmgroup: hypolipidemic agent - HMG-CoA reductase inhibitor.
Pharmaceutical action: Hypolipidemic drug, selective competitive inhibitor of HMG-CoA reductase, which converts 3-hydroxy-3-methylglutaryl CoA into mevalonate, a precursor of cholesterol.
The main target of the action is the liver, where cholesterol synthesis and LDL catabolism are performed. Inhibits the activity of HMG-CoA reductase (90% of the drug circulates in the blood).
Increases the number of LDL receptors on the surface of hepatocytes, increasing the uptake and catabolism of LDL, which leads to inhibition of the synthesis of VLDLP, reducing the total number of LDL and VLDL.
Reduces the concentration of cholesterol-LDL, cholesterol-non-HDLP, cholesterol VLDL, total cholesterol, TG, TG-VLDL, apolipoprotein B (ApoV), the ratio of cholesterol-LDL / cholesterol-HDL, total cholesterol / cholesterol-HDL cholesterol, choleterol-HDL cholesterol-LDL / cholesterol, HDL-cholesterol HDL, ApoV / ApoA-I, increases the concentration of cholesterol-HDL, ApoA-I. Lipid-lowering action is directly proportional to the size of the prescribed dose.
The therapeutic effect appears within 1 week after the start of therapy, after 2 weeks reaches 90% of the maximum, the maximum effect is usually reached by 4 weeks and after that remains constant.
Effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia (regardless of race, gender or age), including in patients with diabetes and familial hypercholesterolemia.
The additive effect is observed in combination with fenofibrate (in relation to reducing the concentration of TG) and nicotinic acid (in relation to reducing the concentration of cholesterol-HDL).
Pharmacokinetics: Bioavailability - 20%. Food reduces the rate of absorption. Communication with plasma proteins (mainly with albumin) - 90%. TCmax - 3-5 hours. It penetrates the placental barrier. Accumulates in the liver. Distribution volume - 134 l.
Metabolized in the liver 10% of the administered dose. As in the case of other HMG-CoA reductase inhibitors, a specific membrane cholesterol transporter, which plays an important role in its hepatic elimination, is involved in the process of hepatic capture of the drug.Rosuvastatin has been shown to be a non-core substrate for metabolism by cytochrome P450 enzymes.
The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. CYP2C19, CYP3A4, CYP2D6 enzymes are less involved in metabolism. The main metabolite is N-desmethyl, which has 1 / 6-1 / 2 of rosuvastatin activity; lactone metabolites are pharmacologically inactive. T1 / 2 - 19 hours (does not change with increasing dose of the drug). Geometric average plasma clearance - 50 l / h.
Excreted mainly in unchanged form (90%) with faeces (including adsorbed and non-adsorbed rosuvastatin); the rest is with urine. It is not displayed through hemodialysis.
Gender and age do not have a clinically significant effect on rosuvastatin pharmacokinetics.
Pharmacokinetic parameters depend on race: AUC in Japanese and Chinese is 2 times higher than that in Europe and North America.
In patients with mild and moderate renal insufficiency, the plasma concentration of rosuvastatin or N-dismethyl does not change significantly. In patients with severe renal insufficiency (CC <30 ml / min), plasma concentration of rosuvastatin is 3 times higher, and N-dismethyl is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in plasma in patients on hemodialysis is approximately 50% higher than in healthy volunteers.
In patients with various stages of liver failure with a score of 7 and below on the Child-Pyuga scale, there was no increase in Rosuvastatin T1 / 2; in 2 patients with grades 8 and 9 on the Child-Pyuga scale, T1 / 2 lengthening was observed in 2 times. Experience with the use of the drug in patients with more severe liver dysfunction is absent.

Indications

Primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-drug therapies (exercise, weight loss) are insufficient.
Familial homozygous hypercholesterolemia as an adjunct to diet and other cholesterol-lowering therapy (LDL-apheresis) or in cases where such therapy is not suitable for the patient.

