ROSTRAL EZ

Dosage Form: Film Coated Tablet

Generic Name: Rosuvastatin Calcium and Ezetimibe

Pharmacopoeia: IP

Strength: 10 /10mg, 20/10 mg

CLINICAL PARTICULARS:

ROSTRAL EZ is Indicated in Adults:

As an adjunct to diet in patients with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).

Alone or as an adjunct to other LDL-C-lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.

Posology

ROSTRAL EZ can be administered within the dosage range of 5mg+10mg to 40mg+10mg as a single daily dose. The recommended starting dose is 5mg+10mg or 10 mg+10mg once per day. The combination of Rosuvastatin + Ezetimibe can be administered at any time of the day, with or without food. Each tablet should be taken with water at the same time daily and is not to be chewed or crushed. Therapy should be individualized according to the target lipid levels, the recommended goal of therapy, and the patient's response. The dose should also consider the potential risk for adverse reactions. A dose adjustment can be made after 4 weeks of therapy where necessary. The usual maximum dose is 40mg+10mg once per day. This combination product is not indicated for first-line use.

Pediatric Population:

The safety and efficacy of ezetimibe + rosuvastatin in children below the age of 18 years have not yet been established.

Elderly:

A start dose of 5 mg rosuvastatin is recommended in patients > 70 years (see section 4.4). The combination is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, should only be done with the mono-components and after setting the appropriate doses the switch to the fixed combination medicinal product of the appropriate strength is possible.

Hepatic Impairment:

No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5 – 6). Treatment with ROSTRAL EZ is not recommended in patients with moderate (Child-Pugh score 7 – 9) or severe (Child-Pugh score > 9) liver dysfunction (see sections 4.4 and 5.2). ROSTRAL EZ is contraindicated in patients with active liver disease.

Renal Impairment:

No dose adjustment is necessary in patients with mild renal impairment. The recommended start dose is rosuvastatin 5 mg in patients with moderate renal impairment (creatinine clearance < 60 ml/min). The fixed combination medicinal product is not suitable for initial therapy. Mono-component preparations should be used to start the treatment or to modify the dose. The ROSTRAL EZ 40 mg / 10 mg dose is contraindicated in patients with moderate renal impairment. The use of ROSTRAL EZ in patients with severe renal impairment is contraindicated for all doses.

Race:

Increased systemic exposure of rosuvastatin has been seen in Asian subjects. The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry. The fixed combination medicinal product is not suitable for initial therapy. Mono-component preparations should be used to start the treatment or to modify the dose. ROSTRAL EZ 40 mg / 10 mg film-coated tablets are contraindicated in these patients.

Genetic polymorphisms: Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have specific types of polymorphisms, a lower daily dose of ROSTRAL EZ is recommended.

Pre-disposing factors to myopathy: The recommended start dose is rosuvastatin 5 mg in patients with pre-disposing factors to myopathy. The fixed combination medicinal product is not suitable for initial therapy. Mono-component preparations should be used to start the treatment or to modify the dose. ROSTRAL EZ 40 mg / 10 mg film-coated tablets are contraindicated in some of these patients.

Concomitant Therapy:

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when ROSTRAL EZ is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir; see sections 4.4 and 4.5). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing ROSTRAL EZ therapy. In situations where co-administration of these medicinal products with ROSTRAL EZ is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered.

Method of Administration:

For oral use. ROSTRAL EZ should be taken each day once at the same time of the day, with or without food. The tablet should be swallowed whole with a drink of water.

Hypersensitivity to the active substances or to any of the excipients.

Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures.

Active liver disease or unexplained persistent elevations in serum transaminases and any serum transaminase elevation exceeding 3× the upper limit of normal (ULN).

In patients with severe renal impairment (creatinine clearance < 30 ml/min). ‒ In patients with myopathy.

in patients receiving concomitant combination of sofosbuvir/ velpatasvir/ voxilaprevir

In patients receiving concomitant ciclosporin (see section 4.5).

The 40 mg / 10 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

Moderate renal impairment (creatinine clearance < 60 ml/min).

Hypothyroidism.

Personal or family history of hereditary muscular disorders.

Previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate.

Alcohol abuse.

Situations where an increase in plasma levels of rosuvastatin may occur.

Asian patients.

Concomitant use of fibrates.

Severe Cutaneous Adverse Reactions:

Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appear, ROSTRAL EZ should be discontinued immediately, and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS or DRESS with the use of ROSTRAL EZ, treatment with rosuvastatin must not be restarted in this patient at any time.

Skeletal Muscle Effects:

Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and with doses > 20 mg. As with other HMGCoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in postmarketing use is higher at the 40 mg dose. In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.

