Rozister® duo
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROZISTER® DUO (ROZISTERDUO)
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 20 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe,
or 40 mg rosuvastatin (as rosuvastatin calcium) and 10 mg ezetimibe;
Excipients: lactose monohydrate; sodium croscarmellose; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silicon dioxide; magnesium stearate;
Film coating:
dosage 5 mg/10 mg – Opadry Yellow 02F220026: hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E171), polyethylene glycol (macrogol), iron oxide yellow (E172), talc, iron oxide red (E172);
dosage 10 mg/10 mg – Opadry Beige 02F270003: hypromellose (hydroxypropylmethylcellulose), iron oxide yellow (E172), titanium dioxide (E171), polyethylene glycol 4000 (macrogol), talc;
dosage 20 mg/10 mg – Vivacoat PC-2P-308: hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E171), talc, polyethylene glycol 4000 (macrogol), iron oxide yellow (E172);
dosage 40 mg/10 mg – Opadry White OY-L-28900: lactose monohydrate, hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E171), polyethylene glycol 4000 (macrogol).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
dosage 5 mg/10 mg – light yellow, round, biconvex, film-coated tablets approximately 10 mm in diameter, engraved with «EL5» on one side;
dosage 10 mg/10 mg – beige, round, biconvex, film-coated tablets approximately 10 mm in diameter, engraved with «EL4» on one side;
dosage 20 mg/10 mg – yellow, round, biconvex, film-coated tablets approximately 10 mm in diameter, engraved with «EL3» on one side;
dosage 40 mg/10 mg – white, round, biconvex, film-coated tablets approximately 10 mm in diameter, engraved with «EL2» on one side.
Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors in combination with other hypolipidemic agents. Rosuvastatin and ezetimibe.
ATC code C10BA06.
Pharmacological properties.
Pharmacodynamics.
The medicinal product contains ezetimibe and rosuvastatin – two hypolipidemic compounds with complementary mechanisms of action. It reduces elevated levels of total cholesterol (total TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-HDL cholesterol (non-HDL-C), as well as increases high-density lipoprotein cholesterol (HDL-C) levels through dual inhibition of cholesterol absorption and synthesis.
Rosuvastatin
Mechanism of action
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 cholesterol precursor. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol reduction.
Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing LDL uptake and catabolism, and suppresses the hepatic synthesis of very-low-density lipoproteins (VLDL), thereby reducing the total number of LDL and VLDL particles.
Pharmacodynamic effects
Rosuvastatin reduces elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglyceride levels, and slightly increases high-density lipoprotein cholesterol (HDL-C) levels. It also reduces apolipoprotein B, non-HDL cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), very-low-density lipoprotein triglycerides (VLDL-TG), 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-dependent effect in patients with primary hypercholesterolemia (types IIa and IIb) (adjusted mean percent change from baseline)
| Dose |
N |
LDL-C |
Total Cholesterol |
HDL-C |
Triglycerides |
Non-HDL-C |
Apo B |
Apo A-I |
| Placebo |
13 |
-7 |
-5 |
3 |
-3 |
-7 |
-3 |
0 |
| 5 mg |
17 |
-45 |
-33 |
13 |
-35 |
-44 |
-38 |
4 |
| 10 mg |
17 |
-52 |
-36 |
14 |
-10 |
-48 |
-42 |
4 |
| 20 mg |
17 |
-55 |
-40 |
8 |
-23 |
-51 |
-46 |
5 |
| 40 mg |
18 |
-63 |
-46 |
10 |
-28 |
-60 |
-54 |
0 |
The therapeutic effect becomes apparent within 1 week after starting rosuvastatin therapy; after 2 weeks of treatment, the effect reaches 90% of the maximum possible. The maximum effect is generally achieved within 4 weeks after the start of treatment and is maintained thereafter.
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 groups, such as patients with diabetes or patients with a history of familial hypercholesterolemia.
Pooled data from phase III studies show that rosuvastatin effectively reduced cholesterol levels in the majority of patients with type IIa and IIb hypercholesterolemia (mean baseline LDL-C level 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 EAS-recommended target LDL-C levels (< 3 mmol/L).
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 is 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 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
Available information from a series of preclinical studies assessing 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.
Studies have shown that cardiovascular disease and mortality are directly proportional to total cholesterol and LDL-C levels 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 cardiovascular conditions and a history of acute coronary syndromes.
Clinical efficacy and safety
According to published clinical trial data, the use of ezetimibe, 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.
Concomitant use of rosuvastatin and ezetimibe
Clinical efficacy
A 6-week, randomized, double-blind, parallel-group clinical trial was designed to evaluate the safety and efficacy of adding ezetimibe (10 mg) to ongoing rosuvastatin therapy, compared to gradually increasing rosuvastatin doses from 5 to 10 mg or from 10 to 20 mg (n = 440). The pooled data demonstrated that adding ezetimibe to ongoing rosuvastatin therapy at doses of 5 mg or 10 mg reduced LDL-C levels by 21%. In contrast, doubling the rosuvastatin dose to 10 mg or 20 mg resulted in a 5.7% reduction in LDL-C (difference between groups 15.2%, p < 0.001).
