Crestor, 40 mg 28 pcs.

Indications

Primary Fredrickson hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet, when diet and other non-drug therapies (e.g., exercise, weight loss) are not sufficient.
– Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (e.g., LDL-apheresis), or in cases where such therapy is not effective enough.
– Hypertriglyceridemia (type IV by Fredrickson) as an adjunct to diet.
– For slowing the progression of atherosclerosis as an adjunct to the diet in patients who are indicated for therapy to reduce the concentration of total cholesterol and LDL-C.
– Primary prevention of major cardiovascular complications (stroke, infarction, arterial revascularization) in adult patients without clinical signs of CHD, but with increased risk of its development (age over 50 years for men and over 60 years for women, increased concentration of C-reactive protein (≥ 2 mg/L) with at least one additional risk factor, such as hypertension, low HDL-C, smoking, family history of early-onset CHD).

Active ingredient

Rosuvastatin

Composition

Each tablet contains the active ingredient: rosuvastatin 10, 20 or 40 mg as calcium rosuvastatin.

Auxiliary substances: lactose monohydrate 89.50 mg (for 10 mg dosage), 179.00 mg (for 20 mg dosage), 164.72 mg (for 40 mg dosage); Microcrystalline cellulose 29.82 mg (for 10 mg dosage), 59.64 mg (for 20 mg dosage), 54.92 mg (for 40 mg dosage); calcium phosphate 10.90 mg (for 10 mg dosage), 21.80 mg (for 20 mg dosage), 20.00 mg (for 40 mg dosage); Crospovidone 7.50 mg (for 10 mg dosage), 15.00 mg (for 20 mg dosage), 15.00 mg (for 40 mg dosage); magnesium stearate 1.88 mg (for 10 mg dosage), 3.76 mg (for 20 mg dosage), 3.76 mg (for 40 mg dosage);

Pill coating: lactose monohydrate 1.80 mg (for 10 mg dosage), 3.60 mg (for 20 mg dosage), 3.60 mg (for 40 mg dosage); hypromellose 1.26 mg (for 10 mg dosage), 2.52 mg (for 20 mg dosage), 2.52 mg (for 40 mg dosage), triacetin (glycerol triacetate) 0.36 mg (for 10 mg dosage), 0.72 mg (for 20 mg dosage), 0.72 mg (for 40 mg dosage); titanium dioxide 1.06 mg (for 10 mg dosage), 2.11 mg (for 20 mg dosage), 2.11 mg (for 40 mg dosage); iron oxide red dye 0.02 mg (for 10 mg dosage), 0.05 mg (for 20 mg dosage), 0.05 mg (for 40 mg dosage).

How to take, the dosage

To the mouth, do not chew or crush the tablet, swallow it whole with water. The drug can be taken at any time of the day regardless of meals.

People should start a standard hypocholesterolemic diet prior to initiating therapy with Crestor® and continue it during treatment. The drug dose should be adjusted individually depending on therapy goals and therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended starting dose for patients starting the drug or switching from other HMG-CoA reductase inhibitors should be 5 mg or 10 mg of Crestor® once daily. When choosing the initial dose, individual cholesterol concentration should be taken into account, as well as possible risk of cardiovascular complications, and the potential risk of side effects should be assessed. If necessary, the dose may be increased to a larger one in 4 weeks (see section “Pharmacodynamics”). Due to the possible development of side effects at a dose of 40 mg, compared to lower doses of the drug (see section “Side effects”). Due to the possible development of side effects of 40 mg dose compared to lower doses of the drug (see section “Side effects”), increasing the dose to 40 mg, after an additional dose above the recommended initial dose for 4 weeks of therapy, may be conducted only in patients with severe hypercholesterolemia and with a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in whom the desired therapy result was not reached with the dose of 20 mg and will be under the supervision of a specialist (see section “Special indications”). We recommend especially close monitoring of patients receiving 40 mg.

