Expiration date: 03/2025

Clinico-pharmacological group

(Lipid lowering drug)

Release form, composition and packaging

Tablets, film-coated from light-yellow or light orange (possible a grayish tint) to orange, round, biconvex, engraved with "N" on one side and "5" on the other, in the cross-section - - white or almost white.

Excipients: cellulose microcrystalline - 47.82 mg, crospovidon 30 mg, lactose - 54.97 mg, povidone K30 - 8.5 mg; sodium fumarate - 3.5 mg.

The composition of the shell: Opadry 85F23426 orange II (polyvinyl alcohol-partially hydrolyzed - 1.8 mg titanium dioxide (E171) - 1.025 mg, macrogol 3350 - 0.909 mg, talc - 0.666 mg, dye iron oxide yellow (E172) - 0.075 mg, dye iron oxide black (E172) - 0.003 mg, colorant sunset yellow (E110) - 0.022 mg).

10 PCs. - blisters of PVC/PVA/aluminum foil (3) - packs cardboard.

10 PCs. - blisters of PVC/PVA/aluminum foil (9) - packs of cardboard.

Tablets, film-coated from light pink to pink, round, biconvex, engraved with "N" on one side and "10" on the other, in the cross-section - - white or almost white.

1 tablet contains:

rosuvastatin calcium 5.21 mg,

that corresponds to the content of rosuvastatin 5 mg

Excipients: cellulose microcrystalline - 45.22 mg, crospovidon 30 mg, lactose - 52.36 mg, povidone K30 - 8.5 mg; sodium fumarate - 3.5 mg.

The composition of the shell: Opadry 85F24155 II pink (polyvinyl alcohol partially hydrolyzed - 1.8 mg titanium dioxide (E171) - 1.105 mg, macrogol 3350 - 0.909 mg, talc - 0.666 mg, dye iron oxide yellow (E172) - 0.009 mg, colorant iron oxide red (E172) - 0.005 mg dye azorubin aluminum lacquer (E122) - 0.005 ppm, Indigo Carmine aluminum lacquer (E132) - 0.001 mg).

10 PCs. - blisters of PVC/PVA/aluminum foil (3) - packs cardboard.

10 PCs. - blisters of PVC/PVA/aluminum foil (9) - packs of cardboard.

Tablets, film-coated from light pink to pink, round, biconvex, engraved with "N" on one side and "20" on the other, in the cross-section - - white or almost white.

1 tablet contains:

rosuvastatin calcium 10.42 mg,

that corresponds to the content of rosuvastatin 10 mg

Excipients: cellulose microcrystalline - 90.45 mg, crospovidone 60 mg, lactose - 104.72 mg, povidone K30, 17 mg, sodium fumarate - 7 mg.

The composition of the shell: Opadry 85F24155 II pink (polyvinyl alcohol partially hydrolyzed - 3.6 mg, titanium dioxide (E171) - 2.21 mg, macrogol 3350 - 1.818 mg, talc - 1.332 mg, dye iron oxide yellow (E172) - 0.018 mg, colorant iron oxide red (E172) - 0.01 mg dye azorubin aluminum lacquer (E122) - 0.009 ppm, Indigo Carmine aluminum lacquer (E132) - 0.003 mg).

10 PCs. - blisters of PVC/PVA/aluminum foil (3) - packs cardboard.

10 PCs. - blisters of PVC/PVA/aluminum foil (9) - packs of cardboard.

Tablets, film-coated from light pink to pink, oval, engraved with "N" on one side and "40" on the other, in the cross-section - - white or almost white.

1 tablet contains:

rosuvastatin calcium 20.83 mg,

that corresponds to the content of rosuvastatin 20 mg

Excipients: cellulose microcrystalline - 80.03 mg, crospovidone 60 mg, lactose - 94.3 mg, povidone K30, 17 mg, sodium fumarate - 7 mg.

The composition of the shell: Opadry 85F24155 II pink (polyvinyl alcohol partially hydrolyzed - 3.6 mg, titanium dioxide (E171) - 2.21 mg, macrogol 3350 - 1.818 mg, talc - 1.332 mg, dye iron oxide yellow (E172) - 0.018 mg, colorant iron oxide red (E172) - 0.01 mg dye azorubin aluminum lacquer (E122) - 0.009 ppm, Indigo Carmine aluminum lacquer (E132) - 0.003 mg).

