Rozulip® plus
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROZULIPÒPLUS (ROSULIPÒPLUS)
Composition:
Active substances: rosuvastatin, ezetimibe;
1 capsule contains two tablets:
1 tablet of rosuvastatin 10 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;
or 1 tablet of rosuvastatin 20 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;
or 1 tablet of rosuvastatin 40 mg (as rosuvastatin zinc) and 1 tablet of ezetimibe 10 mg;
Excipients:
for rosuvastatin tablet:
microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate;
for ezetimibe tablet:
povidone, sodium croscarmellose, microcrystalline cellulose, mannitol, sodium lauryl sulfate, low-substituted hydroxypropylcellulose, magnesium stearate;
capsule shell composition for 10 mg/10 mg:
yellow iron oxide (E 172), titanium dioxide (E 171), gelatin;
capsule shell composition for 20 mg/10 mg and 40 mg/10 mg:
yellow iron oxide (E 172), red iron oxide (E 172), titanium dioxide (E 171), gelatin.
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
Capsules 10 mg/10 mg:
Hard gelatin capsules, unmarked, self-sealing, with yellow body and yellow cap. Each capsule contains two tablets.
Rosuvastatin 10 mg tablet: white or almost white, round tablets with the imprint
on one side and no marking on the other side, odorless or nearly odorless;
Ezetimibe 10 mg tablet: white or almost white, round, flat tablets with a bevel edge, engraved with a stylized letter E on one side and number 612 on the other side, odorless or nearly odorless;
Capsules 20 mg/10 mg:
Hard gelatin capsules CONI–SNAP 0, unmarked, self-sealing, with yellow body and caramel-colored cap. Each capsule contains two tablets.
Rosuvastatin 20 mg tablet: white or almost white, round tablets with an imprint on one side and no marking on the other side, odorless or nearly odorless;
Ezetimibe 10 mg tablet: white or almost white, round, flat tablets with a bevel edge, engraved with a stylized letter E on one side and number 612 on the other side, odorless or nearly odorless;
Capsules 40 mg/10 mg:
Hard gelatin capsules CONI–SNAP 0, unmarked, self-sealing, with yellow body and red cap. Each capsule contains two tablets.
Rosuvastatin 40 mg tablet: white or almost white, oval tablets with a bevel edge, engraved with a stylized letter E and number 598 on one side, odorless or nearly odorless;
Ezetimibe 10 mg tablet: white or almost white, round, flat tablets with a bevel edge, engraved with a stylized letter E on one side and number 612 on the other side, odorless or nearly odorless.
Pharmacotherapeutic group.
HMG-CoA reductase inhibitors in combination with other lipid-lowering agents.
ATC code C10BA06.
Pharmacological properties.
Pharmacodynamics.
Rosuvastatin.
Mechanism of action.
Rosuvastatin is a selective competitive inhibitor of HMG-CoA reductase—the enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol.
The primary site of action of rosuvastatin is the liver, where cholesterol synthesis occurs.
Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, thereby promoting LDL uptake and catabolism. This, in turn, leads to suppression of very-low-density lipoprotein (VLDL) production, thereby reducing total levels of LDL and VLDL.
Pharmacodynamic effects.
Rosuvastatin reduces elevated levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, while slightly increasing high-density lipoprotein cholesterol (HDL-C) levels.
It also reduces levels of apolipoprotein B, non-HDL cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), VLDL triglycerides, and slightly increases apolipoprotein A-I levels (see Table 1). 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.
Table 1
Dose-response in patients with primary hypercholesterolemia type IIa and IIb
(adjusted mean percent change from baseline)
| Dose |
N |
LDL-C |
Total Cholesterol |
HDL-C |
Triglycerides |
non-HDL-C |
apoB |
apoA-I |
| Placebo |
13 |
|
|
3 |
|
|
|
0 |
| 5 mg |
17 |
|
|
13 |
|
|
|
4 |
| 10 mg |
17 |
|
|
14 |
|
|
|
4 |
| 20 mg |
17 |
|
|
8 |
|
|
|
5 |
| 40 mg |
18 |
|
|
10 |
|
|
|
0 |
The therapeutic effect becomes apparent within 1 week after initiation of rosuvastatin therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum possible. Maximum effect is generally achieved within 4 weeks after the start of treatment.
Ezetimibe.
Mechanism of action.
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, which mediates 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 additive cholesterol reduction. After 2 weeks of clinical use in 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54% compared to placebo.
Pharmacodynamic effects.
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 levels of total cholesterol and LDL-C and inversely with HDL-C levels.
The effect of ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.
Pharmacokinetics.
Combined use of rosuvastatin and ezetimibe.
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 in terms of adverse effects between rosuvastatin and ezetimibe cannot be excluded.
Rosuvastatin.
Absorption.
Cmax of rosuvastatin in plasma is reached approximately 5 hours after oral administration. Bioavailability is approximately 20%.
Distribution.
Rosuvastatin is extensively taken up by the liver, which plays a major role in 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 to albumin.
Metabolism.
Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for cytochrome P450 enzyme-based metabolism. The main isoenzyme involved is CYP2C9, with minor contributions from 2C19, 3A4, and 2D6. The main identified metabolites are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolite is considered clinically inactive. Rosuvastatin accounts for more than 90% of the activity of circulating HMG-CoA reductase inhibitors.
Excretion.
Approximately 90% of the rosuvastatin dose is excreted unchanged in feces (including both absorbed and unabsorbed rosuvastatin). The remainder of the active substance is excreted in urine. Approximately 5% is found unchanged in urine. The elimination half-life is approximately 19 hours. The half-life does not change with increasing dose. The mean geometric clearance is approximately 50 L/h (coefficient of variation 21.7%).
As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the cholesterol membrane transporter OATP-C. This transporter plays an important role in the hepatic elimination of rosuvastatin.
Linearity.
Systemic exposure to rosuvastatin increases proportionally with dose. After administration of multiple daily doses, pharmacokinetic parameters do not change.
Special patient groups.
Age and sex.
There is no clinically significant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to or lower than those in adult volunteers.
Ethnic groups.
Pharmacokinetic studies demonstrate approximately a 2-fold increase in median plasma concentration-time curve area (AUC) and Cmax of rosuvastatin in Mongoloid race representatives (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian patients; in Indians, an increase of approximately 1.3-fold in median AUC and Cmax is observed. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Negroid race representatives.
Patients with renal impairment.
In patients with mild or moderate renal function impairment, plasma concentrations of rosuvastatin and N-desmethyl are not significantly altered. In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentration of rosuvastatin is 3 times higher and N-desmethyl concentration is 9 times higher than in healthy volunteers. Steady-state plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.
Patients with hepatic impairment.
Among patients with varying degrees of hepatic insufficiency, no increase in the half-life of rosuvastatin was observed if the Child-Pugh score did not exceed 7. However, in two patients with Child-Pugh scores of 8 and 9, the half-life was prolonged at least twofold.
Experience with the use of rosuvastatin in patients with a Child-Pugh score above 9 is lacking.
Genetic polymorphism.
Transport proteins OATP1B1 and BCRP are involved in the pharmacokinetics of HMG-CoA reductase inhibitors, including rosuvastatin. In patients with genetic polymorphisms of SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP), there is a risk of increased exposure to rosuvastatin. Specific polymorphisms SLCO1B1 c.521CC and ABCG2 c.421AA are associated with higher rosuvastatin exposure (AUC) compared to genotypes SLCO1B1 c.521TT or ABCG2 c.421CC. This specific genotyping is generally not used in clinical practice, but patients in whom these polymorphisms are identified should be prescribed a lower daily dose of rosuvastatin.
Children.
Two pharmacokinetic studies of rosuvastatin (in tablet form), involving patients aged 10–18 or 6–18 years (total of 214 patients) with heterozygous familial hypercholesterolemia, showed that the drug's effect in children corresponds to that in adult patients. The dose-dependent effect of rosuvastatin and its effect over 2 years of use were studied.
Ezetimibe.
Absorption.
After oral administration, ezetimibe is rapidly absorbed and actively conjugated to form the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The mean maximum plasma concentration (Cmax) of ezetimibe-glucuronide 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 water.
Concomitant food intake (low or high fat content) does not affect the oral bioavailability of ezetimibe. 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) was 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 during enterohepatic recirculation. The elimination half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Excretion.
After administration of 20 mg 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 groups.
Age and sex.
Plasma concentration of total ezetimibe is slightly higher (approximately 20%) in women than in men. Reduction in LDL-C levels and safety profile are approximately similar in men and women taking ezetimibe. Therefore, dose adjustment based on sex is not required.
Elderly patients.
In elderly patients (over 65 years), plasma concentration of total ezetimibe is 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 single 10 mg dose of ezetimibe, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe was 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 administration (10 mg daily) in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), AUC 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, the medicinal product Rosulip® Plus is not recommended for use in this patient category (see section "Special precautions for use").
Patients with renal impairment.
After single 10 mg dose of ezetimibe in patients with severe renal impairment (n = 8; creatinine clearance ≤ 30 mL/min/1.73 m²), the 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 function impairment.
In this study, one patient (who had a kidney transplant and was receiving multi-drug therapy, including cyclosporine) had a 12-fold higher level of total ezetimibe.
Children.
Pharmacokinetics of ezetimibe are similar in children aged 6 years and older and adults. Pharmacokinetic data for children under 6 years of age are unavailable. Clinical experience with the use of ezetimibe in children and adolescents included patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or sitosterolemia.
Clinical characteristics.
Indications.
The medicinal product is indicated as an adjunct to diet for the treatment of adult patients with primary hypercholesterolemia, in whom adequate disease control is achieved with concomitant administration of rosuvastatin and ezetimibe as monotherapy at the same doses as those contained in the fixed-dose combination product.
Contraindications.
