Rozythin
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSETIN (ROSETIN)
Composition:
Active substances: rosuvastatin, ezetimibe;
One film-coated tablet contains 10 mg rosuvastatin, equivalent to rosuvastatin calcium 10.40 mg, and 10 mg ezetimibe, or 20 mg rosuvastatin, equivalent to rosuvastatin calcium 20.80 mg, and 10 mg ezetimibe;
Excipients: lactose monohydrate; sodium croscarmellose; povidone K30; sodium lauryl sulfate; microcrystalline cellulose PH 102; hypromellose 2910; colloidal anhydrous silicon dioxide; magnesium stearate, purified water;
Film coating Opadry beige 02F270003: hypromellose 2910, iron oxide yellow (E 172), titanium dioxide (E 171), macrogol 4000, talc (E553b), purified water;
Film coating Vivacoat yellow PC-2P-308: hypromellose 2910, titanium dioxide (E 171), talc (E553b), macrogol 4000, iron oxide yellow (E 172), purified water.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
tablets 10 mg/10 mg – beige, round, biconvex, film-coated tablets with a diameter of approximately 10 mm, embossed with «EL4» on one side;
tablets 20 mg/10 mg – yellow, round, biconvex, film-coated tablets with a diameter of approximately 10 mm, embossed with «EL3» on one side.
Pharmacotherapeutic group. Hypolipidemic agents, combinations. Combinations of different hypolipidemic agents. Rosuvastatin and ezetimibe. ATC code C10BA06.
Pharmacological Properties
Pharmacodynamics
Rosuvastatin
Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol reduction. Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, and suppresses hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL particles.
Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, and slightly increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces apolipoprotein B, non-HDL cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglycerides, and slightly increases apolipoprotein A-I levels. Rosuvastatin also reduces the ratios of LDL-C/HDL-C, total cholesterol/HDL-C, non-HDL-C/HDL-C, and apolipoprotein B/apolipoprotein A-I.
The therapeutic effect becomes evident within 1 week after initiation of rosuvastatin therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum achievable. Maximum effect is generally achieved within 4 weeks after starting treatment.
Clinical Efficacy and Safety
Rosuvastatin has demonstrated efficacy in adults with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender, or age, as well as in patients from special populations, such as patients with diabetes or those with a history of familial hypercholesterolemia.
Based on pooled Phase III trial data, rosuvastatin effectively reduced cholesterol levels in most patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C approximately 4.8 mmol/L) to target values established by the European Atherosclerosis Society (EAS; 1998) guidelines; approximately 80% of patients receiving the 10 mg dose achieved EAS-recommended target LDL-C levels (< 3 mmol/L).
Ezetimibe
Ezetimibe is a representative of a new class of lipid-lowering agents that selectively inhibit intestinal absorption of cholesterol and related plant sterols. Ezetimibe is orally active and has a mechanism of action distinct from other classes of cholesterol-lowering agents (e.g., statins, bile acid sequestrants (resins), fibrate acid derivatives, and plant stanols). The molecular target of ezetimibe is the Niemann-Pick C1-Like 1 (NPC1L1) sterol transporter, responsible for the uptake of cholesterol and phytosterols in the intestine.
Ezetimibe localizes to the brush border of the small intestine and inhibits cholesterol absorption, thereby reducing delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver, and together these mechanisms provide additional cholesterol reduction. After 2 weeks of clinical use in 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54% compared to placebo. A series of preclinical studies were conducted to determine the selectivity of ezetimibe in inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol without affecting the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and D.
Epidemiological studies have established that cardiovascular disease and mortality increase proportionally with total cholesterol and LDL-C levels and inversely with HDL-C levels.
Combination therapy with ezetimibe and statins has demonstrated efficacy in reducing the risk of cardiovascular disease in patients with existing cardiovascular conditions and a history of acute coronary syndromes.
Clinical Efficacy and Safety
Clinical studies have shown that ezetimibe, used either as monotherapy or in combination with statins, significantly reduces levels of total cholesterol, LDL-C, apolipoprotein B (apo-B), and triglycerides, and increases HDL-C levels in patients with hypercholesterolemia.
Pharmacokinetics
Rosuvastatin
Absorption
Maximum plasma concentration (Cmax) of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.
Distribution
Rosuvastatin is extensively metabolized in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, primarily albumin.
Metabolism
Metabolism of rosuvastatin is limited (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a very weak substrate for cytochrome P450-mediated metabolism. CYP2C9 is the main isoenzyme involved in metabolism, while isoenzymes 2C19, 3A4, and 2D6 play a minor role. The main identified metabolites are N-desmethyl and lactone forms. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone form is considered clinically inactive. More than 90% of the pharmacological activity directed at inhibition of circulating HMG-CoA reductase is provided by rosuvastatin itself.
Elimination
Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (comprising both absorbed and unabsorbed active substance), and the remainder is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase with higher doses. Mean geometric plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin occurs via the membrane transporter OATP-C. This transporter plays an important role in the hepatic elimination of rosuvastatin.
Linearity/Non-linearity
Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with multiple daily doses.
Special Patient Populations
Age and Gender
There is no clinically significant effect of age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia are similar to those in adult volunteers.
Race
Pharmacokinetic studies demonstrate approximately a 2-fold increase in median plasma concentration-time curve area (AUC) and Cmax of rosuvastatin in Mongoloid populations (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian patients; in Indians, a 1.3-fold increase in median AUC and Cmax is observed. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Negroid populations.
Patients with Renal Impairment
In a study involving patients with varying degrees of renal dysfunction, mild or moderate renal disease did not affect plasma concentrations of rosuvastatin or its N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rosuvastatin increased 3-fold and N-desmethyl metabolite concentrations increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.