If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, ROSTRAL EZ and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with ROSTRAL EZ should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Creatine Kinase Measurement:

Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (> 5× ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK > 5× ULN, treatment should not be started.

Liver Disease and Alcohol:

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

Renal Effects:

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease (see section 4.8). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.

Diabetes Mellitus:

Some evidence suggests that statins as a class raise blood glucose and, in some patients, at high risk of future diabetes, may produce a level of hyperglycemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 – 6.9 mmol/l, BMI > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Race:

Pharmacokinetic studies show an increase in exposure of rosuvastatin in Asian subjects compared with Caucasians.

Pediatric Population:

The safety and efficacy of ezetimibe plus rosuvastatin in children below the age of 18 years have not yet been established, therefore its use is not recommended in this age group.

Interaction With Other Medicinal Products and Other Forms of Interaction

Antacids:

Simultaneous administration of rosuvastatin and an antacid suspension containing aluminum and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. Administer the combination of Rosuvastatin + Ezetimibe at least 2 hours before the antacid.

Darolutamide:

Darolutamide increases the rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use.

Regorafenib:

Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. Cholestyramine Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%.

Bile Acid Sequestrants:

In patients taking a bile acid sequestrants administer the combination of Rosuvastatin +Ezetimibe at least 2 hours before or at least 4 hours after the bile acid sequestrants.

Niacin:

Concomitant use of niacin with rosuvastatin may cause myopathy and rhabdomyolysis.

Fenofibrates:

Fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Fenofibrate may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors. Gemfibrozil:

Concomitant gemfibrozil administration results in the increase of total ezetimibe concentrations approximately 1.7-fold. Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC. Gemfibrozil may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors.

Fibric Acid Derivatives:

Other fibric acids, including nicotinic acid, may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors.

Anticoagulant:

Co-administration of rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in INR (> 4, baseline 2-3). In patients taking vitamin K antagonists and rosuvastatin concomitantly, INR should be determined before starting the combination of Rosuvastatin + Ezetimibe and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Oral Contraceptives:

Co-administration of oral contraceptives with rosuvastatin resulted in an increase in plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%, respectively.

Inhibitors of Breast Cancer Resistance Protein (BCRP):

Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

Colchicine:

Cases of myopathy, including rhabdomyolysis, have been reported with HMG CoA reductase inhibitors, including rosuvastatin, co-administered with colchicine.

Daptomycin:

The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin.

Erythromycin:

Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC0-t and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase ingut motility caused by erythromycin. Overdosage In the event of an overdose, symptomatic and supportive measures should be employed. In symptomatic patients, monitor serum creatinine, BUN, creatinine phosphokinase and urine myoglobin for indications of renal impairment secondary to rhabdomyolysis. Liver function tests should be performed in symptomatic patients. Hemodialysis is unlikely to be of benefit.

ROSTRAL EZ is contraindicated during pregnancy and breast-feeding. Women of childbearing potential should use appropriate contraceptive measures.

Pregnancy:

No clinical data’s are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryo fetal development, birth or postnatal development. Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the fetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity. If a patient becomes pregnant during use of ROSTRAL EZ, treatment should be discontinued immediately.

Breast-Feeding:

Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk. Rosuvastatin is excreted in the milk of rats. There is no data with respect to excretion in milk in humans.

Fertility:

No clinical trial data are available on the effects of ezetimibe or rosuvastatin on human fertility. Ezetimibe had no effects on the fertility of male or female rats, rosuvastatin at higher doses showed testicular toxicity in monkeys and dogs.

Effects On Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been carried out. However, when driving vehicles or operating machines, it should be considered that dizziness has been reported.

The adverse reactions seen with rosuvastatin and Ezetimibe are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse reactions. The overall incidence of side effects was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.

According to available data 1,200 patients took rosuvastatin and ezetimibe combination in clinical studies. As reported in published literature, the most frequent common adverse events related to rosuvastatin + ezetimibe combination treatment in hypercholesterolemia patients are hepatic transaminases, gastrointestinal problems and muscle pain. These are known undesirable effects of the active substances. However, a pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out.

Tabulated list of Adverse Reactions:

The frequencies of adverse reactions are ranked according to the following convention: 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) and not known (cannot be estimated from the available data).

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal Effects:

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in < 1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift (from none or trace to +) was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease. Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low.

Pediatric Population:

The safety and efficacy of ezetimibe + rosuvastatin in children below the age of 18 years have not yet been established.

Liver Effects:

As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; most cases were mild, asymptomatic and transient. The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) are higher at the 40 mg dose.

In the event of an overdose, symptomatic and supportive measures should be employed.