Separate use of the ezetimibe plus rosuvastatin 5 mg regimen reduced LDL-C levels more than rosuvastatin 10 mg alone (difference 12.3%, p < 0.001), and the ezetimibe plus rosuvastatin 10 mg regimen reduced LDL-C levels more than rosuvastatin 20 mg alone (difference 17.5%, p < 0.001).
According to published data, a 6-week randomized study was designed to evaluate the efficacy and safety of rosuvastatin 40 mg alone versus in combination with ezetimibe 10 mg in patients at high risk of ischemic heart disease (n = 469). In the group receiving rosuvastatin/ezetimibe, a significantly higher proportion of patients achieved the ATP III target LDL-C level (< 100 mg/dL, 94.0% vs. 79.1%, p < 0.001) compared to the rosuvastatin monotherapy group. Rosuvastatin 40 mg provided effective improvement in atherogenic lipid profile in this high-risk population.
In a randomized, open-label, 12-week study, the reduction in LDL-C levels was evaluated in each treatment group (rosuvastatin 10 mg/ezetimibe 10 mg, rosuvastatin 20 mg/ezetimibe 10 mg, simvastatin 40 mg/ezetimibe 10 mg, simvastatin 80 mg/ezetimibe 10 mg). In the low-dose rosuvastatin combination groups, the reduction from baseline was 59.7%, significantly exceeding the result in the low-dose simvastatin combination groups (55.2% (p < 0.05)). When high-dose combinations were used, LDL-C levels decreased by 63.5% with rosuvastatin combinations compared to 57.4% with high-dose simvastatin combinations (p < 0.001).
Pediatric patients
The European Medicines Agency has waived the obligation to submit results of studies on the use of cholesterol-lowering agents in all pediatric subgroups (see section "Dosage and administration" for information on use in children).
Pharmacokinetics
Combined therapy with rosuvastatin and ezetimibe
Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC. A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to the occurrence of adverse reactions.
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 to 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.
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 at 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 multiple daily doses, pharmacokinetic parameters do not change.
Special patient groups
Age and gender
There is no clinically significant effect of patient age or gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children and adolescents with heterozygous familial hypercholesterolemia were similar to those in adult volunteers.
Race
Pharmacokinetic studies demonstrate approximately a 2-fold increase in median plasma concentration-time curve area (AUC) and Cmax of rosuvastatin in Mongoloid race individuals (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) compared to Caucasian race patients; in Indians, median AUC and Cmax are increased approximately 1.3-fold. Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Negroid race individuals.
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 concentrations increased 9-fold compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than in healthy volunteers.
Patients with hepatic impairment
In a study involving patients with varying degrees of hepatic dysfunction, no increase in rosuvastatin exposure was observed in patients with Child-Pugh scores of 7 or less. However, 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 with Child-Pugh scores of 9 or higher is lacking.
Genetic polymorphism
The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, involves transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased rosuvastatin exposure. Specific polymorphism types 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 not routinely used in clinical practice, but patients identified with these polymorphism types are recommended to receive a lower daily dose of rosuvastatin.
Children
Two pharmacokinetic studies of rosuvastatin (in tablet form) involving patients aged 10–17 or 6–17 years (total 214 patients) with heterozygous familial hypercholesterolemia showed that the drug's exposure in children corresponds to that in adult patients. Rosuvastatin exposure was predictable based on dose and duration of administration over a period of more than 2 years.
Ezetimibe
Absorption
After oral administration, ezetimibe is rapidly absorbed and actively conjugated to form the pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
In plasma, mean Cmax of ezetimibe-glucuronide is reached within 1–2 hours, and of ezetimibe within 4–12 hours.
Absolute bioavailability of ezetimibe cannot be determined because the compound is insoluble in water for injection.
Concomitant food intake (low- or high-fat meals) does not affect the oral bioavailability of ezetimibe, including at a dose of 10 mg. 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 glucuronide conjugation (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 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 was detected in plasma as a proportion of total plasma radioactivity. Approximately 78% and 11% of the administered radioactive dose were excreted in feces and urine, respectively, over 10 days. Within 48 hours, plasma radioactivity levels were no longer detectable.
Special patient groups
Children
Ezetimibe pharmacokinetics are similar in adults and children aged 6 years and older. Pharmacokinetic data from studies involving 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 (over 65 years), total ezetimibe plasma concentrations 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 plasma concentration-time curve area (AUC) values of total ezetimibe were 1.7 times higher in patients with mild hepatic impairment (5–6 points on the Child-Pugh scale) than in healthy volunteers. In a 14-day study of ezetimibe (10 mg daily) in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale), AUC values of total ezetimibe increased approximately 4-fold on day 1 and day 14 compared to healthy volunteers. Dose adjustment is not required for patients with mild hepatic impairment. Since the effects of increased ezetimibe exposure in patients with moderate or severe hepatic impairment (more than 9 points on the Child-Pugh scale) are unknown, ezetimibe is not recommended for use in these patients (see section "Special 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. No dose adjustment is required for patients with renal dysfunction.