Patients with Hepatic Impairment
In a study involving patients with varying degrees of hepatic dysfunction, no increase in rosuvastatin exposure was observed in patients with Child–Pugh scores of 7 or less. However, in two patients with Child–Pugh scores of 8 and 9, systemic exposure was at least doubled compared to patients with lower scores. Experience with rosuvastatin in patients with Child–Pugh scores of 9 or higher is lacking.
Genetic Polymorphism
Transport proteins OATP1B1 and BCRP are involved in the pharmacokinetics of HMG-CoA reductase inhibitors, including rosuvastatin. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher rosuvastatin exposure (AUC) compared to SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not routinely used in clinical practice, but patients identified with these polymorphisms should be prescribed a lower daily dose of rosuvastatin.
Ezetimibe
Absorption
After oral administration, ezetimibe is rapidly absorbed and actively conjugated to form the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
The mean Cmax of ezetimibe-glucuronide in plasma is reached within 1–2 hours, and that of ezetimibe within 4–12 hours.
Absolute bioavailability of ezetimibe cannot be determined because the compound is insoluble in aqueous solutions for injection.
Concomitant food intake (low- or high-fat meals) does not affect the oral bioavailability of ezetimibe, including at the 10 mg dose. Ezetimibe can be taken independently of food intake.
Distribution
Ezetimibe and ezetimibe-glucuronide are bound to human plasma proteins by 99.7% and 88–92%, respectively.
Metabolism
Ezetimibe metabolism occurs in the small intestine and liver via glucuronidation (Phase II reaction), followed by biliary excretion. Minimal oxidative metabolism (Phase I reaction) has been observed at all stages of transformation. Ezetimibe and ezetimibe-glucuronide are the main substances detected in plasma, accounting for approximately 10–20% and 80–90% of total drug content in plasma, respectively. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma via enterohepatic recirculation. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Elimination
After administration of 20 mg of 14C-ezetimibe to volunteers, approximately 93% of total ezetimibe was detected in plasma relative to total plasma radioactivity. Approximately 78% and 11% of the administered radioactive dose were excreted in feces and urine, respectively, within 10 days. No detectable levels of radioactivity were observed in plasma after 48 hours.
Special Patient Populations
Elderly Patients
In elderly patients (over 65 years), plasma concentrations of total ezetimibe are approximately twice as high as in younger patients (18–45 years). LDL-C reduction and safety profile are approximately similar between elderly and younger patients receiving ezetimibe. Therefore, no dose adjustment is required for elderly patients.
Patients with Hepatic Impairment
After a single 10 mg dose of ezetimibe, mean AUC values of total ezetimibe were 1.7 times higher in patients with mild hepatic impairment (5–6 points on the Child–Pugh scale) than in healthy volunteers. In a 14-day study of ezetimibe (10 mg daily) in patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), AUC values of total ezetimibe increased approximately 4-fold on day 1 and day 14 compared to healthy volunteers. Dose adjustment is not required for patients with mild hepatic impairment. Since the effects of increased ezetimibe exposure in patients with moderate or severe hepatic impairment (more than 9 points on the Child–Pugh scale) are unknown, ezetimibe is not recommended for use in this patient group (see section "Special Warnings and Precautions for Use").
Patients with Renal Impairment
After a single 10 mg dose of ezetimibe, mean AUC values of total ezetimibe increased approximately 1.5-fold in patients with severe renal impairment (n = 8; creatinine clearance ≤ 30 mL/min/1.73 m²) compared to healthy volunteers (n = 9). This result is not considered clinically significant. No dose adjustment is required for patients with renal impairment.
In this study, one patient (who had a kidney transplant and was on multiple therapies, including cyclosporine) had total ezetimibe levels 12 times higher.
Gender
Plasma concentrations of total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are approximately similar between men and women receiving ezetimibe. Therefore, no dose adjustment is required based on patient gender.
Clinical characteristics.
Indications.
Primary hypercholesterolemia / homozygous familial hypercholesterolemia
The medicinal product is indicated as an adjunctive therapy to diet or other non-pharmacological interventions (e.g., physical exercise, weight reduction) for the treatment of adult patients with primary (heterozygous familial and non-familial) hypercholesterolemia or homozygous familial hypercholesterolemia, in whom adequate disease control is achieved with concomitant administration of rosuvastatin and ezetimibe as monotherapy agents at the same doses as in the fixed-dose combination product.
Contraindications.
- Hypersensitivity to rosuvastatin, ezetimibe, or to any of the excipients;
- active liver disease, including persistent elevations of serum transaminases of unknown etiology and any serum transaminase elevations exceeding three times the upper limit of normal (ULN);
- severe renal impairment (creatinine clearance < 30 mL/min);
- myopathy;
- concomitant use of cyclosporine;
- concomitant use of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
- pregnancy and breastfeeding; the medicinal product is contraindicated in women of childbearing potential who are not using appropriate contraceptive measures (see section "Use in pregnancy or lactation").
Rosuvastatin 40 mg is contraindicated in patients with predisposition to myopathy/rhabdomyolysis.
Risk factors include:
- moderate renal impairment (creatinine clearance < 60 mL/min);
- hypothyroidism;
- personal or family history of hereditary muscular disorders;
- history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- conditions that may lead to increased plasma concentration of the medicinal product;
- Mongoloid race;
- concomitant use of fibrates.
(See sections "Special precautions for use", "Interaction with other medicinal products and other types of interactions", and "Pharmacokinetics").
Interaction with other medicinal products and other types of interactions.
Contraindicated combinations
Cyclosporine
Concomitant use of the Rosetin medicinal product with cyclosporine is contraindicated (see section "Contraindications"). During concomitant use of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7 times higher than those observed in healthy volunteers (see Table 1). Concomitant use does not affect cyclosporine plasma concentrations.
