Roxera® plus
Ukraine
Table of Contents
INSTRUCTION for medical use of the medicinal product Roxera® Plus (Roxera® Plus)
Composition:
Active substances: rosuvastatin, ezetimibe;
One film-coated tablet contains: 5 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe, or 10 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe, or 15 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe, or 20 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe, or 40 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe;
Excipients: microcrystalline cellulose; lactose; mannitol (E 421); crospovidone, type A; sodium croscarmellose; magnesium stearate; povidone K 30; sodium lauryl sulfate; colloidal anhydrous silicon dioxide;
Film coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide yellow (E 172) (contained in 10 mg/10 mg and 15 mg/10 mg tablets), iron oxide red (E 172) (contained in 15 mg/10 mg, 20 mg/10 mg and 40 mg/10 mg tablets), iron oxide black (E 172) (contained in 40 mg/10 mg tablets).
Medicinal form. Film-coated tablets.
Main physicochemical properties:
Tablets 5 mg/10 mg: white or almost white, round, slightly biconvex, film-coated tablets with beveled edges and engraved «R1» on one side;
Tablets 10 mg/10 mg: pale brownish-yellow to pale brown-yellow, round, slightly biconvex, film-coated tablets with beveled edges and engraved «R2» on one side;
Tablets 15 mg/10 mg: pale pink-orange, round, slightly biconvex, film-coated tablets with beveled edges and engraved «R3» on one side;
Tablets 20 mg/10 mg: pale pink, round, slightly biconvex, film-coated tablets with beveled edges and engraved «R4» on one side;
Tablets 40 mg/10 mg: pale greyish-violet to pale grey-violet, round, slightly biconvex, film-coated tablets with beveled edges and engraved «R5» on one side.
Pharmacotherapeutic group. Lipid-lowering agents, combinations. Combinations of different lipid-lowering 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 reducing cholesterol concentration.
Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, and leads to inhibition of hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the overall 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 levels of 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.
Therapeutic effects are evident within one week after initiation of rosuvastatin therapy; after two weeks of treatment, the effect reaches 90% of the maximum achievable. Maximum effect is typically achieved within four 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 those with diabetes or a history of familial hypercholesterolemia.
Based on pooled data from phase III studies, 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 drug at a dose of 10 mg achieved the EAS-recommended target LDL-C level (<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 drugs (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 cholesterol and phytosterol uptake in the intestine.
Ezetimibe localizes to the brush border of the small intestine and inhibits cholesterol absorption, thereby reducing intestinal cholesterol delivery to the liver; statins reduce cholesterol synthesis in the liver, and together these mechanisms provide additive 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, ethinylestradiol, or fat-soluble vitamins A and D.
Epidemiological studies have established that cardiovascular disease and mortality are directly proportional to levels of total cholesterol and LDL-C and inversely proportional to HDL-C levels.
Concomitant use of ezetimibe with statins has demonstrated efficacy in reducing the risk of cardiovascular disease in patients with existing cardiovascular conditions or 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 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 was the main isoenzyme involved in metabolism, while isoenzymes 2C19, 3A4, and 2D6 were less involved. 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 inhibiting 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 half-life does not increase with higher doses. The 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. With repeated daily dosing, pharmacokinetic parameters do not change.
Special Patient Groups
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 with heterozygous familial hypercholesterolemia is similar to that in adult volunteers.
Race
Pharmacokinetic studies show approximately a 2-fold increase in median plasma concentration-time curve area (AUC) and Cmax of rosuvastatin in individuals of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to those of Caucasian race; 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 kidney 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 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 lower. However, at least a 2-fold increase in systemic exposure was observed in two patients with Child-Pugh scores of 8 and 9 compared to patients with lower scores. Experience with patients having 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.
Children
Two pharmacokinetic studies of rosuvastatin (in tablet form) involving patients aged 10 to 17 or 6 to 17 years (total of 214 patients) with heterozygous familial hypercholesterolemia showed that the drug's effect in children corresponds to that in adult patients. Rosuvastatin exposure was predictable based on dose over a 2-year period.