In this study, one patient (who had a kidney transplant and was receiving multi-drug therapy, including cyclosporine) had total ezetimibe levels 12 times higher.
Gender
Total plasma ezetimibe concentrations 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, no dose adjustment is required based on patient gender.
Clinical characteristics.
Indications.
Prevention of cardiovascular complications
As replacement therapy to reduce the risk of cardiovascular complications 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 at the same doses as in the combination product.
Primary hypercholesterolemia / homozygous familial hypercholesterolemia
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 at the same doses as in the combination product.
Contraindications.
The medicinal product 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 increases in serum transaminase levels exceeding three times the upper limit of normal (ULN) (see section "Special precautions");
- Severe renal impairment (creatinine clearance < 30 mL/min);
- Myopathy (see section "Special precautions");
- Concomitant treatment with cyclosporine (see section "Interaction with other medicinal products and other forms of interaction");
- Concomitant use of the sofosbuvir/velpatasvir/voxilaprevir combination (see section "Interaction with other medicinal products and other forms of interaction");
- Pregnancy and breastfeeding, as well as in women of childbearing potential who are not using appropriate contraceptive measures (see section "Use during pregnancy or breastfeeding").
The medicinal product in the 40 mg/10 mg dosage is contraindicated in patients with myopathy or risk factors for myopathy/rhabdomyolysis, such as: 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; belonging to the Mongoloid race; concomitant use of fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
Interaction with other medicinal products and other forms of interaction.
Concomitant use contraindicated
Cyclosporine
Concomitant use of the medicinal product with cyclosporine is contraindicated (see section "Contraindications"). During concomitant administration 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
Concomitant use of protease inhibitors may significantly increase systemic exposure to rosuvastatin, although the exact mechanism of this interaction is unknown (see Table 2). According to published data, in a pharmacokinetic study, concomitant administration of 10 mg rosuvastatin and a combination product containing two protease inhibitors (atazanavir 300 mg/ritonavir 100 mg) in healthy volunteers was associated with approximately 3-fold and 7-fold increases in steady-state AUC and Cmax of rosuvastatin, respectively. Concomitant use of rosuvastatin and certain protease inhibitor combinations may be possible only after careful dose adjustment of rosuvastatin, taking into account the expected increase in rosuvastatin exposure (see sections "Special precautions", "Dosage and administration", and Table 2 in the section "Interaction with other medicinal products and other forms of interaction").
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", and Table 2 in the section "Interaction with other medicinal products and other forms of interaction").
Fibrates
Concomitant use of rosuvastatin and gemfibrozil results in a 2-fold increase in Cmax and AUC of rosuvastatin (see section "Special precautions").
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"). Such patients should initiate therapy with a 5 mg dose of rosuvastatin.
In patients taking ezetimibe and fenofibrate, there is a risk of developing cholelithiasis and gallstone disease (see sections "Special precautions" and "Adverse reactions").
In case of suspected gallstone disease in a patient taking ezetimibe and fenofibrate, gallbladder examination 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). Combination therapy with ezetimibe and other fibrates has not been studied.
Fibrates may increase cholesterol excretion into bile, leading to gallstone disease. In preclinical animal studies, ezetimibe increased cholesterol levels in gallbladder bile, although not in all animal species. The risk of stone formation associated with ezetimibe use cannot be excluded.
Statins
No clinically significant pharmacokinetic interactions were observed when ezetimibe was used concomitantly with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
Cyclosporine
In a study involving eight kidney transplant patients with creatinine clearance > 50 mL/min receiving stable doses of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4-fold increase (range 2.3 to 7.9-fold) in mean AUC of total ezetimibe compared to healthy control participants receiving ezetimibe alone in another study (n = 17). In another study, in a kidney transplant patient with severe renal insufficiency receiving cyclosporine and multiple other drugs, exposure to total ezetimibe was 12 times higher than in control participants receiving ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers, daily administration of 20 mg ezetimibe for 8 days and a single 100 mg dose of cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (ranging from a 10% decrease to a 51% increase) compared to administration of cyclosporine 100 mg alone. A controlled study evaluating the effect of ezetimibe on cyclosporine exposure when used concomitantly in kidney transplant patients has not been conducted. Caution is advised when initiating ezetimibe with cyclosporine. Cyclosporine plasma concentrations should be monitored in patients receiving both ezetimibe and cyclosporine (see section "Special precautions").
Fusidic acid
The risk of myopathy, including rhabdomyolysis, may be increased by concomitant systemic use of fusidic acid with 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 use should be discontinued for the entire duration of fusidic acid therapy (see section "Special precautions").
Other interactions
Ezetimibe
Concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (see Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may lead to adverse reactions (see section "Special precautions").
Antacids
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.
Concomitant use of rosuvastatin and antacid suspensions containing aluminum hydroxide and magnesium hydroxide reduces rosuvastatin plasma concentrations by approximately 50%. This effect was less pronounced when antacids were administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.