The 40 mg dose is not recommended for patients who have not previously seen a physician. After 2-4 weeks of therapy and/or when increasing the dose of Crestor® it is necessary to monitor lipid metabolism parameters (dosage adjustment is required if necessary).

Application in special patient groups

Elderly patients

Dose adjustment is not required.

Patients with impaired renal function

Dose adjustment is not required in patients with mild to moderate impaired renal function. In patients with severe renal dysfunction (CKD less than 30 ml/min) the use of Crestor® is contraindicated. A dose of 40 mg is contraindicated in patients with moderate renal dysfunction (CKD 30-60 ml/min) (see sections “Cautionary Note” and “Pharmacodynamics”). In patients with moderate renal dysfunction, a starting dose of 5 mg is recommended.

Patients with impaired liver function

Crestor® is contraindicated in patients with active liver disease (see section “Contraindications”).

Ethnic groups

When studying pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increased systemic concentration of rosuvastatin was noted in Japanese and Chinese (see section “Special Indications”). This fact should be considered when prescribing Crestor® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended starting dose for mongoloid patients is 5 mg. A dose of 40 mg is contraindicated in patients of mongoloid race (see “Contraindications”).

Genetic polymorphisms

Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA there was an increased exposure (AUC) of rosuvastatin compared to SLCO1B1 c.521TT and ABCG2 c.421CC genotype carriers. For patients who are carriers of c.521CC or c.421AA genotypes the recommended maximum dose of Crestor® is 20 mg once daily (see sections “Pharmacokinetics”, “Precautions” and “Interaction with other medicinal products”).

Patients susceptible to myopathy

The drug is contraindicated in a dose of 40 mg in patients with factors that may indicate a predisposition to myopathy (see Contraindications). When doses of 10 mg and 20 mg are prescribed, the recommended starting dose for this group of patients is 5 mg (see Contraindications).

Companion therapy

Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When co-administration of Crestor® with medicinal products (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see sections “Cautions” and “Interaction with other medicinal products”). Read the instructions for use for these drugs before prescribing them together with Crestor®. In such cases, the possibility of prescribing an alternative therapy or stopping Crestor® temporarily should be assessed. If use of the above drugs is necessary, the benefit/risk ratio of concomitant therapy with Crestor® should be assessed and the possibility of reducing its dose should be considered (see section “Interaction with other medicinal products”).

Interaction

Influence of other drugs on rosuvastatin

Transport protein inhibitors: Rosuvastatin binds to several transport proteins, in particular OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Table 4 and sections “Administration and Dose” and “Precautions”).

Cyclosporine: Concomitant use of rosuvastatin and cyclosporine had an average AUC of 7 times higher than that observed in healthy volunteers (see Table 4). No effect on the plasma concentration of cyclosporine.

Human immunodeficiency virus (HIV) protease inhibitors: co-administration of rosuvastatin with certain HIV protease inhibitors or with a combination of HIV protease inhibitors may increase the exposure (AUC) of rosuvastatin up to 7-fold (see Table 4). A dose adjustment of rosuvastatin is required depending on the expected degree of increase in exposure (see sections “Contraindications” and “Dosage and administration”).

Hemfibrozil and other hypolipidemic agents: The combined use of rosuvastatin and gemfibrozil results in a 2-fold increase in the maximum plasma concentration of rosuvastatin and the AUC of rosuvastatin (see section “Special Precautions”). Based on the data on specific interactions, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible.

Hemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used simultaneously with HMG-CoA reductase inhibitors, possibly due to the fact that they may cause myopathy when used in monotherapy (see section “Special Indications”). When concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) the initial dose of the drug should not exceed 5 mg, taking a dose of 40 mg is contraindicated in concomitant administration with fibrates (see sections “Contraindications”, “Dosage and administration”, “Special indications”).

Ezetimibe: Concomitant administration of Crestor® in dose 10 mg and ezetimibe in dose 10 mg was accompanied by 1.2-fold increase in AUC of rosuvastatin in patients with hypercholesterolemia (see Table 4). An increased risk of side effects due to pharmacodynamic interaction between the drug Crestor® and ezetimibe cannot be excluded.