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 injectable solutions.
Concomitant food intake (with low or high fat content) does not affect the oral bioavailability of ezetimibe, including at a dose of 10 mg. Ezetimibe can be taken independently of meals.
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) was observed throughout the transformation process. Ezetimibe and ezetimibe-glucuronide are the main substances detected in plasma, accounting for approximately 10–20% and 80–90% of total drug-related material 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.
Excretion
After oral administration of 20 mg 14C-ezetimibe to volunteers, approximately 93% of total ezetimibe-related radioactivity was detected in plasma. Approximately 78% and 11% of the administered radioactive dose were excreted in feces and urine, respectively, over 10 days. No measurable radioactivity levels were observed in plasma after 48 hours.
Special Patient Groups
Children
The pharmacokinetics of ezetimibe are similar in adults and children aged 6 years and older. Pharmacokinetic data for children under 6 years of age are unavailable. Clinical experience with ezetimibe in children and adults included patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, and sitosterolemia.
Elderly Patients
In elderly patients (aged 65 years and older), 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 in elderly and younger patients taking ezetimibe. Therefore, dose adjustment is not 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 (Child-Pugh score 5–6) than in healthy volunteers. In a 14-day study of ezetimibe (10 mg daily) in patients with moderate hepatic impairment (Child-Pugh score 7–9), 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 (Child-Pugh score >9) are unknown, ezetimibe is not recommended for use in these patients (see section "Special Warnings and Precautions for Use").
Patients with Renal Impairment
After a single 10 mg dose of ezetimibe in patients with severe renal impairment (n = 8; creatinine clearance ≤ 30 mL/min/1.73 m²), mean AUC of total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9). This result is not considered clinically significant. Dose adjustment is not required for patients with renal dysfunction.
In one patient in this study (who had a kidney transplant and was on multiple therapies, including cyclosporine), total ezetimibe levels were 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 in men and women taking ezetimibe. Therefore, dose adjustment based on gender is not required.
Clinical characteristics
Indications
Prevention of cardiovascular complications
Roxera® Plus is indicated for reduction of the risk of cardiovascular complications as replacement therapy in patients with ischemic heart disease (IHD) and a history of acute coronary syndrome (ACS), in whom adequate disease control is achieved by concomitant administration of rosuvastatin and ezetimibe as monotherapy agents at the same doses as those contained in the combination product.
Primary hypercholesterolemia / homozygous familial hypercholesterolemia
Roxera® Plus is indicated as 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 by concomitant administration of rosuvastatin and ezetimibe as monotherapy agents at the same doses as those contained in the combination product.
Contraindications
Roxera® Plus is contraindicated in:
- hypersensitivity to the active substances or to any of the other components of the medicinal product;
- 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 treatment with cyclosporine;
- concomitant use of the combination of sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions");
- pregnancy and during breastfeeding; in women of childbearing potential who are not using appropriate contraceptive measures.
Roxera® Plus, film-coated tablets, 40 mg/10 mg, are contraindicated in patients with myopathy or pre-existing risk factors for myopathy/rhabdomyolysis; such factors include: moderate renal impairment (creatinine clearance < 60 mL/min); hypothyroidism; personal or family history of hereditary muscle disorders; history of myotoxicity associated with other HMG-CoA reductase inhibitors or fibrates; alcohol abuse; conditions that may lead to increased plasma concentrations of rosuvastatin; Mongoloid race; concomitant use of fibrates.
Interaction with other medicinal products and other types of interactions
Concomitant use is contraindicated
Cyclosporine
Concomitant use of Roxera® Plus with cyclosporine is contraindicated (see section "Contraindications"). During concomitant administration of rosuvastatin and cyclosporine, rosuvastatin AUC values were on average approximately 7-fold higher than those observed in healthy volunteers (see Table 1). Concomitant use does not affect cyclosporine plasma concentrations.