Anticoagulants
Concomitant use of ezetimibe (10 mg once daily) did not significantly affect warfarin bioavailability or prothrombin time in a study involving 12 healthy adult males. However, post-marketing reports have indicated increased international normalized ratio (INR) in patients receiving ezetimibe added to warfarin or fluindione. When adding ezetimibe to warfarin, another coumarin anticoagulant, or fluindione, appropriate INR monitoring is required (see section "Special precautions").
As with other HMG-CoA reductase inhibitors, initiation or dose increase of rosuvastatin in patients concomitantly using vitamin K antagonists (e.g., warfarin or another coumarin anticoagulant) may lead to an increase in INR. Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. In such cases, appropriate INR monitoring is advisable.
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) was observed.
Study results indicate that ezetimibe does not induce cytochrome P450 enzymes responsible for its metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and medicinal products metabolized by cytochromes P450: 1A2, 2D6, 2C8, 2C9, 3A4 – or N-acetyltransferase.
In clinical interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinylestradiol and levonorgestrel), glipizide, tolbutamide, or midazolam when used concomitantly. Cimetidine did not affect ezetimibe bioavailability when co-administered with ezetimibe.
Cholestyramine
When used concomitantly with cholestyramine, the mean AUC of total ezetimibe (ezetimibe and ezetimibe-glucuronide) decreased 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.
Effect of rosuvastatin on concomitant medicinal products
Vitamin K antagonists
As with other HMG-CoA reductase inhibitors, initiation or dose increase of rosuvastatin in patients concomitantly using vitamin K antagonists (e.g., warfarin or another coumarin anticoagulant) may lead to an increase in international normalized ratio (INR). Discontinuation or dose reduction of rosuvastatin may lead to a decrease in INR. Appropriate INR monitoring is advisable in such situations.
Oral contraceptives / hormone replacement therapy (HRT)
Concomitant use of rosuvastatin and oral contraceptives resulted in 26% and 34% increases in AUC of ethinylestradiol and norgestrel, respectively. This increase in plasma levels should be considered when selecting the dose of oral contraceptives. Data on the pharmacokinetics of drugs 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.
Ticagrelor
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 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 concomitant interacting drugs. For example, when used with gemfibrozil, the maximum rosuvastatin dose would be 20 mg (1.9-fold increase), and when used with atazanavir/ritonavir combination, 10 mg rosuvastatin (3.1-fold increase).
If a medicinal product increases rosuvastatin AUC by less than 2-fold, the initial dose need not be reduced, but caution should be exercised when increasing the dose above 20 mg.
Table 2
Effect of concomitant medicinal products on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical study data
| Increased rosuvastatin AUC by 2 times or more |
||
| Dosing regimen of the interacting medicinal product |
Rosuvastatin dosing regimen |
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-fold |
| Cyclosporine 75 mg 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 |
| Simprevir 150 mg once daily, 7 days |
10 mg, single dose |
↑ 2.8-fold |
| Velpatasvir 100 mg once daily |
10 mg, single dose |
↑ 2.7-fold |
| Obitasvir 25 mg / paritaprevir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily, 14 days |
5 mg, single dose |
↑ 2.6-fold |
| Teriflunomide |
Data not available |
↑ 2.5-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 |
| Capmatinib 400 mg twice daily |
10 mg, single dose |
↑ 2.1-fold |
| Clopidogrel 300 mg loading dose, followed by 75 mg after 24 hours |
20 mg, single dose |
↑ 2-fold |
| Fostamatinib 100 mg twice daily |
20 mg, single dose |
↑ 2.0-fold |
| Febuxostat 120 mg once daily |
10 mg, single dose |
↑ 1.9-fold |
| Gemfibrozil 600 mg twice daily, 7 days |
80 mg, single dose |
↑ 1.9-fold |
| Increased rosuvastatin AUC less than 2-fold |
||
| Dosing regimen of the interacting medicinal product |
Rosuvastatin dosing regimen |
Changes in rosuvastatin AUC* |
| Elvitegravir 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 |
Data not available |
↑ 1.4-fold |
| Itraconazole 200 mg once daily, 5 days |
10 mg, single dose |
↑ 1.4-fold ** |
| Ezetimibe 10 mg once daily, 14 days |
10 mg once daily, 14 days |
↑ 1.2-fold ** |
| Decreased rosuvastatin AUC |
||
| Dosing regimen of the interacting medicinal product |
Rosuvastatin dosing regimen |
Changes in rosuvastatin AUC* |
| Erythromycin 500 mg four times daily, 7 days |
80 mg, single dose |
↓ 20% |
| Baicalein 50 mg three times daily, 14 days |
20 mg, single dose |
↓ 47% |
* Data presented as change by x-fold represent the ratio between administration of rosuvastatin in combination versus alone. Data presented as % change represent the percentage difference relative to values when rosuvastatin is administered alone.
Increase is indicated by ↑, decrease by ↓.
** Several interaction studies were conducted with different doses of rosuvastatin; the table presents the most significant ratio.
Medicinal products/combinations that had no clinically significant effect on rosuvastatin AUC when co-administered: 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.