Antacids: Simultaneous use of rosuvastatin and suspensions of antacids containing magnesium and aluminum hydroxide leads to decrease of plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Eritromycin: Simultaneous use of rosuvastatin and erythromycin decreases AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by taking erythromycin.

Cytochrome P450 isoenzymes: The results of in vivo and in vitro studies showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected. No clinically significant interaction of rosuvastatin with fluconazole (CYP2C9 and CYP3A4 isoenzymes inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzymes inhibitor) was observed.

Fusidic acid: There have been no studies on the interaction between rosuvastatin and fusidic acid. As with other statins, there have been post-marketing reports of cases of rhabdomyolysis when co-administering rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, temporary discontinuation of rosuvastatin is possible.

Drug interactions that require dose adjustment rosuvastatin (see. Table 4)

The dose of Crestor® should be adjusted if its co-administration with drugs that increase rosuvastatin exposure is necessary. Read the instructions for use for these drugs before prescribing them together with Crestor®. If an increase in exposure by 2 times or more is expected, the initial dose of Crestor® should not exceed 5 mg once daily. The maximum daily dose of Crestor® should also be adjusted so that the expected exposure to rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, maximum daily dose of Crestor® in concomitant use with cyclosporine is 5 mg (7.1-fold increase of exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase of exposure), with gemfibrozil – 20 mg (1.9-fold increase of exposure).

There is no need to adjust the initial dose of Crestor® if the increase in exposure is expected to be less than 2-fold, however, caution should be exercised when increasing the dose of Crestor® above 20 mg.

Table 4. Effect of concomitant therapy on rosuvastatin exposure (AUC, data are given in descending order of exposure value) – results of published clinical studies

.

¹ The data presented as multiples of AUC are the ratio of the value of this parameter on concomitant therapy to the value of the parameter during rosuvastatin monotherapy. The data presented as % are the difference in % between the AUC on concomitant therapy and the value of the indicator in rosuvastatin monotherapy.

The following drugs and their combinations have no clinically significant effect on rosuvastatin exposure when used together: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg 3 times per day, 7 days; fluconazole 200 mg once daily, 11 days; fosamprenavir 700 mg/ritonavir 100 mg 2 times daily, 8 days; ketoconazole 200 mg 2 times daily, 7 days; rifampin 450 mg once daily, 7 days; silymarin 140 mg 3 times daily, 5 days.

Influence of rosuvastatin use on other drugs

Vitamin K antagonists: The initiation of rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (such as warfarin) may result in an increase in the International Normalized Ratio (INR). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in INR. In such cases it is recommended to monitor INR.

Injection of oral contraceptives/hormone replacement therapy: concomitant use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and AUC of nogestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting a dose of oral contraceptives. There are no pharmacokinetic data on concomitant use of Crestor® and hormone replacement therapy, therefore, it is impossible to exclude a similar effect when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Special Instructions

Renal effects

In patients receiving high doses of Crestor® (mainly 40 mg), there was tubular proteinuria, which in most cases was transient. Such proteinuria was not indicative of acute kidney disease or progression of renal disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

Motor system disorders

The following musculoskeletal effects have been reported with all doses of Crestor® and especially with doses greater than 20 mg: Myalgia, myopathy, in rare cases rhabdomyolysis.

Creatine phosphokinase activity determination

The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible causes of increased CPK activity, which may lead to misinterpretation of the results. If the initial CPK activity is significantly elevated (5 times higher than the upper limit of normal) the measurement should be repeated in 5-7 days. The therapy should not be started if the repeated test confirms the initial CPK activity (more than 5 times higher than the upper limit of normal).

Before initiating therapy

Patients with existing risk factors for myopathy/rhabdomyolysis should exercise caution when prescribing Crestor®, as well as other HMG-CoA reductase inhibitors (see “Caution”). section “Caution”), the risk/benefit ratio of therapy should be considered and clinical monitoring should be performed.