Concomitant use is not recommended
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 with certain combined protease inhibitor products is possible only after careful dose adjustment of rosuvastatin, taking into account the expected increase in rosuvastatin exposure (see sections "Special precautions for use", "Dosage and administration", and Table 1 in section "Interaction with other medicinal products and other types of interactions").
Inhibitors of transport proteins
Rosuvastatin is a substrate for certain transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections "Dosage and administration", "Special precautions for use", and Table 1 in section "Interaction with other medicinal products and other types of interactions").
Fibrates
Concomitant use of rosuvastatin and gemfibrozil results in a 2-fold increase in Cmax and AUC of rosuvastatin (see section "Special precautions for use").
Based on data from specific studies, no significant pharmacokinetic interaction with fenofibrate is expected; however, a 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 40 mg/10 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions for use"). Such patients should initiate therapy with a 5 mg dose of rosuvastatin.
In patients receiving ezetimibe and fenofibrate, there is a risk of developing cholelithiasis and gallstone disease (see sections "Special precautions for use" and "Adverse reactions").
In patients suspected of gallstone disease while taking ezetimibe and fenofibrate, gallbladder examination is indicated, and such therapy should be discontinued (see section "Adverse reactions").
Concomitant administration of fenofibrate or gemfibrozil moderately increases the concentration of total ezetimibe (approximately 1.5–1.7 times, respectively). Combination therapy of ezetimibe with other fibrates has not been studied.
Fibrates may increase biliary cholesterol excretion, leading to gallstone disease. In preclinical animal studies, ezetimibe increased cholesterol levels in gallbladder bile, although not in all species. The risk of stone formation associated with ezetimibe use cannot be excluded.
Fusidic acid
Studies on the interaction between rosuvastatin and fusidic acid have not been conducted. 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 currently unknown. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is necessary, rosuvastatin therapy should be discontinued throughout the duration of fusidic acid treatment (see section "Special precautions for use").
Other interactions
Antacids
Concomitant administration of antacids reduces the extent of ezetimibe absorption but does not affect its bioavailability. This reduction in absorption is not considered clinically significant.
Concomitant use of rosuvastatin and antacid suspensions containing aluminum hydroxide and magnesium hydroxide results in approximately a 50% reduction in plasma rosuvastatin concentrations. 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 the bioavailability of warfarin or prothrombin time in a study involving 12 healthy adult males. However, post-marketing reports have described increases in the international normalized ratio (INR) in patients who received ezetimibe added to warfarin or fluindione. Appropriate monitoring of INR is required when adding ezetimibe to warfarin, other coumarin anticoagulants, 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 other coumarin anticoagulants) may result in increased INR.
Discontinuation of rosuvastatin or dose reduction may lead to decreased INR. Appropriate INR monitoring is advisable 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 specific studies, no clinically significant interaction with digoxin is expected.
Oral contraceptives / hormone replacement therapy (HRT)
Concomitant use of rosuvastatin and oral contraceptives resulted in 26% and 34% increases in AUC of ethinylestradiol and norgestimate, respectively. Such increases in plasma levels should be considered when selecting the dose of oral contraceptives. Pharmacokinetic data in patients concomitantly using rosuvastatin and HRT are lacking; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.
Tickagrelor
Ticagrelor may cause renal impairment and affect renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, concomitant use of ticagrelor and rosuvastatin has led to decreased renal function, elevated creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.
Interactions requiring dose adjustment of rosuvastatin
When concomitant use of rosuvastatin with other medicinal products that increase rosuvastatin exposure is necessary, the rosuvastatin dose should be adjusted. If an approximately 2-fold or greater increase in AUC 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 is 20 mg (1.9-fold increase), and when used with atazanavir/ritonavir combination, the maximum rosuvastatin dose is 10 mg (3.1-fold increase).