Rosulip® Plus is contraindicated:
- in patients with hypersensitivity to the active substances (rosuvastatin, ezetimibe) or to any of the excipients of the medicinal product;
- in patients with active liver disease, including persistent elevations of serum transaminases of unknown etiology and any increase in serum transaminase levels three times or more above the upper limit of normal (ULN);
- during pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures;
- in patients with severe renal impairment (creatinine clearance < 30 mL/min);
- in patients with myopathy;
- in patients receiving concomitant therapy with the combination of sofosbuvir/velpatasvir/voxelaprevir;
- in patients receiving concomitant cyclosporine;
- in children.
Rosulip® Plus, 40 mg / 10 mg capsules, are contraindicated in patients who have an increased risk of developing myopathy/rhabdomyolysis.
Factors contributing to such risk 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 the drug;
- belonging to the Mongoloid race;
- concomitant use of fibrates.
Interaction with other medicinal products and other forms of interaction.
Concomitant use is contraindicated
Cyclosporine
Concomitant use of Rosulip® Plus 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 2). Concomitant use does not affect cyclosporine plasma concentrations.
Concomitant use not recommended
Protease inhibitors
Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combined medicinal product containing two protease inhibitors (300 mg atazanavir / 100 mg ritonavir) in healthy volunteers resulted in increases in rosuvastatin AUC and Cmax by approximately 3 and 7 times, respectively. Concomitant use of rosuvastatin with certain combined protease inhibitor products may be considered 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 2).
This combination is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should be performed only with monocomponent agents, and after establishing the required doses, transition to the corresponding fixed-dose combination may be considered.
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 2 in the section "Interaction with other medicinal products and other forms of interaction").
Gemfibrozil and other lipid-lowering agents
Concomitant use of Rosulip® Plus and gemfibrozil resulted in a 2-fold increase in rosuvastatin AUC and Cmax (see section "Special precautions for use").
Based on data from specific studies, no clinically significant pharmacokinetic interaction with fenofibrate is expected; however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of niacin (nicotinic acid) (≥1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, likely because they may cause myopathy when used individually. The 40 mg / 10 mg dose is contraindicated with concomitant use of fibrates (see sections "Contraindications" and "Special precautions for use").
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 receiving ezetimibe and fenofibrate, gallbladder imaging is indicated and such therapy should be discontinued (see section "Adverse reactions").
Concomitant use of fenofibrate or gemfibrozil moderately increases total ezetimibe concentrations (approximately 1.5–1.7 times, respectively).
Combined therapy with ezetimibe and other fibrates has not been studied.
Fibrates may increase cholesterol excretion into bile, leading to gallstone disease. In animal studies, ezetimibe occasionally increased cholesterol levels in gallbladder bile, but not in all species. No increased risk of stone formation has been identified with therapeutic use of ezetimibe.
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 yet known. 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 throughout the duration of fusidic acid therapy (see section "Special precautions for use").
Ticagrelor
Ticagrelor may cause renal impairment and may 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.
Other interactions
Antacids
Concomitant use of Rosulip® Plus with antacid suspensions containing aluminum hydroxide or magnesium hydroxide reduced rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after Rosulip® Plus. The clinical significance of this interaction has not been studied.
Concomitant use of antacids reduces the extent of ezetimibe absorption but does not affect its bioavailability. This reduction in absorption is not considered clinically significant.
Erythromycin
Concomitant use of rosuvastatin and erythromycin reduced 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 study results indicate that rosuvastatin does not inhibit or induce cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, drug interactions due to P450-mediated metabolism are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
Preclinical studies have shown that ezetimibe does not induce cytochrome P450 enzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by cytochromes P450: 1A2, 2D6, 2C8, 2C9, 3A4 — or by N-acetyltransferase.
Vitamin K antagonists
As with other HMG-CoA reductase inhibitors, initiation of rosuvastatin therapy or dose escalation in patients receiving concomitant vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may increase the international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. Appropriate monitoring of INR is recommended in such cases.
Concomitant use of ezetimibe (10 mg once daily) had no significant effect on warfarin bioavailability or prothrombin time in a study involving 12 healthy adult males. However, post-marketing reports have described increased INR in patients when ezetimibe was added to warfarin or fluindione. When adding Rosulip® Plus to warfarin, another coumarin anticoagulant, or fluindione, appropriate monitoring of INR is required (see section "Special precautions for use").
Oral contraceptives / Hormone replacement therapy (HRT)
Concomitant use of rosuvastatin and oral contraceptives increased AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. Pharmacokinetic data in patients receiving rosuvastatin and HRT are lacking; therefore, a similar effect cannot be excluded. However, this combination has been widely used in women during clinical trials and was well tolerated.
Clinical drug interaction studies with ezetimibe did not reveal any effect on the pharmacokinetics of oral contraceptives, including ethinylestradiol and levonorgestrel.
Cholestyramine
When used concomitantly with cholestyramine, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe (ezetimibe and ezetimibe-glucuronide) decreased by approximately 55%. When adding ezetimibe to cholestyramine, the gradual reduction in low-density lipoprotein cholesterol (LDL-C) may be delayed.