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 in combination 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.
There have been several reports of myasthenia gravis induced by statin use, or exacerbation of pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, use of the medicinal product Rosister® Duo should be discontinued. Cases of myasthenia gravis relapse have been reported upon re-exposure to statins.
Renal effects
Proteinuria detected by dipstick testing, predominantly of tubular origin, has been observed in patients treated with higher doses of rosuvastatin, particularly 40 mg, and was mostly transient or intermittent in most cases. 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 rosuvastatin 40 mg dose. Renal function should be regularly monitored in patients receiving rosuvastatin 40 mg.
Skeletal muscle effects
Skeletal muscle disorders, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients receiving rosuvastatin at any dose, particularly above 20 mg. Cases of myopathy and rhabdomyolysis have been reported with ezetimibe use. 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), treatment with ezetimibe, any statin, or other concomitantly used medicinal products should be immediately discontinued. Patients initiating therapy should be informed about the risk of myopathy and should promptly report any muscle pain, tenderness, or weakness (see section "Adverse reactions").
In the international IMPROVE-IT study, 18,144 patients with established coronary heart disease (CHD) and acute coronary syndrome (ACS) were randomized to receive a medicinal product containing ezetimibe/simvastatin 10/40 mg daily (n = 9,067) or simvastatin 40 mg daily (n = 9,077). During a median follow-up of 6 years, the incidence of myopathy was 0.2% with ezetimibe/simvastatin combination and 0.1% with simvastatin. Myopathy was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥10 times ULN, or with creatine kinase levels ≥5 to <10 times UL, measured on two consecutive occasions. The incidence of rhabdomyolysis was 0.1% with ezetimibe/simvastatin combination and 0.2% with simvastatin. Acute rhabdomyolysis was defined as muscle weakness or pain of unknown etiology with serum creatine kinase ≥10 times ULN and confirmed renal impairment, or with creatine kinase levels ≥5 to <10 times ULN with confirmed renal impairment on two consecutive occasions, or with creatine kinase ≥10,000 IU/L without signs of renal impairment (see section "Adverse reactions").
In published data from clinical trials involving over 9,000 patients with chronic kidney disease randomized to receive ezetimibe 10 mg in combination with a statin 20 mg daily (n = 4,650) or placebo (n = 4,620) (mean follow-up period 4.9 years), the incidence of myopathy was 0.2% with ezetimibe in combination with simvastatin and 0.1% with placebo (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 times ULN), repeat testing should be performed within 5–7 days to confirm results. If repeat testing confirms baseline CK levels >5 times ULN, treatment initiation should not be started.
Before starting treatment
The medicinal product, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients predisposed to myopathy/rhabdomyolysis. Risk factors include:
- renal dysfunction;
- hypothyroidism;
- personal or family history of hereditary muscle disorders;
- history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
- alcohol abuse;
- age >70 years;
- conditions that may lead to increased plasma levels of the drug (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Posology and method of administration");
- concomitant use of fibrates.
In such patients, the treatment-related risk should be weighed against the expected benefit; clinical monitoring is also recommended. Treatment should not be initiated if baseline CK levels are markedly elevated (>5 times ULN).
During therapy
Patients should be advised to promptly report unexplained muscle pain, weakness, or cramps, especially if accompanied by malaise or fever. In such patients, CK levels should be measured. The drug should be discontinued if CK levels are markedly elevated (>5 times ULN) or if muscle symptoms are severe and cause daily discomfort (even if CK levels are ≤5 times ULN). Therapy may be resumed with the same or an alternative HMG-CoA reductase inhibitor at the lowest dose and under close monitoring once symptoms resolve and CK levels return 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 creatine kinase levels that persist even after discontinuation of statins.
During clinical trials, no evidence of increased skeletal muscle effects was observed in a small number of patients receiving rosuvastatin and concomitant medications. However, increased incidence of myositis and myopathy has been observed in patients receiving 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 the medicinal product with gemfibrozil is not recommended. The benefit of further lipid-lowering with the medicinal product in combination with fibrates should be carefully weighed against the potential risks associated with such combinations. A rosuvastatin dose of 40 mg is contraindicated when used concomitantly with fibrates (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
The medicinal product should not be used in patients with acute, serious conditions indicating myopathy or risk of developing renal failure due to rhabdomyolysis (such as sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances, or uncontrolled seizures).
Fusidic acid
The medicinal product should not be used concomitantly with fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In 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.
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 necessary, for example, to treat severe infections, concomitant use of the medicinal product and fusidic acid may be considered only under strict 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 40 mg/10 mg dosage of the medicinal product is contraindicated in patients who abuse alcohol.
It is recommended to assess liver biochemical parameters before starting treatment and 3 months thereafter. The medicinal product 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 (predominantly 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 the medicinal product.
Rare cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including rosuvastatin.
In studies of patients receiving statin in combination with ezetimibe, gradual increases in transaminase levels (≥3 times ULN) have been observed. Liver function tests should be performed at the start of therapy and according to recommendations for statins (see sections "Pharmacokinetics", "Contraindications", and "Posology and method of administration").