10 PCs. - blisters of PVC/PVA/aluminum foil (3) - packs cardboard.

10 PCs. - blisters of PVC/PVA/aluminum foil (9) - packs of cardboard.

Pharmacological action

Hypolipidemic drug, is a selective competitive inhibitor of HMG-COA reductase enzyme that transforms Z-hydroxy-3-methylglutarylcoenzyme a to mevalonate, a precursor of cholesterol (CH). The main target of action of rosuvastatin is the liver, where the Cholesterol synthesis and catabolism of LDL. Rosuvastatin increases the number of LDL receptors on the surface of liver cells, increasing the capture and catabolism of LDL, which in turn leads to inhibition of the synthesis of VLDL, thereby reducing the total number of LDL and VLDL. Rosuvastatin reduces the increased concentration of Cholesterol-LDL, total cholesterol, triglycerides, increases the concentration of HDL-C, and reduces the concentration of apolipoprotein b (Apob), HS-elpvp, XC-VLDL, TG-VLDL and increases the concentration of apolipoprotein A-1 (Apoa-1), reduces the ratio of Cholesterol-LDL/HDL - C, total Cholesterol/HDL-C and HS-elpvp/HDL-C ratio and Apob/Apoa-1.

The therapeutic effect appears within 1 week after initiation of therapy rosuvastatina, after 2 weeks of treatment reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by 4 weeks and maintained with regular admission.

Pharmacokinetics

Suction

Cmax of rosuvastatin in the blood plasma is reached after approximately 5 h after ingestion. The absolute bioavailability is approximately 20%

Distribution

Linking plasma proteins (mostly to albumin) is approximately 90%. Rosuvastatin accumulates mainly in the liver - the main organ of Cholesterol synthesis and clearance of Cholesterol-LDL. Vd is approximately 134 L.

Metabolism

Biotransformiroetsa to a small extent (about 10%), as a non-core substrate for the metabolic enzyme cytochrome P450. The main isoenzyme involved in the metabolism of rosuvastatin, a is CYP2C9. The isoenzymes CYP2C19, CYP3A4 and CYP2D6 involved in the metabolism to a lesser extent. The main identified metabolites of rosuvastatin are N-desmethyl and lactonase metabolites. N-desmethyl about 50% less active than rosuvastatin, lactonase metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for the inhibition of circulating HMG-COA reductase inhibitor rosuvastatin is provided, the rest of its metabolites.

Excretion

T1/2 - about 19 h. T1/2 does not change with increasing doses of the drug. About 90% of the rosuvastatin dose is excreted unchanged in the feces. The remaining part is excreted in the urine. The mean value of plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). As in the case of other inhibitors of HMG-COA reducase in the process of capture of rosuvastatin by the liver is involved membrane anion Transporter XC, performs an important role in the hepatic elimination of rosuvastatin.

Pharmacokinetics in special clinical cases

Gender and age do not have a clinically meaningful effect on the pharmacokinetics of rosuvastatin.

In patients with mild and moderate renal failure, the magnitude of the plasma concentration of rosuvastatin or the N-desmethyl does not change significantly. In patients with severe renal insufficiency (QC < 30 ml/min), the concentration of rosuvastatin in plasma is 3 times higher, and the concentration of N-desmethyl 9 times higher than in healthy volunteers.

The concentration of rosuvastatin in plasma of patients on hemodialysis were approximately 50% higher than in healthy volunteers.

In patients with different stages of hepatic insufficiency (a score of 7 and below on a scale child-Pugh) revealed no increase in T1/2 of rosuvastatin. 2 patients with scores of 8 and 9 on the scale of child-Pugh noted an increase in T1/2, at least 2 times. Experience with the use of rosuvastatin in patients with a score above 9 on a scale child-Pugh missing.

A comparative study of the pharmacokinetics of rosuvastatin in Chinese and Japanese patients living in Asia, showed approximately two-fold increase in the average AUC values, in comparison with indicators of the Europeans living in Europe and Asia. Is not revealed the influence of genetic factors and environmental factors on the observed differences in pharmacokinetic parameters. Pharmacokinetic analysis among different ethnic groups of patients did not reveal clinically important differences among Europeans, Latinos, blacks or African Americans.