Statins
No clinically significant pharmacokinetic interaction was observed when ezetimibe was coadministered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
Other medicinal products
Based on specific studies, no clinically significant interaction between rosuvastatin and digoxin is expected.
Clinical drug interaction studies with ezetimibe showed that combination therapy did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, or midazolam. Cimetidine did not affect ezetimibe bioavailability when 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 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 exposure does not exceed that observed with 40 mg rosuvastatin daily without interacting drugs. For example, when used with gemfibrozil, the maximum rosuvastatin dose is 20 mg (1.9-fold increase), and when used with the atazanavir/ritonavir combination, the maximum rosuvastatin dose is 10 mg (3.1-fold increase).
If the expected increase in drug exposure (AUC) is less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the rosuvastatin dose above 20 mg.
Table 2
Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude), based on published data from clinical studies
| Dosing regimen of the interacting drug |
Rosuvastatin dosing regimen |
Changes in rosuvastatin AUC* |
| Increase in rosuvastatin AUC by two-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 from 75 mg twice daily up to 200 mg twice daily, 6 months |
10 mg once daily, 10 days |
↑ 7.1-fold |
| Darolutamide 600 mg twice daily, 5 days |
5 mg, single dose |
↑ 5.2-fold |
| Regorafenib 160 mg once daily for 14 days |
5 mg, single dose |
↑ 3.8-fold |
| Atazanavir 300 mg / ritonavir 100 mg once daily, 8 days |
10 mg, single dose |
↑ 3.1-fold |
| Velpatasvir 100 mg once daily |
10 mg, single dose |
↑ 2.7-fold |
| Paritaprevir 150 mg / ombitasvir 25 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days |
5 mg, single dose |
↑ 2.6-fold |
| Glecaprevir 200 mg / elbasvir 50 mg once daily, 11 days |
10 mg, single dose |
↑ 2.3-fold |
| Glecaprevir 400 mg / pibrentasvir 120 mg once daily, 7 days |
5 mg once daily, 7 days |
↑ 2.2-fold |
| Lopinavir 400 mg / ritonavir 100 mg twice daily, 17 days |
20 mg once daily, 7 days |
↑ 2.1-fold |
| Clopidogrel 300 mg loading dose, followed by 75 mg after 24 hours |
20 mg, single dose |
↑ 2-fold |
| Increase in rosuvastatin AUC less than two-fold |
||
| Gemfibrozil 600 mg twice daily, 7 days |
80 mg, single dose |
↑ 1.9-fold |
| Eltrombopag 75 mg once daily, 5 days |
10 mg, single dose |
↑ 1.6-fold |
| Darunavir 600 mg / ritonavir 100 mg twice daily, 7 days |
10 mg once daily, 7 days |
↑ 1.5-fold |
| Tipranavir 500 mg / ritonavir 200 mg twice daily, 11 days |
10 mg, single dose |
↑ 1.4-fold |
| Dronedarone 400 mg twice daily |
Unknown |
↑ 1.4-fold |
| Itraconazole 200 mg once daily, 5 days |
10 mg, single dose |
↑ 1.4-fold ** |
| Decrease 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 expressed as change by x-fold represent the ratio between co-administration of rosuvastatin and rosuvastatin administered alone. Data expressed as percentages represent the percentage difference relative to values observed with rosuvastatin administered alone.
Increase is indicated by ↑, decrease by ↓.
** Several interaction studies with different doses of rosuvastatin have been conducted — the table presents the most significant ratio observed.
Medicinal products/combinations that showed no clinically relevant effect on rosuvastatin AUC ratio upon concomitant administration: aleglitazar 0.3 mg, 7 days; fenofibrate 67 mg, 7 days, three times daily; fluconazole 200 mg, 11 days, once daily; fosamprenavir 700 mg/ritonavir 100 mg, 8 days, twice daily; ketoconazole 200 mg, 7 days, twice daily; rifampicin 450 mg, 7 days, once daily; silymarin 140 mg, 5 days, three times daily.
This combination is not suitable for initiating therapy. Initiation of treatment or dose adjustment, if necessary, should be performed only with single-component agents; after the required doses are established, a switch to the corresponding fixed-dose combination may be considered.
Special precautions for use.
Severe skin adverse reactions
Cases of 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 lead to fatal outcomes. When prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If symptoms suggestive of such a reaction occur, the drug 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), treatment must be discontinued immediately and the drug must never be used again.
Effect on skeletal muscle
Skeletal muscle disorders such as myalgia, myopathy, and rarely rhabdomyolysis have been observed in patients taking rosuvastatin at any dose, particularly at doses exceeding 20 mg. Cases of myopathy and rhabdomyolysis have also 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 myopathy is suspected, characterized by muscle weakness and creatine phosphokinase (CPK) levels elevated more than 10 times the upper limit of normal (ULN), ezetimibe, any statin, or other concurrently administered medicinal products should be discontinued immediately. Patients initiating therapy with Rozulip® Plus should be informed about the risk of myopathy and should report immediately any muscle pain, tenderness, or weakness (see section "Adverse reactions").