In a study involving kidney transplant patients with creatinine clearance > 50 mL/min receiving a stable dose of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold increase (range: 2.3 to 7.9-fold) in mean AUC of total ezetimibe compared to control healthy subjects receiving ezetimibe alone in another study (n = 17). In another study, a 12-fold increase in exposure of total ezetimibe was observed in a kidney transplant patient with severe renal impairment receiving cyclosporine and multiple other drugs, compared to control subjects receiving ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of cyclosporine on day 7 led to a 15% increase in cyclosporine AUC (range: 10% decrease to 51% increase) compared to administration of a single 100 mg dose of cyclosporine alone. A controlled study on the effect of concomitant ezetimibe administration on cyclosporine exposure in kidney transplant patients has not been conducted. Caution should be exercised when initiating treatment in patients receiving cyclosporine. Cyclosporine concentrations should be monitored in patients receiving both cyclosporine and the medicinal product.
Gemfibrozil and other lipid-lowering agents
The 40 mg dose of rosuvastatin is contraindicated when co-administered with fibrates.
Combinations not recommended
Fibrates and other lipid-lowering agents
Concomitant use of rosuvastatin and gemfibrozil results in a doubling of rosuvastatin Cmax and AUC (see section "Special precautions for use").
Concomitant administration of fenofibrate or gemfibrozil moderately increases total ezetimibe concentrations (approximately 1.5–1.7-fold, respectively). Combination therapy with ezetimibe and other fibrates has not been studied.
Although no significant pharmacokinetic interaction with fenofibrate is expected based on data from dedicated studies, pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they may cause myopathy when used alone. The combination of 40 mg rosuvastatin/10 mg ezetimibe is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions for use"). Patients receiving fibrates should initiate therapy with a 5 mg dose of rosuvastatin.
The fixed-dose combination is not to be used as first-line lipid-lowering therapy. Combination therapy should be initiated after appropriate dose titration of rosuvastatin or both components.
Patients receiving ezetimibe and fenofibrate are at risk of developing cholelithiasis and gallstone disease (see sections "Special precautions for use" and "Adverse reactions").
Patients receiving ezetimibe and fenofibrate should undergo gallbladder evaluation if gallstone disease is suspected, and treatment with ezetimibe and fenofibrate should be discontinued (see section "Adverse reactions").
Fibrates may increase biliary cholesterol excretion, leading to gallstone disease. Preclinical animal studies showed that ezetimibe increased cholesterol levels in gallbladder bile, although not in all species. The risk of stone formation associated with ezetimibe use cannot be excluded.
Inhibitors of transporter proteins
Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transporters may increase rosuvastatin plasma concentrations and increase the risk of myopathy (see sections "Special precautions for use", "Dosage and administration", and Table 1).
Protease inhibitors
Concomitant use of protease inhibitors may significantly increase systemic exposure to rosuvastatin, although the exact mechanism of this interaction is unknown (see Table 1). In particular, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination product containing two protease inhibitors (atazanavir 300 mg/ritonavir 100 mg) in healthy volunteers was associated with approximately 3-fold and 7-fold increases in steady-state AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin and certain combined protease inhibitor products may be possible only after careful dose adjustment of rosuvastatin based on the expected increase in rosuvastatin exposure (see sections "Special precautions for use", "Dosage and administration", and Table 1).
Fusidic acid
The risk of myopathy, including rhabdomyolysis, may be increased with concomitant systemic use of fusidic acid and statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic) is not fully understood. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions for use").
Other interactions
Antacids
Concomitant use of antacids reduces ezetimibe absorption but does not affect its bioavailability. This reduction in absorption is not considered clinically significant.
Concomitant administration of rosuvastatin and antacid suspensions containing aluminium hydroxide and magnesium hydroxide reduces rosuvastatin plasma concentrations by approximately 50%. This effect is less pronounced when antacids are administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.
Anticoagulants
Concomitant use of ezetimibe (10 mg once daily) did not significantly affect warfarin bioavailability or prothrombin time in a study involving 12 healthy adult males. However, post-marketing reports have described increases in international normalized ratio (INR) in patients receiving ezetimibe added to warfarin or fluindione. Appropriate monitoring of INR is required when ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione (see section "Special precautions for use").
As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin or dose escalation in patients concomitantly using vitamin K antagonists (e.g., warfarin or another coumarin anticoagulant) may increase INR.
Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. Appropriate monitoring of INR is recommended in such cases.
Erythromycin
It is known that concomitant use of rosuvastatin and erythromycin reduces rosuvastatin AUC by 20% and Cmax by 30%. This interaction may be due to increased intestinal motility caused by erythromycin.
Cytochrome P450 enzymes
In vitro and in vivo studies indicate that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions mediated by cytochrome P450 metabolism are not expected. No clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes) has been observed.
Preclinical studies have shown that ezetimibe does not induce cytochrome P450 enzymes involved in its metabolism. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicinal products metabolized by cytochromes P450: 1A2, 2D6, 2C8, 2C9, 3A4 – or N-acetyltransferase.
Cholestyramine
When used concomitantly with cholestyramine, the mean AUC of total ezetimibe (ezetimibe and ezetimibe-glucuronide) is reduced by approximately 55%. When adding ezetimibe to cholestyramine, the gradual reduction in LDL-C may be delayed (see section "Dosage and administration").
Digoxin
Based on data from dedicated studies, no clinically significant interaction with digoxin is expected.
Oral contraceptives/hormone replacement therapy (HRT)
Concomitant use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and norgestimate by 26% and 34%, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of drugs in patients concomitantly using rosuvastatin and HRT; therefore, a similar effect cannot be excluded. However, the combination has been widely used in women in clinical trials and was well tolerated.
Statins. No clinically significant pharmacokinetic interaction was observed when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
Ezetimibe/rosuvastatin
Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in rosuvastatin AUC in patients with hypercholesterolemia. A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, considering the adverse reactions profile.