Race
In pharmacokinetic studies, increased systemic exposure to the drug was observed in patients of Mongoloid race compared to Caucasians (see sections "Contraindications" and "Posology and method of administration").
Protease inhibitors
Increased systemic exposure to rosuvastatin has been observed in individuals receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Both the benefit of lipid-lowering with rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased plasma concentrations of rosuvastatin at the start of therapy and with dose escalation in patients receiving protease inhibitors should be considered. Concomitant use of the 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 "Posology and method of administration").
Interstitial lung disease
Isolated cases of interstitial lung disease have been reported with some statins, particularly with long-term use (see section "Adverse reactions"). Symptoms include dyspnea, non-productive cough, and worsening of general health (fatigue, weight loss, fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
Diabetes mellitus
Evidence suggests that statins increase blood glucose levels and may cause 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, which 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.
Published data from clinical trials show an overall incidence of diabetes mellitus of 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
No studies on the safety and efficacy of concomitant use of ezetimibe with fibrates have been conducted. In patients receiving rosuvastatin/ezetimibe and fenofibrate who are suspected of having gallstones, gallbladder examination and discontinuation of such therapy are indicated (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Anticoagulants
When adding the medicinal product to warfarin, other coumarin anticoagulants, or fluindione, appropriate monitoring of INR is required.
Children aged 10 to 17 years
The effect of rosuvastatin on linear growth (height), body weight, BMI (body mass index), and development of secondary sexual characteristics according to Tanner scale 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 experience with the use of the medicinal product in children and adolescents is limited, and long-term effects of rosuvastatin use (>1 year) on sexual maturation are unknown.
In clinical trials in children and adolescents receiving rosuvastatin for 52 weeks, CK levels >10 times ULN and muscle symptoms following 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, patients should be informed about signs and symptoms of severe skin reactions and closely monitored. If signs or symptoms suggestive of these reactions occur, the medicinal product 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 the medicinal product, treatment should be discontinued immediately and the medicinal product should never be used again.
The medicinal product contains lactose. Patients with rare hereditary intolerance to galactose, total lactase deficiency, or glucose-galactose malabsorption should not take this product.
The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding.
The medicinal product 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 product during pregnancy. Reproductive toxicity has been observed in some animal studies. If a patient becomes pregnant while taking the product, treatment should be discontinued immediately.
There are no clinical data on the use of ezetimibe during pregnancy. Animal studies using ezetimibe as monotherapy did not show evidence of direct or indirect harmful effects on pregnancy, embryofetal development, parturition, or postnatal development.
Breastfeeding
The medicinal product should not be used during breastfeeding. Rosuvastatin passes into the milk of rats. There are no data on the passage of rosuvastatin into human breast milk.
Since another medicinal product of this class passes into human breast milk and considering that HMG-CoA reductase inhibitors may cause serious adverse reactions in infants, women requiring treatment with rosuvastatin should be advised not to breastfeed.
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 at high doses has shown toxic effects in monkeys and dogs.
Ability to influence reaction speed when driving or operating machinery.
No studies on the effect of rosuvastatin or ezetimibe on the ability to drive or operate machinery have been conducted. 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 course of treatment.
The recommended daily dose is 1 tablet taken orally, independent of food intake.
Prior to switching to this medicinal product, patients should be stabilized on individual doses of the separate components when used concomitantly. The dose of this fixed combination should be based on the doses of the individual components at the time of transition.
This medicinal product is not suitable for initiating therapy. At the start of treatment or when a dose adjustment of any active substance in the fixed combination is required for any reason (e.g., newly diagnosed condition, change in patient status, or drug interactions), the individual components should be used separately to determine the appropriate dosage.
This medicinal product 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 Patient Populations
Elderly 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 further dose adjustment is required.
Patients with Renal Impairment
No dose adjustment is necessary for patients with mild renal impairment. The recommended starting dose for patients with moderate renal impairment (creatinine clearance < 60 mL/min) is rosuvastatin 5 mg. The 40 mg/10 mg dosage strength is contraindicated in patients with moderate renal impairment. The use of this medicinal product is contraindicated in patients with severe renal impairment at any dose (see sections "Pharmacokinetics" and "Contraindications").
Patients with Hepatic Impairment
No dose adjustment is required for patients with mild hepatic impairment (5–6 points on the Child–Pugh scale). The medicinal product is not recommended for patients with moderate (7–9 points on the Child–Pugh scale) or severe (more than 9 points on the Child–Pugh scale) hepatic impairment (see sections "Pharmacokin游戏副本 and "Special Warnings and Precautions for Use").
The medicinal product is contraindicated in patients with acute liver disease (see section "Contraindications").
Race
Increased systemic exposure to the drug has been observed in patients of Mongolian race (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use"). The recommended starting dose of rosuvastatin for Asian patients is 5 mg. The 40 mg/10 mg dosage strength is contraindicated in patients of Mongolian race (see section "Contraindications").