Creatine kinase levels
Creatine kinase (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 × ULN), repeat testing should be performed within 5–7 days to confirm the results. If repeat testing confirms that baseline CK exceeds 5 times the ULN, treatment should not be initiated.
Before starting treatment
Rozulip® Plus, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
- Renal impairment;
- Hypothyroidism;
- Personal or family history of inherited 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 "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", and "Pharmacokinetics");
- Concomitant use of fibrates.
In such patients, the treatment-related risk should be evaluated against the expected benefit; clinical monitoring is also recommended. If baseline CK levels are markedly elevated (> 5 × ULN), treatment should not be initiated.
During treatment
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. The drug should be discontinued if CK levels are markedly elevated (> 5 × ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK ≤ 5 × ULN). After symptoms resolve and CK levels return to normal, therapy with rosuvastatin or an alternative HMG-CoA reductase inhibitor may be restarted at the lowest dose 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 features of IMNM include proximal muscle weakness and elevated serum creatine kinase levels that persist even after discontinuation of statins.
Clinical studies did not provide evidence of increased skeletal muscle effects in a small number of patients taking Rozulip® Plus and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors concomitantly 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 Rozulip® Plus with gemfibrozil is not recommended. The benefit of further lipid-lowering with Rozulip® Plus in combination with fibrates or niacin should be carefully weighed against the potential risks associated with such combinations. The 40 mg dose is contraindicated when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Rozulip® Plus should not be used in patients with acute, serious conditions indicating myopathy or potential for renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures).
Fusidic acid
Rozulip® Plus should not be used concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For patients requiring systemic fusidic acid therapy, statin treatment should be discontinued for the entire duration of fusidic acid therapy. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). 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 fusidic acid therapy is required, such as for the treatment of severe infections, concomitant use of Rozulip® Plus and fusidic acid may be considered only under close medical supervision.
Effect on liver
Like other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume alcohol excessively and/or have a history of liver disease.
It is recommended to assess liver biochemical parameters before starting treatment and again after 3 months. Treatment with rosuvastatin 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.
In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating therapy with Rozulip® Plus.
Due to unknown effects of increased ezetimibe exposure in patients with moderate or severe hepatic impairment, rosuvastatin/ezetimibe is not recommended in this patient population (see section "Pharmacokinetics").
During clinical trials in patients receiving statin/ezetimibe combination therapy, gradual increases in transaminase levels (≥ 3 × ULN) were observed. When using ezetimibe in combination with a statin, liver function tests should be performed at the start of therapy and according to statin recommendations (see sections "Pharmacokinetics", "Contraindications", and "Dosage and administration").
Effect on kidneys
Proteinuria, detected by urine dipstick testing and 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 post-marketing reports of serious renal events is higher with the 40 mg rosuvastatin dose. In patients taking rosuvastatin 40 mg, kidney function should be monitored regularly during follow-up.
Race
Pharmacokinetic studies indicate approximately twofold higher exposure in Mongoloid race patients compared to Caucasians. Dose adjustment of rosuvastatin is required for these patients (see sections "Dosage and administration", "Contraindications", and "Pharmacokinetics"). For Asian race patients, the initial dose of rosuvastatin should be 5 mg. Increased plasma concentrations of rosuvastatin have been observed in Asian patients (see sections "Special precautions for use" and "Pharmacokinetics").
Increased systemic exposure should be considered when treating Mongoloid race patients whose hypercholesterolemia is not adequately controlled with rosuvastatin doses up to 20 mg.
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in individuals taking rosuvastatin concomitantly with various protease inhibitors combined 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 should be considered at the start of therapy and when increasing the rosuvastatin dose in patients receiving protease inhibitors. Concomitant use of the drug with protease inhibitors is not recommended unless the rosuvastatin dose is adjusted (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").
Interstitial lung disease
Rare cases of interstitial lung disease have been reported during long-term treatment with some statins (see section "Adverse reactions"). Manifestations may include dyspnea, non-productive cough, and general deterioration (fatigue, weight loss, 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 cause hyperglycemia in some patients at high risk of diabetes, which may require treatment. 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 5.6–6.0 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglycerides, arterial hypertension) should be monitored both clinically and biochemically according to national guidelines.
In the JUPITER study, the overall incidence of diabetes was 2.8% in the rosuvastatin group and 2.3% in the placebo group, primarily in patients with fasting glucose levels between 5.6 and 6.9 mmol/L.
As with other HMG-CoA reductase inhibitors, rosuvastatin use has been associated with increases in HbA1c and serum glucose levels. In some cases, these values may exceed the diagnostic threshold for diabetes, particularly in patients at high risk of developing diabetes.
Rozulip® Plus as monotherapy does not reduce baseline plasma cortisol concentration and does not affect adrenal reserve. Caution is required when Rozulip® Plus is used concomitantly with other medicinal products capable of reducing levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Fibrates
Safety and efficacy studies of concomitant use of ezetimibe with fibrates have not been conducted. In patients taking rosuvastatin/ezetimibe and fenofibrate who are suspected of gallstone disease, 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 Rozulip® Plus is added to warfarin, other coumarin anticoagulants, or fluindione.
