This Site Is Intended For US Healthcare Professionals Only

Prescribing Information Important Safety Information

This Site Is Intended For US Healthcare Professionals Only

Prescribing Information Important Safety Information

Additional Trials with Rosuvastatin and Ezetimibe

Roszet is a combination of rosuvastatin and ezetimibe, which have been studied together extensively. Some key studies for this combination are listed here.

Ballantyne et al: Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study)

American Journal of Cardiology 2007;99:673– 680

Abstract

Patients at risk of coronary heart disease may not achieve recommended low-density lipoprotein (LDL) cholesterol goals on statin monotherapy. This 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. Four hundred sixty-nine patients were randomly assigned to rosuvastatin alone or in combination with ezetimibe for 6 weeks. The primary end point was the percentage of patients achieving the Adult Treatment Panel III (ATP III) LDL cholesterol goal (<100 mg/dl) at week 6. Secondary end points included the percentage of patients achieving other ATP III and 2003 European lipid goals, changes from baseline in lipid, lipoprotein, and inflammatory parameters, and safety and tolerability. Significantly more patients receiving rosuvastatin/ezetimibe than rosuvastatin alone achieved their ATP III LDL cholesterol goal (<100 mg/dl, 94.0% vs 79.1%, p <0.001) and the optional LDL cholesterol goal (<70 mg/dl) for very high-risk patients (79.6% vs 35.0%, p <0.001). The combination of rosuvastatin/ezetimibe reduced LDL cholesterol significantly more than rosuvastatin (−69.8% vs −57.1%, p <0.001). Other components of the lipid/lipoprotein profile were also significantly (p <0.001) improved with rosuvastatin/ezetimibe. Both treatments generally were well tolerated. Rosuvastatin 40 mg was effective at improving the atherogenic lipid profile in this high-risk population. Combination rosuvastatin with ezetimibe 10 mg enabled greater decreases in LDL cholesterol and allowed more patients to achieve LDL cholesterol goals. In conclusion, rosuvastatin plus ezetimibe may improve the management of high-risk patients who cannot achieve goal on maximal statin monotherapy.

Ballantyne et al: Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study

Atherosclerosis 232 (2014) 86e93

Abstract

Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent. Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks. Significantly greater (p < 0.05) reductions in LDL-C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ∼10–14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced β-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable. Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe.

Bays et al: Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study)

Am J Cardiol 2011;108:523–530

Abstract

The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk.

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Important Safety Information