Contraindications

Hypersensitivity
liver disease in the active phase (includinga persistent increase in the activity of “liver” transaminases, as well as any increase in the activity of “liver” transaminases in the blood serum by more than 3 times compared with the upper limit of normal),
severe renal dysfunction (CC <30 ml / min), myopathy, simultaneous administration of cyclosporine,
pregnancy, lactation; women of reproductive age who do not use adequate methods of contraception;
age up to 18 years (efficacy and safety have not been established).
Carefully. Renal failure
hypothyroidism, personal or familial history of hereditary muscular diseases and a previous history of muscular toxicity using other HMG-CoA reductase inhibitors or fibrates),
alcohol addiction,
age over 65 years
history of liver disease, sepsis, hypotension,
extensive surgery, trauma,
severe metabolic, endocrine or electrolyte disorders, proteinuria, uncontrolled epilepsy,
Asians (Japanese and Chinese).

Side effects

The frequency of side effects is dose-dependent: often (1-10%), less often (0.1-1%), rarely (0.01-0.1%).
On the part of the nervous system: often - headache, dizziness, asthenic syndrome; less often - anxiety, depression, insomnia, neuralgia, paresthesia.
On the part of the digestive tract: often - constipation, nausea, abdominal pain; frequency unknown - reversible transient dose-dependent increase in the activity of liver transaminases; less often - dyspepsia (including diarrhea, flatulence, vomiting), gastritis, gastroenteritis.
On the part of the respiratory system: often - pharyngitis; less often - rhinitis, sinusitis, bronchial asthma, bronchitis, cough, shortness of breath, pneumonia.
On the part of the heart rate: less often - angina, increased blood pressure, heartbeat, vasodilation.
From the musculoskeletal system: often - myalgia; less often - arthralgia, arthritis, muscle hypertonus, back pain, pathological pearl of a limb (without injuries); rarely - myopathy, rhabdomyolysis (simultaneously with impaired renal function, while receiving the drug in a dose of 40 mg).
On the part of the urinary system: tubular proteinuria (in less than 1% of cases - for doses of 10 and 20 mg, 3% of leaches - for a dose of 40 mg); less often - peripheral edema (arms, legs, ankles, lower legs), lower abdominal pain, urinary tract infections.
Allergic reactions: less often - skin rash, pruritus; rarely - angioedema.
From the laboratory indicators: a transient dose-dependent increase in the activity of CPK (with an increase in the activity of CPK more than 5 times compared with the upper limit of the norm, therapy should be temporarily suspended).
Other: less often - accidental trauma, anemia, chest pain, diabetes, ecchymosis, flu-like syndrome, periodontal abscess.

Interaction

It does not affect the plasma concentration of cyclosporine. Cyclosporin enhances the effect of rosuvastatin (slows down its elimination, increases AUC 7 times, Cmax - 11 times), vitamin K antagonists (including Warfarin, can lead to an increase in prothrombin time, its monitoring is recommended).
Gemfibrozil enhances the effect of rosuvastatin (increases its Cmax and AUC 2 times).
Antacids containing Al3 + and Mg2 +, reduce the plasma concentration of rosuvastatin by about 50% (antacids should be used 2 hours after taking rosuvastatin, the clinical significance of this interaction has not been studied).
Erythromycin increases gastrointestinal motility, which leads to a reduction in the effect of rosuvastatin (reduces its AUC by 20% and Cmax by 30%).
Enhances the effect of oral contraceptives (increases the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively, which should be considered when selecting the dose of oral contraceptives). Pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy are not available, therefore, a similar effect cannot be excluded when using this combination.
No clinically significant interaction of rosuvastatin with Digoxin or fenofibrate is expected.
Gemfibrozil, other fibrates and lipid-lowering doses of nicotinic acid (high doses or equivalent 1 g / day) increase the risk of myopathy while being used with other HMG-CoA reductase inhibitors, possibly due to the fact that they themselves can cause myopathy when used as monotherapy.
The results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 enzymes. In addition, rosuvastatin is a non-core substrate for these enzymes. There was no clinically significant interaction between rosuvastatin and Fluconazole (an inhibitor of CYP2C9 and CYP3A4) and Ketoconazole (an inhibitor of CYP2A6 and CYP3A4). The combined use of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant).Thus, interactions associated with metabolism through the cytochrome P450 system are not expected.
Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones.