If the medicinal product increases rosuvastatin AUC by less than 2-fold, no initial dose reduction is required, but caution should be exercised when increasing the dose of Roxera® Plus 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
| Increased AUC of rosuvastatin by 2 times or more |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg / 100 mg / 100 mg) + voxilaprevir (100 mg) once daily for 15 days |
10 mg, single dose |
↑ 7.4 times |
| Cyclosporine from 75 mg to 200 mg twice daily, 6 months |
10 mg once daily, 10 days |
↑ 7.1 times |
| Darolutamide 600 mg twice daily, 5 days |
5 mg, single dose |
↑ 5.2 times |
| Regorafenib 160 mg once daily for 14 days |
5 mg, single dose |
↑ 3.8 times |
| Atazanavir 300 mg / ritonavir 100 mg once daily, 8 days |
10 mg, single dose |
↑ 3.1 times |
| Roxadustat 200 mg every other day |
10 mg, single dose |
↑ 2.9 times |
| Simeprevir 150 mg once daily, 7 days |
10 mg, single dose |
↑ 2.8 times |
| Velpatasvir 100 mg once daily |
10 mg, single dose |
↑ 2.7 times |
| Paritaprevir 25 mg / ombitasvir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days |
5 mg, single dose |
↑ 2.6 times |
| Teriflunomide |
Unknown |
↑ 2.5 times |
| Glecaprevir 200 mg / elbasvir 50 mg once daily, 11 days |
10 mg, single dose |
↑ 2.3 times |
| Glecaprevir 400 mg / pibrentasvir 120 mg once daily, 7 days |
5 mg once daily, 7 days |
↑ 2.2 times |
| Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days |
20 mg once daily, 7 days |
↑ 2.1 times |
| Capmatinib 400 mg twice daily |
10 mg, single dose |
↑ 2.1 times |
| Clopidogrel 300 mg loading dose, followed by 75 mg after 24 hours |
20 mg, single dose |
↑ 2 times |
| Tafamidis 61 mg twice daily on days 1 and 2, then once daily from day 3 to day 9 |
10 mg, single dose |
↑ 2.0 times |
| Fostamatinib 100 mg twice daily |
20 mg, single dose |
↑ 2.0 times |
| Increased AUC of rosuvastatin less than 2 times |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Febuxostat 120 mg once daily |
10 mg, single dose |
↑ 1.9 times |
| Gemfibrozil 600 mg twice daily, 7 days |
80 mg, single dose |
↑ 1.9 times |
| Eltopag 75 mg once daily, 5 days |
10 mg, single dose |
↑ 1.6 times |
| Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days |
10 mg once daily, 7 days |
↑ 1.5 times |
| Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days |
10 mg, single dose |
↑ 1.4 times |
| Dronedarone 400 mg twice daily |
Unknown |
↑ 1.4 times |
| Itraconazole 200 mg once daily, 5 days |
10 mg, single dose |
↑ 1.4 times ** |
| Decreased AUC of rosuvastatin |
||
| Dosing regimen of the interacting drug |
Dosing regimen of rosuvastatin |
Changes in rosuvastatin AUC* |
| Erythromycin 500 mg four times daily, 7 days |
80 mg, single dose |
↓ 20 % |
| Baicalin 50 mg three times daily, 14 days |
20 mg, single dose |
↓ 47 % |
\Data presented as change by x-fold represent the ratio between co-administration and administration of rosuvastatin alone. Data presented as % change represent the percentage difference compared 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 Table 1.
Drug(s) / combinations that did not have a clinically significant effect on rosuvastatin AUC ratio when co-administered: 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.
In clinical drug interaction studies, ezetimibe in combination therapy did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, or midazolam. Cimetidine, when co-administered with ezetimibe, did not affect the bioavailability of ezetimibe.
Children
Interaction studies have been conducted only in adults. The extent of interaction in children is unknown.
Special precautions for use
Renal effects
Proteinuria detected by dipstick testing is predominantly of tubular origin and has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and in most cases was transient or intermittent. Proteinuria was not a predictor of acute or progressive renal 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.
Effects on skeletal muscle
Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking 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 medicinal products associated with rhabdomyolysis risk.