Indications and Usage
ROSZET 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.
Important Safety Information
Contraindications: ROSZET is contraindicated in patients with active liver disease or decompensated cirrhosis, and hypersensitivity to any component of this product.
Myopathy and Rhabdomyolysis: ROSZET may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase [CK] above ten times the upper limit of normal) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including rosuvastatin.
Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs including other lipid-lowering therapies, and higher ROSZET dosage; Asian patients on ROSZET may be at higher risk for myopathy. The myopathy risk is greater in patients taking ROSZET 40 mg/10 mg daily compared with lower ROSZET dosages.
The concomitant use of ROSZET with cyclosporine or gemfibrozil is not recommended. ROSZET dosage modifications are recommended for patients taking certain anti-viral medications, darolutamide, and regorafenib. Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis.
Discontinue ROSZET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if ROSZET is discontinued. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Immune-Mediated Necrotizing Myopathy: There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
Hepatic Dysfunction: Increases in serum transaminases have occurred with rosuvastatin. Consider liver enzyme testing before ROSZET initiation and thereafter, when clinically indicated. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ROSZET.
Proteinuria and Hematuria: Dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, consider a dose reduction for patients on ROSZET therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
HbA1c and Fasting Serum Glucose: Increases in HbA1c and fasting serum glucose levels have been reported with statins, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus.
Adverse Reactions: Most frequent adverse reactions (incidence >2% and greater than placebo) for rosuvastatin in clinical trials are: headache, nausea, myalgia, asthenia, dizziness, asthenia, constipation, and abdominal pain. Other adverse reactions reported in clinical studies were hypersensitivity (including rash, pruritus, urticaria, and angioedema), and pancreatitis. For ezetimibe co-administered with a statin most frequent adverse reactions (incidence >2% and greater than statin alone) are nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue. For ezetimibe monotherapy most frequent adverse reactions (incidence >2% and greater than placebo) are upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue and influenza.
There have been rare post marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including ROSZET. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation.
Drug Interactions:
Gemfibrozil or Cyclosporin: Avoid concomitant use with ROSZET.
Antivirals: Avoid concomitant use or adjust dose of ROSZET.
Darolutamide: Do not exceed ROSZET 5 mg/10 mg once daily.
Regorafenib: Do not exceed ROSZET 10 mg/10 mg once daily.
Fenofibrates, Niacin, Colchicine: Consider risks and benefits of concomitant use with ROSZET.
Warfarin: Obtain INR before ROSZET initiation and monitor INR during ROSZET initiation or dosage adjustment.
Use in Specific Populations: Discontinue ROSZET when pregnancy is recognized as it may cause fetal harm. Breastfeeding is not recommended during treatment with ROSZET.
Please see full Prescribing Information for ROSZET
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Important Safety Information
Indications and Usage
ROSZET 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.
Important Safety Information
Contraindications: ROSZET is contraindicated in patients with active liver disease or decompensated cirrhosis, and hypersensitivity to any component of this product.
Myopathy and Rhabdomyolysis: ROSZET may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase [CK] above ten times the upper limit of normal) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including rosuvastatin.
Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs including other lipid-lowering therapies, and higher ROSZET dosage; Asian patients on ROSZET may be at higher risk for myopathy. The myopathy risk is greater in patients taking ROSZET 40 mg/10 mg daily compared with lower ROSZET dosages.
The concomitant use of ROSZET with cyclosporine or gemfibrozil is not recommended. ROSZET dosage modifications are recommended for patients taking certain anti-viral medications, darolutamide, and regorafenib. Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis.
Discontinue ROSZET if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if ROSZET is discontinued. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Immune-Mediated Necrotizing Myopathy: There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
Hepatic Dysfunction: Increases in serum transaminases have occurred with rosuvastatin. Consider liver enzyme testing before ROSZET initiation and thereafter, when clinically indicated. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ROSZET.
Proteinuria and Hematuria: Dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients. These findings were more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, consider a dose reduction for patients on ROSZET therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
HbA1c and Fasting Serum Glucose: Increases in HbA1c and fasting serum glucose levels have been reported with statins, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus.
Adverse Reactions: Most frequent adverse reactions (incidence >2% and greater than placebo) for rosuvastatin in clinical trials are: headache, nausea, myalgia, asthenia, dizziness, asthenia, constipation, and abdominal pain. Other adverse reactions reported in clinical studies were hypersensitivity (including rash, pruritus, urticaria, and angioedema), and pancreatitis. For ezetimibe co-administered with a statin most frequent adverse reactions (incidence >2% and greater than statin alone) are nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue. For ezetimibe monotherapy most frequent adverse reactions (incidence >2% and greater than placebo) are upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue and influenza.
There have been rare post marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including ROSZET. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation.
Drug Interactions:
Gemfibrozil or Cyclosporin: Avoid concomitant use with ROSZET.
Antivirals: Avoid concomitant use or adjust dose of ROSZET.
Darolutamide: Do not exceed ROSZET 5 mg/10 mg once daily.
Regorafenib: Do not exceed ROSZET 10 mg/10 mg once daily.
Fenofibrates, Niacin, Colchicine: Consider risks and benefits of concomitant use with ROSZET.
Warfarin: Obtain INR before ROSZET initiation and monitor INR during ROSZET initiation or dosage adjustment.
Use in Specific Populations: Discontinue ROSZET when pregnancy is recognized as it may cause fetal harm. Breastfeeding is not recommended during treatment with ROSZET.
Please see full Prescribing Information for ROSZET