Genetic Polymorphism
Specific types of genetic polymorphism are known to increase rosuvastatin exposure. Patients with such polymorphisms should be given a reduced daily dose of rosuvastatin.
Dosing in Patients Predisposed to Myopathy
The recommended starting dose of rosuvastatin for patients predisposed to myopathy is 5 mg (see section "Special Warnings and Precautions for Use"). The 40 mg/10 mg dosage strength is contraindicated in patients predisposed to myopathy (see section "Contraindications").
Concomitant Therapy
Rosuvastatin is a substrate for several transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is co-administered with certain medicinal products that increase plasma concentrations of rosuvastatin via interactions with these transporter proteins (e.g., cyclosporine and certain protease inhibitors, including ritonavir in combination with atazanavir, lopinavir, and/or tipranavir; see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). Alternative treatments should be considered, and temporary discontinuation of the medicinal product may be necessary. When concomitant use of these medicinal products with this fixed combination cannot be avoided, the benefit and risk of combination therapy 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, use of this medicinal product is not recommended in this age group.
Overdose
In case of overdose, supportive and symptomatic treatment is recommended.
Rosuvastatin
Monitoring of liver function and creatine kinase (CK) levels is required. Hemodialysis is unlikely to be effective.
Ezetimibe
In clinical studies, ezetimibe was administered at a dose of 50 mg/day for 14 days to 15 healthy volunteers and at 40 mg/day for 56 days to 18 patients with primary hypercholesterolemia, and was generally well tolerated. In animal studies, no toxic effects were observed after single oral doses of 5,000 mg/kg in rats and mice and 3,000 mg/kg in dogs.
There have been a few reports of ezetimibe overdose, most of which did not result in adverse events. Reported adverse reactions were not clinically significant.
Adverse reactions
Adverse reactions observed during administration of rosuvastatin are generally mild and transient.
Available data from controlled clinical studies indicate that less than 4% of patients receiving rosuvastatin discontinued the study due to adverse reactions.
Table 3 presents adverse reactions associated with rosuvastatin use, identified based on data from clinical and post-marketing studies.
In clinical studies lasting up to 112 weeks, 2,396 patients received ezetimibe alone at a dose of 10 mg once daily, 11,308 patients received ezetimibe in combination with a statin, and 185 patients received ezetimibe in combination with fenofibrate. Adverse reactions were generally mild in severity and transient in nature. The overall incidence of adverse effects was similar between ezetimibe and placebo groups. Similarly, the rate of treatment discontinuation due to adverse reactions was comparable in both groups.
Adverse reactions associated with ezetimibe occurred more frequently in patients receiving ezetimibe (N = 2,396) compared to those receiving placebo (N = 1,159), as well as in patients receiving concomitant therapy with ezetimibe and statins (N = 11,308) compared to those receiving statin monotherapy (N = 9,361). Post-marketing adverse reactions related to ezetimibe were derived from reports of ezetimibe used alone or in combination with statins.
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); not known (cannot be estimated from available data).
Table 3
Adverse effects 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 |
| Eye disorders |
Ocular myasthenia |
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 nightmares) |
Not known |
|
|
| Paraesthesia |
|
Uncommon |
|
| Myasthenia gravis |
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 system 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 |
|
|
| Muscle 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 system 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-glutamyltransferase levels, abnormal liver function tests |
|
Uncommon |
|
1 The frequency depends on the presence of risk factors (fasting glucose level ≥ 5.6 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, history of arterial hypertension).
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions to rosuvastatin is generally dose-dependent.
Description of individual adverse reactions
Effect on kidneys
Cases of proteinuria, predominantly of tubular origin (identified by test strips), have been observed in patients taking rosuvastatin. Changes in urine 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 cases with elevated protein in urine 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.
Based on clinical studies and post-marketing observations, there is currently no evidence of 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.
Effect on skeletal muscle
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. Patients taking rosuvastatin have shown dose-dependent increases in CK levels; 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").
Effect on liver
As with other HMG-CoA reductase 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, serious renal and hepatic dysfunction (mainly manifested as elevated liver transaminases) were observed more frequently with the 40 mg dose of the drug.
Concomitant use of ezetimibe and fenofibrate
Gastrointestinal disorders: abdominal pain (common).
It is known from a multicenter, double-blind, placebo-controlled clinical trial involving patients with mixed hyperlipidemia, in which 625 patients received treatment for 12 weeks and 576 patients for 1 year. In this study, 172 patients receiving ezetimibe and fenofibrate completed the 12-week treatment, and 230 patients receiving ezetimibe and fenofibrate (including 109 who received only ezetimibe during the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups regarding infrequent adverse events. However, the incidence (95 % CI) of clinically significant elevations in serum transaminases (> 3 times ULN) was 4.5 % (1.9; 8.8) and 2.7 % (1.2; 5.4) with fenofibrate monotherapy and ezetimibe plus fenofibrate, respectively, adjusted for treatment effect. Regarding cholecystectomy rates, they were 0.6 % (0.0; 3.1) and 1.7 % (0.6; 4.0) with fenofibrate monotherapy and ezetimibe plus fenofibrate, respectively.