Cyclosporine
See sections "Contraindications" and "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, Rozulip® Plus is not recommended for this age group.
Liver disease and alcohol abuse
Rozulip® Plus should be used with caution in patients who abuse alcohol and/or have a history of liver disease.
Rozulip® Plus contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.
Use during pregnancy or breastfeeding.
Rozulip® Plus is contraindicated during pregnancy and breastfeeding.
Women of childbearing potential should use appropriate contraceptive methods.
Pregnancy
Rosuvastatin
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.
Ezetimibe
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
Rosuvastatin
There are no data on the passage of rosuvastatin into human breast milk.
Ezetimibe
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 at high doses has shown toxic effects in monkeys and dogs.
Ability to affect reaction speed when driving or operating machinery.
No studies have been conducted to determine the effect of rosuvastatin or ezetimibe on the ability to drive or operate machinery. However, dizziness may occur during treatment and 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 treatment period. The dose should be individually adjusted based on therapeutic goals and treatment efficacy, taking into account the risk of adverse reactions and in accordance with current guidelines.
Combination therapy should only be initiated after determining the appropriate dosage of rosuvastatin or both components of the medicinal product.
Dose adjustments may be made after 4 weeks of therapy.
The recommended daily dose is 1 capsule, taken independently of food intake.
Rosulip® Plus is not suitable for initial therapy. Initiation of treatment or dose adjustment, if necessary, should only be performed using monocomponent agents; once the required doses are established, transition to the corresponding fixed-dose combination may be considered.
Rosulip® Plus capsules 10 mg / 10 mg and 20 mg / 10 mg should not be used to treat patients requiring a rosuvastatin dose of 40 mg.
Rosulip® Plus should be administered ≥ 2 hours before or ≥ 4 hours after bile acid sequestrants.
Elderly Patients
For patients aged > 70 years, the recommended initial dose of rosuvastatin is 5 mg. This fixed combination product is not used as first-line therapy. Combination therapy should only be initiated after appropriate dose selection of rosuvastatin or both components.
Patients with Renal Impairment
Dose adjustment is not required in patients with mild to moderate renal impairment. The recommended initial dose of rosuvastatin in patients with moderate renal impairment (creatinine clearance < 60 mL/min) is 5 mg.
Fixed-dose combination therapy is not recommended as first-line treatment. Combination therapy should only be initiated after appropriate dose selection of rosuvastatin or both components.
Rosulip® Plus 40 mg / 10 mg capsules are contraindicated in patients with moderate renal impairment. Rosuvastatin is contraindicated in patients with severe renal impairment at any dose.
Patients with Hepatic Impairment
Dose adjustment is not required in patients with mild hepatic impairment (5–6 points on the Child-Pugh scale). Rosulip® 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 impairment (see section "Special Warnings and Precautions for Use"). Rosulip® Plus is contraindicated in patients with acute liver disease.
Race
Increased systemic exposure to rosuvastatin has been observed in patients of Mongoloid race (see sections "Pharmacokinetics", "Contraindications", "Special Warnings and Precautions for Use"). The recommended initial dose of rosuvastatin for Asian patients is 5 mg.
Rosulip® Plus is not used as first-line hypolipidemic therapy. Combination therapy should be initiated only after determining the required dosage of rosuvastatin or both components.
Rosulip® Plus 40 mg / 10 mg is contraindicated in patients of Mongoloid race (see section "Contraindications").
Genetic Polymorphism
It is known that certain types of genetic polymorphism increase systemic effects of rosuvastatin. For patients with identified presence of certain polymorphism types, a lower daily dose of Rosulip® Plus is recommended.
Dosing in Patients Predisposed to Myopathy
The recommended initial dose of rosuvastatin in patients predisposed to myopathy is 5 mg. Fixed-dose combination is not used as first-line hypolipidemic therapy. Combination therapy should be initiated only after determining the required dosage of rosuvastatin or both components.
Rosulip® 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 Rosulip® Plus is co-administered with certain drugs capable of increasing rosuvastatin plasma concentrations via interaction with these transporter proteins (such as cyclosporine and certain protease inhibitors, including ritonavir combinations with atazanavir, lopinavir and/or tipranavir). Alternative treatments should be considered, and if necessary, temporary discontinuation of Rosulip® Plus may be warranted. In situations where concomitant use of these drugs with Rosulip® Plus cannot be avoided, the benefits and risks of concomitant therapy should be carefully weighed, and the dose of Rosulip® Plus should be carefully selected.
Children
Safety and efficacy of Rosulip® Plus in children have not been studied. Use is contraindicated.
Overdose
There are no published data on rosuvastatin overdose. There is no specific antidote for rosuvastatin overdose.
In clinical trials, administration of ezetimibe 50 mg/day to 15 healthy volunteers for up to 14 days or 40 mg/day to 18 patients with primary hypercholesterolemia for 56 days was generally well tolerated. In animal studies, no toxicity was observed after single oral doses of 5000 mg/kg ezetimibe in rats and mice and 3000 mg/kg in dogs.