Dosage

The drug is taken orally at any time of the day, regardless of meals. The tablet should be swallowed whole with water without chewing or crushing. If necessary, taking the drug at a dose of 5 mg should split the 10mg tablet in half.

Before the start of the rosuvastatin therapy the patient is required to begin to comply with the standard hypolipidemic diet and continue to observe her during treatment.

The dose should be selected individually depending on indications and therapeutic response, taking into account the current recommendations for target levels of lipids.

The recommended starting dose of rosuvastatin for patients who start taking the drug or for patients transferred from the reception of other inhibitors of HMG-COA reductase is 5 or 10 mg 1 times/day. When selecting the starting dose should be guided by the content of cholesterol in a patient and to take into account the risk of developing cardiovascular complications, and to assess the potential risk of side effects. If necessary after 4 weeks, the dose may be increased.

Patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who have not achieved the desired result at the dose of 20 mg over a 4-week treatment, increasing the dose to 40 mg should be under the supervision of a physician in connection with a possible increase in the risk of side effects. Especially advised careful monitoring of patients receiving the drug in a dose of 40 mg After 2-4 weeks of therapy and/or the dose of the drug Devastor necessary control of lipid metabolism.

At patients of elderly age (over 65 years) are recommended to begin treatment with a dose of 5 mg.

Patients with renal insufficiency mild or moderate severity dose adjustment is not required. Contraindicated use of the drug Devastor in any dose pripojeni failure, severe (CC less than 30 ml/min). Contraindicated use of the drug Devastor at a dose of 40 mg in patients with moderate renal impairment (CC less than 60 ml/min). Patients with moderate renal impairment, the recommended initial dose of 5 mg.

For patients of Asian race the recommended starting dose is 5 mg. the drug is Contraindicated Devastor at a dose of 40 mg for patients of Asian race.

Contraindicated use of the drug Devastor at a dose of 40 mg patients with factors that may indicate a predisposition to the development of myopathy. In appointing the drug in doses of 10 mg and 20 mg recommended starting dose for patients in this group 5 mg.

Overdose

While receiving multiple daily doses pharmacokinetic parameters of rosuvastatin are not changed.

Treatment: treatment of overdose, if necessary, symptomatic therapy required monitoring liver function and the activity of KFK. There is no specific antidote. Hemodialysis is not effective.

Drug interactions

While the use of rosuvastatin and cyclosporine AUC of rosuvastatin was on average 7 times higher than the value which was observed in healthy volunteers, plasma concentration of cyclosporine is not changed. Concurrent use leads to increased plasma concentration of rosuvastatin in plasma by 11 times.

Beginning of rosuvastatin therapy or increase in dosage in patients receiving both vitamin K antagonists (e.g. warfarin) may cause an increase in prothrombin time (increase in MHO). Cancellation of rosuvastatin or reduction of the dose may lead to reduction of the MHO (in such cases, monitoring MHO).

Concomitant use of rosuvastatin and ezetimibe showed no changes in AUC or Cmax none of the drug. However, their pharmacodynamic interaction and the occurrence of adverse effects cannot be ruled out.

Concomitant use of rosuvastatin and gemfibrozil leads to an increase 2 times the Cmax in plasma and AUC of rosuvastatin. According to special studies, appropriate pharmacokinetic interaction with fenofibrate not marked, but it is possible pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses of nicotinic acid, increase the risk of myopathy when used simultaneously with inhibitors of HMG-COA reductase (probably due to the fact that inhibitors of HMG-COA can cause myopathy and when used as monotherapy).

Although the exact mechanism of the interaction of rosuvastatin with protease inhibitors is unknown, their simultaneous use can cause permanent strengthening effect of rosuvastatin. In pharmacokinetic studies in healthy volunteers, concomitant use of 20 mg rosuvastatin and a combination of protease inhibitors (lopinavir 400 mg/ritonavir 100 mg) caused a approximately 2 - and 5-fold increase in AUC and Cmax, respectively. Therefore concurrent use of rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.