Patients with a history of IHD and ACS
In the IMPROVE-IT study, which included 18,144 patients receiving either ezetimibe/simvastatin 10 mg/40 mg (n = 9,067; of whom 6 % had their dose increased to 10 mg/80 mg) or simvastatin 40 mg (n = 9,077; of whom 27 % had their dose increased from 40 mg to 80 mg), safety profiles were similar over a mean follow-up period of 6 years. The percentage of discontinuations due to adverse events was 10.6 % in patients receiving ezetimibe/simvastatin and 10.1 % in those receiving simvastatin. The incidence of myopathy was 0.2 % with ezetimibe/simvastatin and 0.1 % with simvastatin. Myopathy was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥ 10 times the ULN, or with creatine kinase levels ≥ 5 to < 10 times the ULN on two consecutive measurements. The incidence of rhabdomyolysis was 0.1 % with ezetimibe/simvastatin and 0.2 % with simvastatin. Rhabdomyolysis was defined as muscle weakness or pain of unknown etiology with serum creatine kinase levels ≥ 10 times the ULN in the presence of signs of renal impairment, or ≥ 5 to < 10 times the ULN on two consecutive measurements in the presence of signs of renal impairment, or ≥ 10,000 IU/L in the absence of signs of renal impairment. The incidence of consecutive elevations in transaminase levels (≥ 3 times ULN) was 2.5 % with ezetimibe/simvastatin and 2.3 % with simvastatin (see section "Special warnings and precautions for use"). Adverse events related to the gallbladder occurred in 3.1 % of patients receiving ezetimibe/simvastatin and 3.5 % of those receiving simvastatin. The rate of hospitalization for cholecystectomy was 1.5 % in both treatment groups. Cancer (defined as any malignant neoplasm) was diagnosed in 9.4 % and 9.5 % of patients, respectively.
Patients with chronic kidney disease
In the SHARP study involving over 9,000 patients receiving 10 mg/20 mg ezetimibe/simvastatin daily (n = 4,650) or placebo (n = 4,620), safety profiles were generally comparable over a mean observation period of 4.9 years. Only serious adverse events and treatment discontinuations due to any adverse events were recorded during this study. The rates of discontinuation due to adverse events were comparable (10.4 % in patients receiving ezetimibe/simvastatin vs. 9.8 % in those receiving placebo). The incidence of myopathy/rhabdomyolysis was 0.2 % in patients receiving ezetimibe/simvastatin and 0.1 % in those receiving placebo. Consecutive elevation of transaminase levels (≥ 3 times ULN) occurred in 0.7 % of patients receiving ezetimibe/simvastatin compared to 0.6 % of those receiving placebo. During the study, there were no statistically significant increases in pre-specified adverse events, including cancer (9.4 % with ezetimibe plus simvastatin vs. 9.5 % with placebo), hepatitis, cholecystectomy, or complications of gallstone disease or pancreatitis.
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 trials, 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 those receiving statin alone. Levels normalized after discontinuation of treatment or with continued therapy (see section "Special warnings and precautions for use"). It is known that in clinical trials, increases in CK > 10 times ULN were recorded in 4 out of 1,674 (0.2 %) patients receiving ezetimibe monotherapy and in 1 out of 786 (0.1 %) placebo patients. Similar CK increases were observed in 1 out of 917 (0.1 %) patients receiving ezetimibe with a statin and in 4 out of 929 (0.4 %) patients receiving statin alone. No increase in myopathy or rhabdomyolysis associated with ezetimibe treatment was observed compared to control groups (placebo or statin monotherapy) (see section "Special warnings and precautions for use").
Children
The safety and efficacy of the drug in children (under 18 years of age) have not yet been established.
Rosuvastatin
In children and adolescents 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, adolescents, and adults is similar.
Ezetimibe
Children aged 6 to 17 years
According to published data from a study involving children aged 6 to 10 years with heterozygous familial or non-familial hypercholesterolemia (n = 138), elevations in ALT and/or AST levels (≥ 3 times ULN on consecutive measurements) were observed in 1.1 % (1 participant) of the ezetimibe group compared to 0 % in the placebo group. No cases of elevated CK levels (≥ 10 times ULN) were recorded. No cases of myopathy were observed.
In a separate study involving children aged 10 to 17 years with heterozygous familial hypercholesterolemia (n = 248), elevations in ALT and/or AST levels (≥ 3 times ULN on consecutive measurements) were observed in 3 % (4 patients) of the ezetimibe/simvastatin group compared to 2 % (2 patients) in the simvastatin monotherapy group; CK elevation rates (≥ 10 times ULN) were 2 % (2 patients) and 0 %, respectively. No cases of myopathy were recorded.
This study did not compare rare adverse drug reactions.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of the reach of children.
Packaging.
10 tablets per blister; 3 blisters per carton.
Prescription status. Prescription only.
Manufacturer. EL PEN PHARMACEUTICAL CO. INC.
Manufacturer's location and address of its business site.
95 Marathos Avenue, Pikermi, 190 09, Greece.