If suspicion of myopathy arises, characterized by muscle weakness and creatine phosphokinase (CPK) levels elevated more than 10 times the upper limit of normal (ULN), treatment with ezetimibe, any statins, or other concomitantly administered medicinal products should be discontinued immediately. Patients initiating therapy with the medicinal product Roxera® Plus should be informed about the risk of myopathy and should report immediately any muscle pain, tenderness, or weakness (see section "Adverse reactions").
In several cases, statins have been reported to cause de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, treatment with Roxera® Plus should be discontinued. Recurrences have been reported when (re)introducing the same or another statin.
Creatine kinase levels
Creatine kinase (CK) levels should not be measured after significant physical exertion or in the presence of alternative causes of elevated CK, which may complicate interpretation of results. If the initial CK level is markedly elevated (> 5 times ULN), repeat testing should be performed within 5–7 days to confirm results. If repeat testing confirms that the initial CK value exceeds 5 times ULN, treatment should not be initiated.
Before starting treatment
Roxera® Plus, like other HMG-CoA reductase inhibitors, should be prescribed with caution to patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
- renal impairment;
- 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 "Dosage and administration");
- concomitant use of fibrates.
In such patients, the treatment-related risk should be evaluated against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if the initial CK level is markedly elevated (> 5 times ULN).
During therapy
Patients should be advised 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. Treatment 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 ≤ 5 times ULN). Therapy with Roxera® Plus or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose and under close supervision once symptoms have resolved and CK levels have returned to normal. 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 features of IMNM include proximal muscle weakness and elevated serum CK levels, which persist even after discontinuation of statins.
During clinical trials, no increased effect on skeletal muscle was observed in a small number of patients taking rosuvastatin and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking 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, the concomitant use of Roxera® Plus with gemfibrozil is not recommended. The benefit of further lipid-lowering with Roxera® Plus in combination with fibrates should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose of rosuvastatin is contraindicated when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Roxera® Plus should not be used in patients with acute, serious conditions indicating myopathy or potential for developing renal failure due to rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
Fusidic acid
Roxera® Plus should not be used concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients in 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 in combination.
Patients should seek immediate medical advice 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, when prolonged systemic use of fusidic acid is necessary, e.g., for treatment of severe infections, concomitant use of Roxera® Plus and fusidic acid may be considered only under close medical supervision.
Hepatic effects
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 use of Roxera® Plus 40 mg/10 mg is contraindicated in patients who abuse alcohol.
It is recommended to check liver function biochemistry before starting treatment and 3 months thereafter. Roxera® Plus treatment should be discontinued or the dose reduced if serum transaminase levels exceed three times the upper limit of normal. The frequency of reports of serious hepatic events (mainly elevated liver transaminases) in the post-marketing period was higher with the 40 mg dose.
In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with Roxera® Plus.
Rare fatal and non-fatal cases of liver failure have been reported in patients taking statins, including rosuvastatin.
During studies in patients taking a combination of statin and ezetimibe, gradual increases in transaminase levels (≥ 3 times ULN) were observed. Liver function tests should be performed at the beginning of therapy with Roxera® Plus and according to statin recommendations (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").
Race
Pharmacokinetic studies have shown increased systemic exposure to the drug in patients of Mongoloid race compared to Caucasians (see sections "Contraindications" and "Dosage and administration").
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 when increasing the rosuvastatin dose in patients receiving protease inhibitors should be considered. Concomitant use of the medicinal product 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 "Dosage and administration").
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 deterioration in general health (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Diabetes mellitus
Some 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 use outweighs this risk, and therefore it 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.
Fibrates
Studies on the safety and efficacy of concomitant use of ezetimibe with fibrates have not been conducted. In patients taking rosuvastatin/ezetimibe and fenofibrate who are suspected of having gallstones, 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
When adding Roxera® Plus to warfarin, other coumarin anticoagulants, or fluindione, appropriate monitoring of INR is required.
Children
The effect of rosuvastatin on linear growth (height), body weight, BMI, and Tanner stage development of secondary sexual characteristics in children aged 10–17 years has been evaluated only over one year. After 52 weeks of investigational treatment, no effect on growth, body weight, BMI, or sexual maturation was observed (see section "Pharmacodynamics"). Clinical trial experience with the use of the drug in children is limited, and the long-term effect of rosuvastatin use (> 1 year) on sexual maturation is unknown.