Ticagrelor
Ticagrelor may cause renal impairment and affect renal excretion of rosuvastatin, increasing the risk of rosuvastatin accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, increased creatine kinase (CK) levels, and rhabdomyolysis. In such cases, monitoring of renal function and CK levels is recommended.
Interactions requiring dose adjustment of rosuvastatin (see also Table 2)
When concomitant use of rosuvastatin with other medicinal products that increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an increase in exposure (AUC) of approximately 2-fold or more is expected, treatment should be initiated with 5 mg rosuvastatin once daily. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure does not exceed that observed with 40 mg rosuvastatin daily without interacting medicinal products. For example, when used with gemfibrozil, the maximum rosuvastatin dose would be 20 mg (1.9-fold increase), and when used with atazanavir/ritonavir combination, 10 mg rosuvastatin (3.1-fold increase).
If the medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose above 20 mg.
Table 1
Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical study data
| Dosing regimen of the interacting medicinal product |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Increase in rosuvastatin AUC by 2-fold or more |
||
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg) + voxilaprevir (100 mg) once daily for 15 days |
10 mg, single dose |
↑ 7.4-fold |
| Cyclosporine 75–200 mg twice daily for 6 months |
10 mg once daily for 10 days |
↑ 7.1-fold |
| Darolutamide 600 mg twice daily for 5 days |
5 mg, single dose |
↑ 5.2-fold |
| Atazanavir 300 mg/ritonavir 100 mg once daily for 8 days |
10 mg, single dose |
↑ 3.1-fold |
| Regorafenib 160 mg once daily for 14 days |
5 mg, single dose |
↑ 3.8-fold |
| Simeprevir 150 mg once daily for 7 days |
10 mg, single dose |
↑ 2.8-fold |
| Velpatasvir 100 mg once daily |
10 mg, single dose |
↑ 2.7-fold |
| Ortho-silasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg once daily/dasabuvir 400 mg twice daily for 14 days |
5 mg, single dose |
↑ 2.6-fold |
| Glecaprevir 200 mg/elbasvir 50 mg once daily for 11 days |
10 mg, single dose |
↑ 2.3-fold |
| Glecaprevir 400 mg/pibrentasvir 120 mg once daily for 7 days |
5 mg once daily for 7 days |
↑ 2.2-fold |
| Lopinavir 400 mg/ritonavir 100 mg twice daily for 17 days |
20 mg once daily for 7 days |
↑ 2.1-fold |
| Clopidogrel 300 mg loading dose, followed by 75 mg after 24 hours |
20 mg, single dose |
↑ 2-fold |
| Gemfibrozil 600 mg twice daily for 7 days |
80 mg, single dose |
↑ 1.9-fold |
| Increase in rosuvastatin AUC less than 2-fold |
||
| Dosing regimen of the interacting medicinal product |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Elvitegravir 75 mg once daily for 5 days |
10 mg, single dose |
↑ 1.6-fold |
| Darunavir 600 mg/ritonavir 100 mg twice daily for 7 days |
10 mg once daily for 7 days |
↑ 1.5-fold |
| Tipranavir 500 mg/ritonavir 200 mg twice daily for 11 days |
10 mg, single dose |
↑ 1.4-fold |
| Dronedarone 400 mg twice daily |
Unknown |
↑ 1.4-fold |
| Itraconazole 200 mg once daily for 5 days |
10 mg, single dose |
↑ 1.4-fold ** |
| Ezetimibe 10 mg once daily for 14 days |
10 mg once daily for 14 days |
↑ 1.2-fold ** |
| Decrease in rosuvastatin AUC |
||
| Dosing regimen of the interacting medicinal product |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Erythromycin 500 mg four times daily for 7 days |
80 mg, single dose |
↓ 20% |
| Baykaline 50 mg three times daily for 14 days |
20 mg, single dose |
↓ 47% |
* Data presented as fold change represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the percentage difference relative to values observed with rosuvastatin administered alone.
Increases are indicated by ↑, no change by ↔, and decreases by ↓.
** Several interaction studies were conducted with different doses of rosuvastatin; the most significant ratio is presented in the table.
In clinical drug interaction studies, ezetimibe, when co-administered, had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam. Cimetidine, when co-administered with ezetimibe, did not affect the bioavailability of ezetimibe.
The following drugs/combinations did not have a clinically significant effect on rosuvastatin AUC when administered concomitantly: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg three times daily for 7 days; fluconazole 200 mg once daily for 11 days; fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; ketoconazole 200 mg twice daily for 7 days; rifampicin 450 mg once daily for 7 days; silymarin 140 mg three times daily for 5 days.
Pediatric Population
Interaction studies have been conducted only in adults. The extent of interaction in pediatric patients is unknown.
Special precautions for use.
Effect on skeletal muscle
Disorders of the musculoskeletal system, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients receiving rosuvastatin at any dose, particularly above 20 mg. Cases of myopathy and rhabdomyolysis have been reported with ezetimibe. Most patients who developed rhabdomyolysis were taking statins concomitantly with ezetimibe. However, cases of rhabdomyolysis have been reported very rarely with ezetimibe monotherapy and very rarely when ezetimibe is used with other agents associated with rhabdomyolysis risk.
If suspicion of myopathy arises, characterized by muscle weakness and elevated creatine kinase (CK) levels more than 10 times the ULN, treatment with ezetimibe, any statin, or other concurrently administered medicinal products must be discontinued immediately. Patients initiating therapy with the medicinal product Rosetin should be informed about the risk of myopathy and should promptly report any muscle pain, tenderness, or weakness (see section "Adverse reactions").
Creatine kinase (CK) levels
CK levels should not be measured following significant physical exertion or in the presence of alternative causes of elevated CK, which may complicate interpretation of results. If baseline CK levels are markedly elevated (> 5 times ULN), repeat testing should be performed within 5–7 days to confirm results. If repeat testing confirms baseline CK levels exceeding 5 times ULN, treatment should not be initiated.