Several cases of ezetimibe overdose have been reported; in most cases, no adverse events occurred. The adverse events observed were not serious.
In case of overdose, symptomatic and supportive measures should be implemented. Monitoring of liver function and creatine kinase (CK) levels is required. Hemodialysis is unlikely to be effective.
Adverse reactions.
Summary of safety profile
Adverse reactions during the use of rosuvastatin were generally mild and reversible. In controlled clinical trials, less than 4% of patients receiving rosuvastatin discontinued the study due to adverse reactions.
In clinical studies lasting up to 112 weeks, ezetimibe 10 mg once daily was administered to a total of 2396 patients: 11,308 patients in combination with statins and 185 patients in combination with fenofibrate. Adverse reactions were generally mild and reversible. The overall incidence of adverse reactions was similar with ezetimibe and placebo, as was the rate of discontinuation due to adverse reactions.
Clinical trial data are available in which 1200 patients received the combination of rosuvastatin and ezetimibe. The most common adverse reactions associated with the combined use of rosuvastatin and ezetimibe in patients with hypercholesterolemia were increased levels of liver transaminases, gastrointestinal disorders, and muscle pain. These are known adverse reactions to the active substances of the medicinal product. However, a pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse events (see section "Pharmacological properties").
Adverse reactions observed with rosuvastatin use are generally mild and transient.
Table 3 presents adverse reactions associated with rosuvastatin, identified based on data from clinical and post-marketing studies.
Adverse reactions are classified by system organ class and frequency: 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 the available data).
| Body System |
Adverse Reactions |
Frequency |
|
| Rosuvastatin |
Ezetimibe |
||
| Blood and lymphatic system disorders |
Thrombocytopenia2,3 |
Uncommon |
Not known |
| Immune system disorders |
Hypersensitivity reactions, including angioedema2 |
Uncommon |
|
| Hypersensitivity reactions, including rash, urticaria, and anaphylactic reactions3 |
|
Not known |
|
| Endocrine disorders |
Diabetes mellitus1,2 |
Common |
|
| Metabolism and nutrition disorders |
Decreased appetite3 |
|
Uncommon |
| Psychiatric disorders |
Depression2,3 |
Not known |
Not known |
| Nervous system disorders |
Headache2,3 |
Common |
Common |
| Dizziness2,3 |
Common |
Not known |
|
| Peripheral neuropathy2 |
Very rare |
|
|
| Memory loss2 |
Very rare |
|
|
| Peripheral neuropathy2 |
Not known |
|
|
| Sleep disorders (including insomnia and nightmares)2 |
Not known |
|
|
| Paraesthesia3 |
|
Uncommon |
|
| Vascular disorders |
Flushing3, hypertension3 |
|
Uncommon |
| Respiratory, thoracic and mediastinal disorders |
Cough2,3 |
Not known |
Uncommon |
| Dyspnoea2,3 |
Not known |
Not known |
|
| Gastrointestinal disorders |
Constipation2,3 |
Common |
Not known |
| Nausea2,3 |
Common |
Uncommon |
|
| Abdominal pain2,3 |
Common |
Common |
|
| Pancreatitis2,3 |
Uncommon |
Not known |
|
| Diarrhoea2,3 |
Not known |
Common |
|
| Dry mouth3 |
|
Uncommon |
|
| Gastritis3 |
|
Uncommon |
|
| Flatulence3 |
|
Common |
|
| Dyspepsia3, gastroesophageal reflux disease3 |
|
Uncommon |
|
| Biliary system disorders |
Elevated liver transaminases2 |
Uncommon |
|
| Jaundice2 |
Very rare |
|
|
| Hepatitis2,3 |
Very rare |
Not known |
|
| Cholelithiasis3 |
|
Not known |
|
| Cholecystitis3 |
|
Not known |
|
| Skin and subcutaneous tissue disorders |
Pruritus2,3 |
Uncommon |
Uncommon |
| Rash2,3 |
Uncommon |
Uncommon |
|
| Urticaria2,3 |
Uncommon |
Uncommon |
|
| Stevens-Johnson syndrome2 |
Not known |
|
|
| Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)2 |
Not known |
|
|
| Multiform erythema3 |
|
Not known |
|
| Muscle and connective tissue disorders |
Myalgia2,3 |
Common |
Common |
| Myopathy (including myositis)2 |
Uncommon |
Not known |
|
| Rhabdomyolysis2 |
Uncommon |
Not known |
|
| Arthralgia2,3 |
Very rare |
Uncommon |
|
| Immune-mediated necrotizing myopathy2 |
Not known |
|
|
| Tendon disorders, sometimes complicated by rupture2 |
Not known |
|
|
| Back pain3 |
|
Uncommon |
|
| Muscle weakness3 |
|
Uncommon |
|
| Limb pain3 |
|
Uncommon |
|
| Muscle spasm, neck pain3 |
|
Uncommon |
|
| Lupus-like syndrome2 |
Uncommon |
- |
|
| Muscle rupture2 |
Uncommon |
- |
|
| Renal and urinary system disorders |
Haematuria2 |
Very rare |
|
| Reproductive system and breast disorders |
Gynaecomastia2 |
Very rare |
|
| General disorders |
Asthenia2,3 |
Common |
Uncommon |
| Oedema2 |
Not known |
|
|
| Peripheral oedema3 |
|
Uncommon |
|
| Fatigue3 |
|
Common |
|
| Chest pain3, pain3 |
|
Uncommon |
|
| Investigations |
Elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)3 |
|
Common |
| Elevated serum creatine kinase (CK), elevated gamma-glutamyl transferase, abnormalities in 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 triglycerides, history of hypertension) — for rosuvastatin. |
|||
2 Adverse reaction profile associated with rosuvastatin use based on clinical studies and extensive post-marketing experience.