In a clinical study in children taking 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").
Severe skin adverse reactions
Severe skin adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with rosuvastatin use, which may be life-threatening or fatal. When prescribing the medicinal product to patients, they should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms indicating these reactions occur, Roxera® Plus should be discontinued immediately and alternative treatment considered.
If a patient develops a serious reaction such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) while taking Roxera® Plus, treatment must be discontinued immediately and the medicinal product must never be used again.
Roxera® Plus contains lactose. This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Roxera® Plus contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding
Roxera® Plus 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 showed no evidence of direct or indirect harmful effects on pregnancy, embryofetal development, parturition, or postnatal development.
Breastfeeding
Roxera® Plus is contraindicated during breastfeeding. Limited data from published reports indicate the presence of rosuvastatin in human breast milk. Rosuvastatin passes into the milk of rats. Due to the mechanism of action of rosuvastatin, there is a potential risk of adverse reactions in the infant.
Studies have shown that ezetimibe passes into the milk of rats. 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 does not affect reproductive function in male and female rats. Rosuvastatin has shown toxic effects in monkeys and dogs at high doses.
Ability to influence the ability to drive and use machines
No studies have been conducted to assess the effect of rosuvastatin or ezetimibe on the ability to drive or operate machinery. However, when driving or operating machinery, it should be considered that dizziness may occur during treatment.
Method of Administration and Dosage
Before initiating treatment, patients should be placed on a standard cholesterol-lowering diet, which should be continued throughout the treatment period.
The recommended daily dose is 1 tablet taken orally, independent of food intake.
Prior to switching to Roxera® Plus, patients should be stabilized on fixed doses of the individual components used concomitantly. The dose of Roxera® Plus should be based on the doses of the individual components at the time of transition.
Roxera® Plus is not indicated for initial therapy. At the initiation of treatment or if a dose adjustment of any active ingredient in the fixed-dose combination is required for any reason (e.g., newly diagnosed condition, change in patient status, or drug interactions), individual components should be used again to determine the appropriate dose.
Roxera® Plus 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").
Additional Information for Special Populations
Geriatric Patients
For patients over 70 years of age, a starting dose of rosuvastatin 5 mg is recommended (see section "Special Warnings and Precautions for Use"). No additional dose adjustment is required.
Patients with Renal Impairment
Dose adjustment is not required in patients with mild renal impairment. The recommended starting dose of rosuvastatin in patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 5 mg. The use of Roxera® Plus 40 mg/10 mg is contraindicated in patients with moderate renal impairment. Roxera® Plus is contraindicated in any dosage in patients with severe renal impairment (see sections "Pharmacokinetics" and "Contraindications").
Patients with Hepatic Impairment
Dose adjustment is not required in patients with mild hepatic insufficiency (5–6 points on the Child–Pugh scale). Roxera® Plus 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 insufficiency (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
Roxera® Plus is contraindicated in patients with acute liver disease (see section "Contraindications").
Race
Increased systemic exposure to the drug has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended starting dose of rosuvastatin in Asian patients is 5 mg. The 40 mg/10 mg dose is contraindicated in patients of Mongoloid race (see section "Contraindications").
Genetic Polymorphism
Specific types of genetic polymorphism are known to increase rosuvastatin exposure. Patients with such polymorphism types should have their daily rosuvastatin dose reduced.
Dosing in Patients Predisposed to Myopathy
The recommended starting dose of rosuvastatin in patients predisposed to myopathy is 5 mg (see section "Special Warnings and Precautions for Use"). The use of Roxera® Plus 40 mg/10 mg 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 can increase plasma concentrations of rosuvastatin via interactions 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 treatment should be considered, and if necessary, temporary discontinuation of Roxera® Plus therapy should be implemented. In situations where concomitant use of these medicinal products with Roxera® Plus cannot be avoided, the benefit-risk balance should be carefully evaluated and the rosuvastatin dose should be selected with caution (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 use of Roxera® Plus is not recommended in this age group.