Before initiating treatment
Rosetin, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
- renal dysfunction;
- hypothyroidism;
- personal or family history of hereditary muscle disorders;
- history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- age > 70 years;
- conditions that may lead to increased plasma levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Method of administration and dosage");
- concomitant use of fibrates.
In such patients, the treatment-related risk should be weighed against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (> 5 times ULN).
During treatment
Patients should be instructed to report immediately any unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. CK levels should be measured in such patients. The drug should be discontinued if CK levels are markedly elevated (> 5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels ≤ 5 times ULN). Therapy may be resumed, after symptoms resolve and CK levels return to normal, either with the same drug or an alternative HMG-CoA reductase inhibitor at the lowest dose and under close supervision. Routine monitoring of CK levels in asymptomatic patients is not necessary. Very rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after statin therapy, including rosuvastatin.
Clinical manifestations of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.
Clinical trials did not show increased skeletal muscle effects in a small number of patients receiving rosuvastatin concomitantly with other drugs. However, increased incidence of myositis and myopathy has been observed in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when used concomitantly with certain HMG-CoA reductase inhibitors. Therefore, concomitant use of the drug with gemfibrozil is not recommended. The benefit of further lipid-lowering with the drug in combination with fibrates should be carefully weighed against the potential risks associated with such combinations. A rosuvastatin dose of 40 mg is contraindicated when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Rosetin should not be used in patients with acute, serious conditions indicating myopathy or risk of renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
Effect on the liver
Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
The combination of 40 mg rosuvastatin/10 mg ezetimibe is contraindicated in patients who abuse alcohol.
Liver function tests should be performed before initiating treatment and again after 3 months. Treatment should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of post-marketing reports of serious hepatic events (mainly elevated liver transaminases) was higher with the 40 mg dose of rosuvastatin.
In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with the drug.
Rare fatal and non-fatal cases of liver failure have been reported in patients taking statins, including rosuvastatin.
During studies in patients receiving statin and ezetimibe combination therapy, gradual increases in transaminase levels (≥ 3 times ULN) were observed. Liver function tests should be performed at the start of therapy and according to statin recommendations (see sections "Pharmacokinetics", "Contraindications", and "Method of administration and dosage").
Liver disease and alcohol
As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
Effect on the kidneys
Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent. Proteinuria was not a predictor of acute or progressive kidney disease (see section "Adverse reactions"). The frequency of reports of serious renal events in post-marketing studies is higher with the 40 mg dose of rosuvastatin. Renal function should be monitored regularly in patients receiving rosuvastatin 40 mg.
The fixed combination is not used as first-line hypolipidemic therapy. Combination therapy should be initiated after determining the required dosage of rosuvastatin or both components.
Diabetes mellitus
Evidence suggests that statins increase blood glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes mellitus. However, the reduction in vascular risk with statin therapy outweighs this risk, and therefore should not be a reason to discontinue statin therapy. Patients at risk (fasting glucose 5.6–6.9 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored clinically and biochemically according to current guidelines.
In clinical trials, the overall incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, predominantly in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.
Interstitial lung disease
Isolated cases of interstitial lung disease have been reported with some statins, particularly with long-term therapy (see section "Adverse reactions"). Symptoms include dyspnea, non-productive cough, and worsening general condition (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation in patients receiving protease inhibitors should be considered. Concomitant use of the drug with protease inhibitors is not recommended until the rosuvastatin dose is adjusted (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").
Fibrates
Studies on the safety and efficacy of concomitant use of ezetimibe with fibrates have not been conducted. In patients suspected of developing gallstones while taking rosuvastatin/ezetimibe and fenofibrate, gallbladder examination is indicated and such therapy should be suspended (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Anticoagulants
Appropriate monitoring of INR is required when adding the drug to warfarin, other coumarin anticoagulants, or fluindione.
Cyclosporine
See sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions" for information on concomitant use with cyclosporine.
Fusidic acid
The drug should not be used concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be discontinued for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly.
Patients should seek immediate medical attention if they experience symptoms such as muscle weakness, pain, or fatigue. Statin therapy may be resumed 7 days after the last dose of fusidic acid.
In exceptional cases where prolonged systemic use of fusidic acid is necessary, e.g., for treatment of severe infections, concomitant use of the drug and fusidic acid may be considered only under close medical supervision.
Race
Pharmacokinetic studies have shown increased systemic exposure to the drug in patients of Mongoloid race compared to Caucasians (see sections "Special precautions for use" and "Method of administration and dosage").
Serious skin adverse reactions
Serious skin adverse reactions, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rosuvastatin, which may be life-threatening or fatal. Patients should be informed of the signs and symptoms of serious skin reactions and monitored closely. If signs or symptoms suggestive of such reactions occur, Rosetin should be discontinued immediately and alternative therapy considered.
If a patient experiences a serious reaction such as SJS or DRESS while taking Rosetin, further treatment with Rosetin is contraindicated.
In isolated cases, statins have been reported to induce de novo myasthenia gravis or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, Rosetin should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.
Children aged 10–18 years
The effect of rosuvastatin on linear growth (height), body weight, BMI (body mass index), and development of secondary sexual characteristics according to Tanner staging in children aged 10–18 years was evaluated only over one year. After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed. Clinical trial experience with the drug in children is limited, and the long-term effect of rosuvastatin (> 1 year) on sexual maturation is unknown.
In a clinical trial in children receiving rosuvastatin for 52 weeks, CK levels > 10 times ULN and muscle symptoms after physical exertion or increased physical activity were observed more frequently compared to adults (see section "Adverse reactions").
The drug contains lactose. Patients with rare hereditary intolerance to galactose, total lactase deficiency, or glucose-galactose malabsorption should not take this drug.