Concomitant use of rosuvastatin and suspensions of antacids containing aluminum and magnesium hydroxide, leads to a decrease in plasma concentrations of rosuvastatin by about 50%. This effect is expressed weaker, if antacids are applied through 2 h after administration of rosuvastatin. The clinical significance of this interaction has not been studied.

Concomitant use of rosuvastatin and erythromycin reduces the rosuvastatin AUC by 20% and rosuvastatin Cmax by 30%, probably due to increased intestinal motility caused by erythromycin reception.

Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol was norgestrel and AUC of 26% and 34%, respectively. This increase in the plasma concentration should be considered when selecting dose oral contraceptives on the background of the use of rosuvastatin.

Based on the studies of the interaction of rosuvastatin with digoxin clinically significant interactions have been identified.

The results of studies in vivo and in vitro showed that rosuvastatin is neither an inhibitor or inducer of isozymes of cytochrome P450. In addition, rosuvastatin is a poor substrate for these isoenzymes. Was not observed clinically significant interactions between rosuvastatin and fluconazole (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, it is not expected interactions associated with cytochrome P450.

Pregnancy and lactation

Devastor contraindicated in pregnancy and during breastfeeding. When the diagnosis of pregnancy in the course of therapy, the drug should be discontinued immediately.

Women of reproductive age should use reliable methods of contraception. As cholesterol and products of its biosynthesis are important for the development of the fetus, the potential risk of inhibition of HMG-COA reductase is greater than the benefit derived from the use of the drug.

Data on the excretion of rosuvastatin into breast milk is not available, so if you need the drug Devastor during lactation breastfeeding should be discontinued.

Side effects

Definition of side effects frequency: very often (?10%), often (?1% but <,10%), 0="" 1="" 01="" -="" p="">,

Allergic reactions: rare - urticaria, pruritus, rash, rarely angioedema, frequency unknown - Stevens-Johnson syndrome.

From the nervous system: often - headache, dizziness, very rarely, polyneuropathy, memory loss.

From the digestive system: often - constipation, nausea, abdominal pain, rarely - slight, asymptomatic, transient dose-dependent increase in the activity of liver enzymes, rarely - jaundice, hepatitis frequency unknown - diarrhea. As the use of other inhibitors of HMG-COA reductase inhibitor, the incidence of side effects is dose dependent in nature.

From the side of musculoskeletal system: often - myalgia, rarely - myopathy, rarely - rhabdomyolysis with acute renal failure, arthralgia. A dose-dependent increase in the activity of CPK is observed in a small number of patients taking rosuvastatin. In most cases, increased activity of KFK has been slight, asymptomatic and transient. In the case of increasing the activity of the KLF more than 5 times the ULN therapy with rosuvastatin should be suspended.

From the urinary system: often - proteinuria for a dose of 40 mg, rare - proteinuria for a dose of 10-20 mg (in most cases, proteinuria decreases or disappears during therapy, and rarely hematuria).

Laboratory indicators: increase in the concentration of glucose, bilirubin, activity of GGT, alkaline phosphatase, disorders of thyroid function.

Other: often - asthenic syndrome.

Testimony

• primary hypercholesterolemia (type IIA, including family heterozygote giperholesterinemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-pharmacological methods of treatment, e.g. physical exercise, weight loss, insufficient,
  
• family homozygous hypercholesterolemia as an adjunct to diet and other cholesterinspiegel therapy or in cases where such treatment is not appropriate for the patient.
  

Contraindications

For tablets 5, 10 and 20 mg

• liver disease in the active phase, including a persistent increase in liver transaminases or any increase in liver transaminases (more than 3 times compared with CAH),
  
• severe violations of the liver (more 9 points on a scale child-Pugh) (no experience),
  
• severe violations of kidney function (KK less 30 ml/min),
  
• myopathy,
  
• concomitant use of cyclosporine,
  
• pregnancy,
  
• breastfeeding,
  
• lack of reliable methods of contraception
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose),
  
• the age 18 years (insufficient data for efficacy and safety),
  
• hypersensitivity to the drug.
  