Overdose
In case of overdose, supportive therapy and symptomatic treatment are 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. The adverse reactions reported were not clinically significant.
Adverse Reactions
Adverse reactions observed during the use of rosuvastatin are generally mild and transient.
In controlled clinical studies, less than 4% of patients receiving rosuvastatin discontinued the study due to adverse reactions.
Table 2 presents adverse reactions associated with rosuvastatin use, identified based on data from clinical and post-marketing studies.
Adverse reactions associated with ezetimibe occurred more frequently in patients receiving ezetimibe (N = 2396) compared to those receiving placebo (N = 1159), as well as in patients receiving concomitant therapy with ezetimibe and statins (N = 11308) compared to those receiving statin monotherapy (N = 9361). Post-marketing adverse reactions related to ezetimibe were obtained from reports on ezetimibe used either alone or in combination with statins.
Adverse reactions are classified by frequency and organ system: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).
Table 2
Adverse reactions based on data from clinical and post-marketing studies
| System Organ Class |
Adverse Reactions |
Frequency |
|
| Rosuvastatin |
Ezetimibe |
||
| Blood and lymphatic system disorders |
Thrombocytopenia |
Uncommon |
Not known |
| Immune system disorders |
Hypersensitivity reactions, including angioedema |
Uncommon |
|
| Hypersensitivity reactions, including rash, urticaria, and anaphylactic reactions |
|
Not known |
|
| Endocrine disorders |
Diabetes mellitus1 |
Common |
|
| Metabolism and nutrition disorders |
Decreased appetite |
|
Uncommon |
| Psychiatric disorders |
Depression |
Not known |
Not known |
| Nervous system disorders |
Headache |
Common |
Common |
| Dizziness |
Common |
Not known |
|
| Polyneuropathy |
Very rare |
|
|
| Memory loss |
Very rare |
|
|
| Peripheral neuropathy |
Not known |
|
|
| Sleep disorders (including insomnia and night terrors) |
Not known |
|
|
| Paraesthesia |
|
Uncommon |
|
| Myasthenia gravis |
Not known |
|
|
| Eye disorders |
Ocular myasthenia |
Not known |
|
| Vascular disorders |
Flushing, hypertension |
|
Uncommon |
| Respiratory, thoracic and mediastinal disorders |
Cough |
Not known |
Uncommon |
| Dyspnea |
Not known |
Not known |
|
| Gastrointestinal disorders |
Constipation |
Common |
Not known |
| Nausea |
Common |
Uncommon |
|
| Abdominal pain |
Common |
Common |
|
| Pancreatitis |
Uncommon |
Not known |
|
| Diarrhea |
Not known |
Common |
|
| Dry mouth |
|
Uncommon |
|
| Gastritis |
|
Uncommon |
|
| Flatulence |
|
Common |
|
| Dyspepsia, gastroesophageal reflux disease |
|
Uncommon |
|
| Biliary disorders |
Elevated liver transaminases |
Uncommon |
|
| Jaundice |
Very rare |
|
|
| Hepatitis |
Very rare |
Not known |
|
| Cholelithiasis |
|
Not known |
|
| Cholecystitis |
|
Not known |
|
| Skin and subcutaneous tissue disorders |
Pruritus |
Uncommon |
Uncommon |
| Rash |
Uncommon |
Uncommon |
|
| Urticaria |
Uncommon |
Uncommon |
|
| Stevens-Johnson syndrome |
Not known |
|
|
| Multiform erythema |
|
Not known |
|
| Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) |
Not known |
||
| Musculoskeletal and connective tissue disorders |
Myalgia |
Common |
Common |
| Myopathy (including myositis) |
Uncommon |
Not known |
|
| Rhabdomyolysis |
Uncommon |
Not known |
|
| Arthralgia |
Very rare |
Uncommon |
|
| Immune-mediated necrotizing myopathy |
Not known |
|
|
| Tendon disorders, sometimes complicated by ruptures |
Not known |
|
|
| Back pain |
|
Uncommon |
|
| Muscle weakness |
|
Uncommon |
|
| Limb pain |
|
Uncommon |
|
| Muscle spasm, neck pain |
|
Uncommon |
|
| Lupus-like syndrome |
Uncommon |
- |
|
| Muscle rupture |
Uncommon |
- |
|
| Renal and urinary disorders |
Hematuria |
Very rare |
|
| Reproductive system and breast disorders |
Gynecomastia |
Very rare |
|
| General disorders |
Asthenia |
Common |
Uncommon |
| Edema |
Not known |