The drug contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding.
The drug is contraindicated during pregnancy and breastfeeding (see section "Contraindications").
Pregnancy
Women of childbearing potential should use appropriate contraceptive methods.
Since cholesterol and other products of cholesterol biosynthesis are essential for fetal development, the potential risk of HMG-CoA reductase inhibition outweighs any possible benefit of using the drug during pregnancy. Reproductive toxicity has been observed in some animal studies. If a patient becomes pregnant while taking the drug, treatment should be discontinued immediately.
There are no clinical data on the use of ezetimibe during pregnancy. Animal studies with ezetimibe as monotherapy did not show evidence of direct or indirect harmful effects on pregnancy, embryofetal development, parturition, or postnatal development.
Breastfeeding
The drug should not be used during breastfeeding. Rosuvastatin passes into breast milk in rats. There are no data on the passage of rosuvastatin into human breast milk.
Since another drug in this class passes into human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring rosuvastatin therapy should be advised not to breastfeed.
Studies have shown that ezetimibe passes into rat breast milk. There are no data on the passage of ezetimibe into human breast milk.
Fertility
Data on the effect of ezetimibe on human fertility are lacking. Ezetimibe had no effect on reproductive function in male and female rats. Rosuvastatin at high doses had toxic effects on monkeys and dogs.
Ability to affect reaction speed when driving or operating machinery.
No studies have been conducted on the effect of rosuvastatin or ezetimibe on the ability to drive or operate machinery. However, dizziness may occur during treatment, which should be considered when driving or operating machinery.
Method of Administration and Dosage
Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout the course of therapy, in accordance with recommendations of current established guidelines.
The medication is not suitable for initial therapy. At the beginning of treatment or whenever a dose adjustment of any active substance in a fixed-dose combination is required for any reason (e.g., newly diagnosed condition, change in patient status, or drug interactions), the individual components should be administered separately to determine the appropriate dosage.
The recommended daily dose is 1 tablet taken orally once daily, independent of food intake, at the same time each day. The tablet should be swallowed whole with water.
Prior to switching to this medicinal product, patients should be stabilized on consistent doses of the individual components used concomitantly. The dose of the fixed combination should be based on the doses of the individual components at the time of transition.
The medication should be taken at least 2 hours before or at least 4 hours after bile acid sequestrants (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Hypercholesterolemia Treatment
The recommended initial dose of rosuvastatin in combination is 5 or 10 mg orally once daily, both for patients who have not previously taken statins and for those switching from another HMG-CoA reductase inhibitor. The choice of initial dose should consider individual patient cholesterol levels, future cardiovascular risk, and the likelihood of adverse reactions. Dose increases to the next level may be considered after 4 weeks (see section "Pharmacodynamics"). Due to the increased incidence of adverse reactions with rosuvastatin 40 mg compared to lower doses (see section "Adverse Reactions"), dose titration to the maximum rosuvastatin dose of 40 mg should only be considered in patients with severe hypercholesterolemia and high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved treatment goals with rosuvastatin 20 mg and who will be under regular monitoring (see section "Special Warnings and Precautions for Use"). Specialist supervision is recommended when initiating rosuvastatin at 40 mg.
The fixed-dose combination should not be used as first-line hypolipidemic therapy. Combination therapy should be initiated only after appropriate dose titration of rosuvastatin or both components has been established.
Cardiovascular Event Prevention
In a cardiovascular risk reduction study, rosuvastatin was administered at a dose of 20 mg once daily.
Additional Information for Special Patient Populations
Elderly Patients
An initial rosuvastatin dose of 5 mg is recommended for patients aged over 70 years (see section "Special Warnings and Precautions for Use"). No further dose adjustment is required.
Patients with Hepatic Impairment
No dose adjustment is required for patients with mild hepatic impairment (5–6 points on the Child–Pugh scale). The medication is not recommended for patients with moderate (7–9 points on the Child–Pugh scale) or severe (more than 9 points on the Child–Pugh scale) hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
The medication is contraindicated in patients with acute liver disease (see section "Contraindications").
Patients with Renal Impairment
No dose adjustment is required for patients with mild renal impairment. The recommended initial dose for patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 5 mg rosuvastatin. The combination of 40 mg rosuvastatin/10 mg ezetimibe is contraindicated in patients with moderate renal impairment. The medication is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacokinetics" and "Contraindications").
Race
Increased systemic exposure to the medication has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended initial rosuvastatin dose for patients of Asian origin is 5 mg. The 40 mg rosuvastatin/10 mg ezetimibe combination is contraindicated in patients of Mongoloid race (see section "Contraindications").
Genetic Polymorphism
Certain types of genetic polymorphism may lead to increased rosuvastatin exposure (see section "Pharmacokinetics"). Patients known to have such polymorphisms should be prescribed a lower daily dose.
Dosing for Patients Predisposed to Myopathy
The recommended initial rosuvastatin dose for patients predisposed to myopathy is 5 mg (see section "Special Warnings and Precautions for Use"). The 40 mg rosuvastatin/10 mg ezetimibe combination is contraindicated in patients predisposed to myopathy (see section "Contraindications").
Concomitant Therapy
Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that may increase rosuvastatin plasma concentrations via interaction with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Alternative treatments should be considered, and temporary discontinuation of the medication may be necessary. When concomitant use of these medicinal products with the medication cannot be avoided, the benefit and risks of combination therapy should be carefully weighed, and rosuvastatin dose should be selected cautiously (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Children
The safety and efficacy of rosuvastatin/ezetimibe tablets in children (under 18 years of age) have not been established; therefore, the medication is not recommended for this age group.
Overdose.
In case of overdose, supportive and symptomatic treatment is recommended.
Rosuvastatin
Monitoring of liver function and creatine kinase (CK) levels is required. Hemodialysis is unlikely to be effective.