At the time of therapy

The patient should be informed of the need to immediately inform the physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially in conjunction with malaise and fever. In such patients, CPK activity should be determined. Therapy should be stopped if CPK activity is significantly increased (more than 5 times the upper limit of normal), or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is not increased more than 5 times the upper limit of normal). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Crestor® or other HMG-CoA reductase inhibitors at lower doses with close patient monitoring.

Routine monitoring of CPK activity in the absence of symptoms is not advisable.

There have been very rare cases of immune-mediated necrotizing myopathy with clinical manifestations as persistent proximal muscle weakness and increased serum CPK activity during treatment or upon discontinuation of statins, including rosuvastatin. Additional muscular and nervous system studies, serologic studies, and therapy with immunosuppressive agents may be required.

There have been no indications of increased skeletal muscle effects when taking Crestor® and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (over 1 g/day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when concomitantly prescribed with some HMG-CoA reductase inhibitors. Thus, concomitant administration of Crestor® and gemfibrozil is not recommended. It is necessary to carefully weigh the ratio of risk and possible benefits when concomitant use of Crestor® and fibrates or lipid-lowering doses of nicotinic acid. Contraindications for use of Crestor® at a dose of 40 mg together with fibrates (see sections

“Interaction with other medicinal products” and “Contraindications”).

2-4 weeks after the start of treatment and/or when increasing the dose of Crestor® it is necessary to monitor lipid metabolism parameters (if necessary, dose adjustment is required).

Hepatic function

Hepatic function tests are recommended before the start of therapy and 3 months after the start of therapy. Crestor® should be discontinued or the dose should be reduced if the serum hepatic transaminase activity is 3 or more times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for underlying diseases should be performed before starting treatment with Crestor®.

Particular populations. Ethnic groups

In pharmacokinetic studies among Chinese and Japanese patients an increase in systemic rosuvastatin concentration has been observed compared to those obtained in European patients (see sections “Administration and Doses” and “Pharmacokinetics”).

HIV protease inhibitors

The combined use of the drug with HIV protease inhibitors is not recommended (see section “Interaction with other medicinal products”).

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease

Single cases of interstitial lung disease have been reported with some statins, especially for long periods of time. Manifestations of the disease may include dyspnea, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Type 2 diabetes mellitus

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, Crestor® therapy has been associated with an increased risk of developing type 2 diabetes mellitus.

Influence on ability to drive vehicles, mechanisms

There have been no studies to study the effect of Crestor® on the ability to drive vehicles and use mechanisms. However, based on the pharmacodynamic properties, Crestor® should have no such effect. Caution should be exercised when driving motor transport or working with high concentration and psychomotor reaction (dizziness may occur during therapy).

Synopsis

Tablets 10 mg: round, biconvex pink film-coated tablets, engraved “ZD4522 10” on one side.

Tablets 20 mg: round biconvex pink film-coated tablets, engraved “ZD4522 20” on one side.

Tablets 40 mg: oval, biconvex pink film-coated tablets, engraved “ZD4522” on one side and 40 on the other.

Contraindications

For 10 mg and 20 mg tablets:

• high sensitivity to rosuvastatin or any of the drug components
• active-phase liver disease, including persistent elevation of serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of normal)
• severe renal function impairment (CK less than 30 ml/min.)
• myopathy
• current use of cyclosporine
• in women: pregnancy, breastfeeding period, lack of adequate contraceptive methods
• patients predisposed to the development of myotoxic complications
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose

For 40 mg tablets:

• high sensitivity to rosuvastatin or any of the components of the drug
• concurrent administration of cyclosporine
• in women: pregnancy, breastfeeding period, lack of adequate contraceptive methods
• liver disease in the active phase, including persistent elevation of serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of normal)
• patients with risk factors for myopathy/rhabdomyolysis, namely:
  • moderate renal function impairment (CK less than 60 ml/min.)
  • hypothyroidism
  • personal or family history of muscle disease
  • myotoxicity with a history of taking other HMG-CoA reductase inhibitors or fibrates
  • excessive alcohol consumption
  • conditions that may increase plasma concentrations of rosuvastatin