Ezetimibe:

In clinical studies, administration of ezetimibe, 50 mg/day, to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5,000 mg/kg of ezetimibe in rats and mice and 3,000 mg/kg in dogs. A few cases of overdosage with ezetimibe have been reported: most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Rosuvastatin:

There is no published literature data on rosuvastatin overdose. There is no specific treatment in the event of overdose with rosuvastatin. Liver function and CK levels should be monitored. Hemodialysis is unlikely to be of benefit.

Pharmacodynamics Properties

Pharmacotherapeutic Group: Lipid modifying agents; combinations of various lipid modifying agents.

Mechanism of Action:

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. ROSTRAL EZ contains ezetimibe and rosuvastatin, 2 lipid-lowering compounds with complementary mechanisms of action. ROSTRAL EZ reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-HDL-C, and increases high-density lipoprotein cholesterol (HDL-C) through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe:

Ezetimibe is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g. statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.

Rosuvastatin:

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic Effects:

Ezetimibe:

Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2-week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.

Rosuvastatin:

Rosuvastatin reduces elevated LDL-C, total-C and TG and increases HDL-cholesterol. It also lowers Apo B, non-HDL-C, VLDL-C, VLDL-TG and increases Apo A-I (see Table 2). Rosuvastatin also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the Apo B / Apo A-I ratios.

Clinical Efficacy and Safety:

Ezetimibe:

In controlled clinical studies, ezetimibe, either as monotherapy or co-administered with a statin significantly reduced total-C, LDL-C, Apo B, and TG and increased HDL-C in patients with hypercholesterolaemia.

Rosuvastatin:

Rosuvastatin is effective in adults with hypercholesterolaemia, with and without hypertriglyceridaemia, regardless of race, sex, or age and in special populations such as diabetics, or patients with familial hypercholesterolaemia.

Ezetimibe + rosuvastatin combination:

A 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy vs. up-titration of rosuvastatin 5 – 10 mg or 10 – 20 mg (N = 440). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL-C by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL-C by 5.7% (between-group difference of 15.2%, p < 0.001). Individually, ezetimibe + rosuvastatin 5 mg reduced LDL-C more than did rosuvastatin 10 mg (12.3% difference, p < 0.001), and ezetimibe + rosuvastatin 10 mg reduced LDL-C more than did rosuvastatin 20 mg (17.5% difference, p < 0.001). A 6-week, randomized study was designed to investigate the efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg in patients at high risk of coronary heart disease (N = 469). Significantly more patients receiving ezetimibe + rosuvastatin than rosuvastatin alone achieved their ATP III LDL-C goal (< 100 mg/dl, 94.0% vs 79.1%, p < 0.001). Rosuvastatin 40 mg was effective at improving the atherogenic lipid profile in this high-risk population. A randomized, open-label, 12-week study investigated the level of LDL reduction in each treatment arm (ezetimibe + rosuvastatin 10 mg / 10 mg, 10 mg / 20 mg; ezetimibe + simvastatin 10 mg, 10 mg / 80 mg). The reduction from baseline with the low dose rosuvastatin combinations was 59.7%, significantly superior to the low dose simvastatin combinations, 55.2% (p < 0.05). Treatment with the high-dose rosuvastatin combo reduced LDL-C 63.5% compared with a reduction of 57.4% with the high-dose simvastatin combination (p < 0.001).

Pediatric Population:

The European Medicines Agency has waived the obligation to submit the results of studies with ROSTRAL EZ in all subsets of the paediatric population in the treatment of elevated cholesterol.

Rosuvastatin and ezetimibe combination therapy Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects. A pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out.

Absorption

Rosuvastatin:

In clinical pharmacology studies in males, peak plasma concentrations of rosuvastatin were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%. The AUC of rosuvastatin does not differ following evening or morning drug administration. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin.

Ezetimibe:

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide means Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ezetimibe 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.

Distribution

Rosuvastatin:

Mean volume of distribution at steady state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Ezetimibe:

Ezetimibe and ezetimibe-glucuronide are bound (>90%) to human plasma proteins.

Metabolism

Rosuvastatin:

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 \ 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

Ezetimibe:

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe- glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe- glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Excretion

Rosuvastatin:

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

Ezetimibe:

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10- day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 – 2,000 times the AUC level for the active metabolites). The co-administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no genotoxic potential.

Ezetimibe:

Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for 4 weeks with ezetimibe (≥ 0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 – 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out. Long-term carcinogenicity tests on ezetimibe were negative.

Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day.

Rosuvastatin

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

Do not store above 30°C temperature and protected from direct sunlight and moisture.