Ezetimibe
There have been some reports of ezetimibe overdose, which in most cases did not result in adverse events. Reported adverse reactions were not clinically significant.
Adverse reactions.
Summary of safety profile
Adverse reactions reported previously with the individual components (ezetimibe or rosuvastatin) may be potential adverse effects when using Rosetin.
In clinical studies lasting up to 112 weeks, ezetimibe 10 mg once daily was administered to a total of 2,396 patients: 11,308 patients in combination with statins or 185 patients in combination with fenofibrate. Adverse reactions were generally mild and reversible. The overall incidence of adverse reactions was similar between ezetimibe and placebo groups, as was the rate of discontinuation due to adverse reactions.
Adverse reactions during rosuvastatin use were generally mild and reversible. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued treatment due to adverse reactions.
Available data from clinical studies indicate that 1,200 patients have received the combination of rosuvastatin and ezetimibe. According to published reports, the most commonly reported adverse reactions associated with the combined use of rosuvastatin and ezetimibe in patients with hypercholesterolemia are increased liver transaminases, gastrointestinal disorders, and muscle pain. These are known adverse reactions of the active substances in the medicinal product. However, a pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse events (see section "Pharmacological properties").
Table of adverse reactions
Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).
Table 2
| System organ class |
Adverse reactions |
Frequency |
|
| Rosuvastatin |
Ezetimibe |
||
| Blood and lymphatic system disorders |
Thrombocytopenia2,5 |
Uncommon |
Frequency not known |
| Immune system disorders |
Hypersensitivity reactions, including angioedema2 |
Uncommon |
|
| Hypersensitivity reactions, including rash, urticaria, and anaphylactic reactions |
|
Frequency not known |
|
| Endocrine disorders |
Diabetes mellitus1,2 |
Common |
|
| Metabolism and nutrition disorders |
Decreased appetite3 |
|
Uncommon |
| Psychiatric disorders |
Depression2,5 |
Frequency not known |
Frequency not known |
| Nervous system disorders |
Headache2,4 |
Common |
Common |
| Dizziness2 |
Common |
Common |
|
| Peripheral neuropathy2 |
Very rare |
|
|
| Memory loss2 |
Very rare |
|
|
| Peripheral neuropathy2 |
Frequency not known |
|
|
| Sleep disorders (including insomnia and nightmares)2 |
Frequency not known |
|
|
| Paraesthesia4 |
|
Uncommon |
|
| Myasthenia gravis |
Frequency not known |
|
|
| Eye disorders |
Ocular myasthenia |
Frequency not known |
|
| Vascular disorders |
Flushing3, arterial hypertension3 |
|
Uncommon |
| Respiratory, thoracic and mediastinal disorders |
Cough3 |
Frequency not known |
Uncommon |
| Dyspnea3 |
Frequency not known |
Frequency not known |
|
| Gastrointestinal disorders |
Constipation2 |
Common |
Frequency not known |
| Nausea2 |
Common |
Uncommon |
|
| Abdominal pain2,3 |
Common |
Common |
|
| Pancreatitis5 |
Uncommon |
Frequency not known |
|
| Diarrhea2,3 |
Frequency not known |
Common |
|
| Dry mouth3 |
|
Uncommon |
|
| Gastritis3 |
|
Uncommon |
|
| Flatulence3 |
|
Common |
|
| Dyspepsia3, gastroesophageal reflux disease3 |
|
Uncommon |
|
| Hepatobiliary disorders |
Elevated liver transaminases |
Uncommon |
|
| Jaundice2 |
Very rare |
|
|
| Hepatitis2,5 |
Very rare |
Frequency not known |
|
| Cholelithiasis5 |
|
Frequency not known |
|
| Cholecystitis |
|
Frequency not known |
|
| Skin and subcutaneous tissue disorders |
Pruritus2,4 |
Uncommon |
Uncommon |
| Rash2,4 |
Uncommon |
Uncommon |
|
| Urticaria2,4 |
Uncommon |
Uncommon |
|
| Stevens-Johnson syndrome2 |
Frequency not known |
|
|
| Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) |
Frequency not known |
|
|
| Multiform erythema5 |
|
Frequency not known |
|
| Musculoskeletal and connective tissue disorders |
Myalgia2,4 |
Common |
Common |
| Myopathy (including myositis)2 |
Uncommon |
Frequency not known |
|
| Rhabdomyolysis2 |
Uncommon |
Frequency not known |
|
| Arthralgia2 |
Very rare |
Uncommon |
|
| Immune-mediated necrotizing myopathy |
Frequency not known |
|
|
| Tendon disorders, sometimes complicated by rupture |
Frequency not known |
|
|
| Back pain4 |
|
Uncommon |
|
| Muscle weakness4 |
|
Uncommon |
|
| Limb pain4 |
|
Uncommon |
|
| Muscle spasm3, neck pain3 |
|
Uncommon |
|
| Immune-mediated necrotizing myopathy2, tendon disorders (sometimes complicated by rupture2), myalgia5, myopathy/rhabdomyolysis5 (see section "Special warnings and precautions for use") |
|
Frequency not known |
|
| Myopathy (including myositis)2, rhabdomyolysis2, lupus-like syndrome |
Uncommon |
|
|
| Muscle rupture |
Uncommon |
|
|
| Hepatobiliary disorders |
Hematuria2 |
Very rare |
|
| Reproductive system and breast disorders |
Gynaecomastia2 |
Very rare |
|
| General disorders |
Asthenia2,5 |
Common |
Uncommon |
| Edema2 |
Frequency not known |
|
|
| Peripheral edema4 |
|
Uncommon |
|
| Fatigue |
|
Common |
|
| Chest pain3, pain3 |
|
Uncommon |
|
| Investigations |
Elevated ALT and/or AST4 |
|
Common |
| Elevated serum CK levels3, elevated gamma-glutamyl transferase levels3, abnormal liver function tests3 |
|
Uncommon |
|
1 Frequency depends on the presence or absence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension) – for rosuvastatin.