3 Adverse reactions observed in clinical studies of ezetimibe (administered as monotherapy or concomitantly with a statin) or during post-marketing use of ezetimibe (either alone or with a statin). Adverse reactions occurred more frequently in patients receiving ezetimibe (n = 2396) than in those receiving placebo (n = 1159), and more frequently in patients receiving ezetimibe concomitantly with a statin (n = 11308) than in those receiving statin alone (n = 9361).
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions tends to be dose-dependent.
Renal effects
Proteinuria detected by urine dipstick testing, predominantly of tubular origin, has been observed in patients taking rosuvastatin. Changes in urinary protein levels from zero or trace to ++ or higher were observed in < 1 % of patients at certain time points during treatment with 10 mg and 20 mg doses, and in approximately 3 % of patients receiving the 40 mg dose. A slight increase in the frequency of change in protein levels from zero or trace to + was observed at the 20 mg dose. In most cases, proteinuria decreased or resolved spontaneously during continued treatment. Based on data from clinical studies and post-marketing surveillance, no causal relationship has been established between proteinuria and acute or progressive kidney disease to date.
Hematuria has been reported during rosuvastatin treatment; however, its frequency was low according to clinical trial data.
Skeletal muscle effects
Skeletal muscle disorders such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been reported with all doses of rosuvastatin, particularly at doses > 20 mg.
Patients taking rosuvastatin have shown dose-dependent increases in creatine kinase (CK) levels; in most cases, this was mild, asymptomatic, and transient. If CK levels are elevated (> 5 × ULN), treatment should be discontinued (see section "Dosage and Administration").
Hepatic effects
As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase levels have been observed in a small number of patients receiving rosuvastatin; in most cases, this was mild, asymptomatic, and transient.
With the use of certain statins, the following adverse events have been reported:
- Sexual dysfunction;
- Isolated cases of interstitial lung disease, particularly with long-term use (see section "Dosage and Administration").
The frequency of reports of rhabdomyolysis and serious renal and hepatic adverse events (predominantly increased hepatic transaminase activity) is higher with rosuvastatin 40 mg dose.
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 abnormalities normalized either after discontinuation of treatment or during continued therapy (see section "Dosage and Administration").
During clinical trials in patients receiving ezetimibe monotherapy, increases in CK > 10 × ULN were observed in 4 out of 1674 (0.2 %) patients and in 1 out of 786 (0.1 %) placebo group 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 associated with ezetimibe treatment was observed compared to control groups (placebo or statin monotherapy) (see section "Dosage and Administration").
Children
The safety and efficacy of Rosulip® Plus in children (under 18 years of age) have not been established to date (see section "Pharmacodynamics").
Rosuvastatin
Elevations in creatine kinase > 10 × ULN and muscle-related symptoms following physical exertion or increased physical activity were observed more frequently in a 52-week clinical study involving children and adolescents compared to adults. However, the safety profile of rosuvastatin in children and adolescents was similar to that in adults.
Ezetimibe
In a study involving children aged 6 to 10 years with heterozygous familial hypercholesterolemia (n = 138), elevations in ALT and/or AST (≥ 3 × ULN) were observed in 1.1 % (1 patient) in the ezetimibe group compared to 0 % in the placebo group. No CK elevations (≥ 10 × ULN) were reported. No cases of myopathy were reported.
In a study involving adolescents aged 10 to 17 years with heterozygous familial hypercholesterolemia (n = 248), elevations in ALT and/or AST (≥ 3 × ULN) were observed in 3 % (4 patients) in the ezetimibe/simvastatin group compared to 2 % (2 patients) in the simvastatin monotherapy group; CK elevations (≥ 10 × ULN) were 2 % (2 patients) and 0 %, respectively. No cases of myopathy were reported.
This study did not compare rare adverse drug reactions.
Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
3 years from the manufacturing date of the first tablet contained in the capsule.
Storage conditions.
Store at temperatures not exceeding 30 °C, in a place inaccessible to children.
Packaging.
10 capsules in a blister; 3 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
EGIS Pharmaceuticals Ltd.
Manufacturer's location and address of place of business.
65 Matyas Kiray Street, Kormend, 9900, Hungary.
118-120 Bekenyfeldi Street, Budapest, 1165, Hungary.