How to take, the course of administration and dosage

Inside, do not chew a pill or chop it; swallow it whole with a glass of water, it can be taken at any time of the day, regardless of the meal. The recommended initial dose is 10 mg once a day; if necessary, the dose may be increased to 20 mg after 4 weeks; Increasing the dose to 40 mg is possible only under the supervision of a physician in patients with severe homozygous familial hypercholesterolemia with a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who have not achieved the desired result of therapy while taking a dose of 20 mg.
Patients with risk factors for the development of myopathy, the initial dose of the drug should be 5 mg.
When prescribed with gemfibrasil, the dose of rosuvastatin should not exceed 10 mg / day.
In renal failure, mild or moderate severity, as well as in the elderly, dose adjustment is not required.
The experience of using the drug in patients with liver failure above 9 on the Childe-Pugh scale is absent.

Overdose

Treatment: symptomatic, control of liver function and CPK activity is necessary; there is no specific antidote, hemodialysis is ineffective.

Special instructions

Before initiating therapy and throughout the entire period of treatment, a standard lipid-lowering diet should be observed. During treatment, every 2–4 weeks, the lipid profile should be monitored and, according to it, the dose of the drug should be adjusted if necessary.
Doses of 40 mg are contraindicated in patients with risk factors for rhabdomyolysis (moderate renal insufficiency (CC less than 60 ml / min), hypothyroidism, own or family history of muscular diseases, myotoxicity in patients receiving other HMG-CoA reductase inhibitors or fibrates, abuse alcohol, conditions accompanied by an increase in the concentration of the drug in the systemic circulation), simultaneous intake of fibrates, patients of the Asian race).
In patients taking the drug in a dose of 40 mg, it is recommended to monitor indicators of renal function.
Determination of CPK activity should not be carried out after intense physical exertion or in the presence of other possible causes of increased CPK, which can lead to a misinterpretation of the results obtained. With an increase in the initial CPK 5 times higher than the upper limit of the norm, after 5-7 days it is necessary to re-measure. You should not begin therapy if the repeated test confirms the initial increased activity of CPK more than 5 times compared with the upper limit of normal.
In patients with existing risk factors for rhabdomyolysis, it is necessary to consider the ratio of the risk and possible benefits of therapy and to conduct clinical observation throughout the course of treatment.
The patient should be informed of 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 and fever. In such patients, the activity of CPK should be monitored. Therapy should be discontinued if the activity of CPK is increased by more than 5 times compared with the upper limit of the norm, or if the muscle 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 the symptoms disappear and the activity of CPK returns to normal, consideration should be given to reappointment of the drug or other HMG-CoA reductase inhibitors in smaller doses with careful monitoring of the patient. Routine monitoring of CPK activity in the absence of rhabdomyolysis symptoms is not advisable.
An increase in the incidence of myositis and myopathy was reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungal agents, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy in combination with some inhibitors of HMG-CoA reductase. Thus, the simultaneous administration of rosuvastatin and gemfibrozil is not recommended. The balance of risk and potential benefit should be carefully weighed when rosuvastatin and fibrates or nicotinic acid are used together.
It is recommended to carry out the determination of indicators of liver function before the start of therapy and 3 months after the start of therapy.If the activity of "liver" transaminases in the serum is 3 times higher than the upper limit of normal, the dose of the drug should be reduced or discontinued.
In most cases, proteinuria diminishes or disappears during therapy and does not mean the onset or the progression of an existing kidney disease.
With a combination of hypercholesterolemia and hypothyroidism or nephrotic syndrome, the treatment of major diseases should be carried out before starting treatment with rosuvastatin.
Caution should be exercised when driving or working related to increased concentration and psychomotor reaction (dizziness may occur during therapy).
Women of reproductive age should use adequate methods of contraception. Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of inhibition of HMG-CoA reductase exceeds the benefits of using the drug during pregnancy. The study in rats (use in doses of 2-50 mg / kg / day) revealed a decrease in fetal weight, a delay in ossification of the bones in the fetus, a decrease in the survival of offspring. In the event of pregnancy during therapy, the drug should be immediately discontinued. Data on the allocation of rosuvastatin with milk of women are not available, so breastfeeding should be stopped.