2 Adverse reaction profile of rosuvastatin based on clinical studies and extensive post-marketing experience.
3 Ezetimibe as monotherapy. Adverse reactions were observed in patients receiving ezetimibe (N = 2396) more frequently than with placebo (N = 1159).
4 Ezetimibe co-administered with a statin. Adverse reactions were observed in patients receiving ezetimibe concomitantly with a statin (N = 11308) more frequently than with statin alone (N = 9361).
5 Additional adverse reactions reported during post-marketing use of ezetimibe (with or without statins).
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to be dose-dependent.
Description of selected adverse reactions
Renal effects
Proteinuria, predominantly of tubular origin (detected by "dipstick test"), has been observed in patients treated with rosuvastatin. Changes in urinary protein content from absent or trace to ++ or higher were recorded after some time in < 1% of patients receiving the drug at rosuvastatin doses of 10 mg and 20 mg, and in approximately 3% of patients receiving 40 mg rosuvastatin. A slight increase in the frequency of proteinuria from absent or trace to + was observed with the 20 mg dose of rosuvastatin. In most cases, the degree of proteinuria decreased or resolved spontaneously while continuing rosuvastatin treatment. Review of clinical trial data and post-marketing experience did not reveal a causal relationship between proteinuria and acute or progressive kidney disease.
Hematuria has been observed in patients taking rosuvastatin, and clinical trial data indicate a low frequency.
Musculoskeletal effects
Skeletal muscle-related changes such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis with or without acute renal failure, have been observed with all doses of rosuvastatin, particularly with doses > 20 mg. Dose-dependent increases in creatine kinase (CK) levels have been observed in patients taking rosuvastatin; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 times ULN), treatment should be discontinued (see section "Dosage and Administration").
Hepatic effects
As with other HMG-CoA reductase inhibitors, a small number of patients taking rosuvastatin experienced dose-dependent increases in transaminase levels; in most cases, this was mild, asymptomatic, and transient.
Adverse reactions observed with some statins:
- sexual dysfunction;
- rare cases of interstitial lung disease, particularly with long-term therapy (see section "Dosage and Administration").
Rhabdomyolysis and serious renal and hepatic dysfunction (mainly manifested as increased hepatic transaminases) have been observed more frequently with rosuvastatin 40 mg.
Ezetimibe in combination with fenofibrate
Gastrointestinal disorders: abdominal pain (common).
In a multifactorial, double-blind, placebo-controlled clinical trial involving patients with mixed hyperlipidemia, 625 subjects were treated for up to 12 weeks and 576 subjects for up to 1 year. In this trial, 172 patients receiving ezetimibe and fenofibrate completed the 12-week treatment period, and 230 patients receiving ezetimibe and fenofibrate (including 109 patients who received only ezetimibe during the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups regarding rare adverse events. The treatment-duration-adjusted incidence (95% CI) of clinically significant increases in serum transaminases (> 3 × ULN consecutively) was 4.5% (1.9, 8.8) with fenofibrate monotherapy and 2.7% (1.2, 5.4) with concomitant ezetimibe and fenofibrate. The corresponding cholecystectomy rates were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) with fenofibrate monotherapy and combination therapy, respectively (see sections "Dosage and Administration", "Interaction with Other Medicinal Products and Other Forms of Interaction").
Laboratory test parameters
In controlled clinical trials of ezetimibe monotherapy, clinically significant increases in serum transaminases (ALT and/or AST ≥ 3 × ULN) were similar with ezetimibe (0.5%) and placebo (0.3%). In combination therapy trials, increases were mostly asymptomatic and not associated with cholestasis. The incidence was 1.3% in patients receiving ezetimibe with a statin and 0.4% in those receiving statin alone. These values normalized after discontinuation of treatment or during continued therapy (see section "Dosage and Administration"). During clinical trials in patients receiving ezetimibe monotherapy, CK increases > 10 × ULN were recorded in 4 out of 1674 (0.2%) and 1 out of 786 (0.1%) placebo patients. Similar CK increases were observed in 1 out of 917 (0.1%) patients receiving ezetimibe with a statin and in 4 out of 929 (0.4%) patients receiving statin alone.
No increased frequency of myopathy or rhabdomyolysis related to ezetimibe treatment was observed compared to control groups (placebo or statin monotherapy) (see section "Dosage and Administration").
Children
In children taking rosuvastatin, CK increases > 10 × ULN and muscle-related symptoms after physical exertion or increased physical activity were observed more frequently than in adults (see section "Adverse Reactions"). However, the safety profile of rosuvastatin in children is similar to that in adults.
In clinical trials involving children aged 6–10 years with heterozygous familial and non-familial hypercholesterolemia (n = 138), increases in ALT and/or AST (≥ 3 × ULN) occurred in 1.1% of patients in the ezetimibe group compared to 0% in the placebo group. CK increases (≥ 10 × ULN) and cases of myopathy were not reported.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Information on any suspected adverse reactions should be submitted according to legislative requirements.
In case of adverse events, adverse reactions, or lack of therapeutic effect, please report to ZENTIVA UKRAINE LLC, 5I Brovarskyi Avenue, Kyiv, 02002, Ukraine; tel./fax: +38 044 517-75-00; e-mail: [email protected].
Shelf life. 3 years.
Storage conditions.
No special temperature storage conditions required.
Keep in the original packaging to protect from moisture and light.
Keep out of the reach of children.
Packaging.
10 film-coated tablets in a blister. 3 or 6 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
ELPEN PHARMACEUTICAL CO., INC.
Manufacturer's address and place of business.
Marathonos Ave. 95, Pikermi Attiki, 19009, Greece;
Zapane, Block 1048, Keratea, 19001, Greece.