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  • concurrent administration of fibrates
  • patients of mongoloid race
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose)

Cautions

For 10 mg and 20 mg tablets:

Having a risk of myopathy/rhabdomyolysis – impaired renal function, hypothyroidism, personal or family history of hereditary muscle disease, and prior history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions with increased plasma concentrations of rosuvastatin; race (Mongoloid race); concomitant administration with fibrates (see section “Pharmacokinetics”); history of liver disease; sepsis; arterial hypotension; major surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures.

For 40 mg tablets:

Mild renal impairment (CK greater than 60 ml/min.); age over

65 years; history of liver disease; sepsis; arterial hypotension; extensive surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures.

Application in pediatric practice

The efficacy and safety of the drug in children under 18 years of age has 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, it is not recommended to use Crestor® in children under 18 years of age.

Patients with impaired liver function

There is no data or experience of using the drug in patients with a Child-Pugh score above 9 (see sections “Pharmacodynamics” and “Special Indications”).

Side effects

Side effects observed while taking Crestor® are usually mild and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mostly dose-dependent.

The incidence of adverse reactions is as follows: Frequent (> 1/100, < 1/10); infrequent (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), unspecified frequency (cannot be calculated from available data).

Table listing of adverse reactions

Table 3 presents a profile of rosuvastatin adverse reactions from clinical trials and wide postmarketing use; adverse reactions are grouped by frequency category and organ system class.

Table 3. Adverse reactions according to clinical trials and postmarketing use

Renal and urinary tract disorders

Patients treated with Crestor® may show proteinuria. Changes in the amount of protein in the urine (from no or trace amounts to ++ or greater) are seen in less than 1% of patients receiving 10-20 mg of the drug and in approximately 3% of patients receiving 40 mg of the drug. Little change in urine protein has been observed with the 20 mg dose. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing renal disease.

Musculoskeletal and connective tissue disorders

The following musculoskeletal effects have been reported with Crestor® at all doses and especially with doses greater than 20 mg Myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure.

Dose-dependent increase in creatine phosphokinase (CPK) activity has been observed in a small number of patients taking rosuvastatin. In most cases it was insignificant, asymptomatic and temporary. In case of increased CPK activity (more than 5 times the upper limit of normal), therapy should be suspended (see section “Special Precautions”).

Hepatic disorders

When using rosuvastatin, a dose-dependent increase in hepatic transaminase activity is observed in a small number of patients. In most cases it is mild, asymptomatic and temporary.

Changes in laboratory parameters

The following changes in laboratory parameters were also observed during the use of Crestor® drug: increased concentration of glucose, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid function disorders.

The following adverse events have been reported with some statins: depression, sleep disorders, including insomnia and “nightmares”, sexual dysfunction, hyperglycemia, increased concentration of glycated hemoglobin. Single cases of interstitial lung disease have been reported, especially with long-term use of the drug (see section “Special indications”).

Overdose

If several daily doses are taken simultaneously, pharmacokinetic parameters of rosuvastatin do not change.

There is no specific treatment for rosuvastatin overdose. In case of overdose it is recommended to perform symptomatic treatment and measures aimed at maintenance of functions of vital organs and systems. Control of liver function and CPK level is necessary. Hemodialysis is unlikely to be effective.

Pregnancy use

Crestor® is contraindicated in pregnancy and lactation.

Women of reproductive age should use adequate methods of contraception.

Since cholesterol and other products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefit of the drug in pregnant women.

In case of pregnancy during therapy the drug administration should be stopped immediately.

There are no data on excretion of rosuvastatin with breast milk, therefore during breast-feeding the drug administration should be stopped (see section “Contraindications”).

Similarities

Mertenil, Crestor, Rosulip, Rosucard, Rosart, Rosuvastatin, Rosistarck, Roxera, Suvardio, Rosuvastatin NW, Cardiolip