For tablets 40 mg

• liver disease in the active phase, including a persistent increase in liver transaminases and any increase in liver transaminases (more than 3 times compared with CAH),
  
• concurrent administration of fibrates, severe violations of the liver (more 9 points on a scale child-Pugh) (no experience),
  
• patients with risk factors for myopathy/rhabdomyolysis: kidney failure (KK less 60 ml/min), hypothyroidism, personal or family analysis of muscle diseases, myotoxicity on a background of reception of other inhibitors of HMG-Co-A-reductase inhibitors or fibrates, a history of excessive alcohol use and conditions that can lead to increased plasma concentrations of rosuvastatin,
  
• concomitant use of cyclosporine,
  
• pregnancy,
  
• breastfeeding,
  
• lack of reliable methods of contraception
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose),
  
• the age 18 years (insufficient data for efficacy and safety),
  
• use in patients of Asian race,
  
• hypersensitivity to the drug.
  

With caution

For tablets 5, 10 and 20 mg: risk factors for myopathy and/or rhabdomyolysis - renal impairment, hypothyroidism, personal or family analysis of hereditary muscular diseases and previous history of muscle toxicity with the use of other inhibitors of HMG-Co-A-reductase inhibitors or fibrates, excessive alcohol use, age older than 65 years, a condition in which increased plasma concentrations of rosuvastatin, race (Asian, race), concomitant use of fibrates, liver diseases in history, sepsis, arterial hypotension, extensive surgical interventions, injuries, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures.

For tablets 40 mg: renal failure (CC more than 60 ml/min), age over 65 years, liver diseases in history, sepsis, arterial hypotension, extensive surgical interventions, injuries, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures.

Special instructions

Proteinuria, mostly of renal origin found in the test results, observed in patients receiving rosuvastatin at a dose of 40 mg and higher, and in most cases is transient. So proteinuria is not a symptom of acute or progressive renal disease. The total number of cases of serious renal complications has been reported during the use of rosuvastatin in a dose of 40 mg. If the drug is Devastor at a dose of 40 mg is recommended to monitor indicators of kidney function.

Influence on skeletal muscles (myalgia, myopathy and very rarely rhabdomyolysis) has been observed in patients receiving the drug Devastor, in particular, in a dose of 20 mg. were very rare cases of rhabdomyolysis with administration of ezetimibe with inhibitors of HMG-COA reductase. Probability of rhabdomyolysis as the use of rosuvastatin, like other inhibitors of HMG-COA reductase, the higher the dose of 40 mg.

Determination of activity of KFK should not be after intense exercise or if there are other possible reasons for the increased activity of KFK for a possible distortion of the results. In the case that the initial activity of CPK is significantly elevated (5 times ULN), 5-7 days should be measured again. You should not start the therapy if the second test confirms the initial activity of CPK (in 5 times above ULN).

It should warn patients about the need to immediately inform the doctor when a new, not previously observed symptoms of unexplained muscle pain, weakness or cramps, especially combined with fever and malaise. Therapy should be discontinued if KLF activity 5 times ULN or in the presence of severe muscle symptoms causing constant discomfort. With the disappearance of symptoms and normalization of activity of KFK, you should consider re-use of rosuvastatin at the lowest dose and careful monitoring. Routine monitoring of CPK activity in the absence of symptoms is inappropriate.

It is recommended to carry out functional diagnostics of the liver before and for 3 months after the start of therapy. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, should be treated for primary disease, before prescribing the drug Devastor.

Effects on ability to drive vehicles and management mechanisms

The research aimed to study the influence of the drug Devastor on the ability to drive vehicles and work with equipment, was conducted. In applying the drug Devastor be careful in connection with what may develop dizziness.

Use in impaired renal function

Patients with renal insufficiency mild or moderate severity dose adjustment is not required. Contraindicated use of the drug Devastor in any dose pripojeni failure, severe (CC less than 30 ml/min). Contraindicated use of the drug Devastor at a dose of 40 mg in patients with moderate renal impairment (CC less than 60 ml/min). Patients with moderate renal impairment, the recommended initial dose of 5 mg.

Use in hepatic impairment

Contraindications: liver disease in the active phase, including a persistent increase in liver transaminases or any increase in liver transaminases (more than 3 times compared with CAH), severe violations of the liver (more 9 points on a scale child-Pugh) (no experience).