|
|
| Peripheral edema |
|
Uncommon |
|
| Fatigue |
|
Common |
|
| Chest pain, pain |
|
Uncommon |
|
| Investigations |
Elevated ALT and/or AST |
|
Common |
| Elevated serum CK levels, elevated gamma-glutamyl transferase levels, hepatic function test abnormalities |
|
Uncommon |
|
| 1 Frequency depends on the presence of risk factors (fasting glucose ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglycerides, history of hypertension). |
|||
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions to rosuvastatin is generally dose-dependent.
Description of individual adverse reactions
Renal effects
Cases of proteinuria, predominantly of tubular origin (detected by "dipstick test"), have been observed in patients taking rosuvastatin. Changes in urinary protein content from absent or trace to ++ or higher were recorded after some time in < 1 % of patients receiving the 10 mg and 20 mg doses, and in approximately 3 % of patients receiving the 40 mg dose. A slight increase in the frequency of proteinuria from absent or trace to + was observed with the 20 mg dose. In most cases, the degree of proteinuria decreased or resolved spontaneously while continuing treatment. Review of clinical trial data and post-marketing experience has not revealed a causal relationship between proteinuria and acute or progressive kidney disease.
Hematuria has been observed in patients taking rosuvastatin, and clinical trial data indicate its 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 the ULN), treatment should be discontinued (see section "Special warnings and precautions for use").
Hepatic effects
As with other HMG-CoA reduct ase inhibitors, dose-dependent increases in transaminase levels have been observed in a small number of patients taking rosuvastatin; 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 "Special warnings and precautions for use").
Rhabdomyolysis and serious renal and hepatic dysfunction (mainly manifested by elevated hepatic transaminases) have been observed more frequently with the 40 mg dose of the drug.
Laboratory test parameters
In controlled clinical trials of ezetimibe monotherapy, clinically significant elevations in serum transaminases (ALT and/or AST ≥ 3 times ULN) were similar with ezetimibe (0.5 %) and placebo (0.3 %). In combination therapy studies, elevations were mostly asymptomatic and not associated with cholestasis. The incidence was 1.3 % in patients receiving ezetimibe concomitantly with a statin and 0.4 % in patients receiving statin alone. These values normalized either after discontinuation of treatment or during continued therapy (see section "Special warnings and precautions for use"). During clinical trials in patients receiving ezetimibe monotherapy, CK elevations > 10 times ULN occurred in 4 out of 1674 (0.2 %) patients and in 1 out of 786 (0.1 %) placebo group patients. Similar CK elevations 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 increase in myopathy or rhabdomyolysis related to ezetimibe treatment was observed compared to control groups (placebo or statin monotherapy) (see section "Special warnings and precautions for use").
Children
In children taking rosuvastatin, CK elevations > 10 times ULN and muscle-related symptoms occurred more frequently after physical exertion or increased physical activity compared to 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), elevations in ALT and/or AST (≥ 3 times ULN) occurred in 1.1 % of patients in the ezetimibe group compared to 0 % in the placebo group. Elevations in CK (≥ 10 times ULN) and cases of myopathy were not reported.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions
Store in the original packaging to protect from moisture and light. The medicinal product does not require special storage temperature conditions.
Keep out of reach of children.
Packaging
10 tablets per blister, 3 or 9 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of business operations
Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.