Label: ROSUVASTATIN AND EZETIMIBE tablet

  • NDC Code(s): 82120-125-30, 82120-126-30, 82120-127-30, 82120-128-30
  • Packager: SCOV3 LLC
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application Authorized Generic

Drug Label Information

Updated August 18, 2021

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use ROSUVASTATIN AND EZETIMIBE tablets safely and effectively. See full prescribing information for rosuvastatin and ezetimibe tablets.

    ROSUVASTATIN AND EZETIMIBE tablets, for oral use
    Initial U.S. Approval: 2021

    INDICATIONS AND USAGE

    Rosuvastatin and ezetimibe tablets is a combination of rosuvastatin, an HMG CoA-reductase inhibitor (statin), and ezetimibe, a dietary cholesterol absorption inhibitor, indicated in adults:

    • As an adjunct to diet in patients with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL- C). (1)
    • Alone or as an adjunct to other LDL-C lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C. (1)

    DOSAGE AND ADMINISTRATION

    • Swallow tablets whole; do not crush, dissolve or chew. (2.1)
    • Dosage range is 5 mg/10 mg to 40 mg/10 mg once daily. (2.1)
    • Recommended dosage depends on the indication for usage, LDL- C, and individual risk for cardiovascular events. (2.1)
    • Assess LDL-C as early as 2 weeks after initiating rosuvastatin and ezetimibe tablets, and adjust dosage as necessary. (2.1)
    • Asian patients: Initiate at 5 mg/10 mg once daily. (2.2, 5.1, 8.8)
    • Patients with severe renal impairment (not on hemodialysis): initiate at 5 mg/10 mg once daily; do not exceed 10 mg/10 mg once daily. (2.3, 5.1, 8.6)
    • Administer rosuvastatin and ezetimibe tablets at least 2 hours before or 4 hours after administration of a bile acid sequestrant. (2.4, 7.2)
    • Administer rosuvastatin and ezetimibe tablets at least 2 hours before administration of an aluminum and magnesium hydroxide combination antacid. (2.4, 7.2)

    DOSAGE FORMS AND STRENGTHS

    Tablets (rosuvastatin/ezetimibe): 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg, 40 mg/10 mg. (3)

    CONTRAINDICATIONS

    • Active liver failure or decompensated cirrhosis (4, 5.3)
    • Hypersensitivity to any component of rosuvastatin and ezetimibe tablets (4)

    WARNINGS AND PRECAUTIONS

    • Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher rosuvastatin and ezetimibe tablets dosage. Discontinue rosuvastatin and ezetimibe tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue rosuvastatin and ezetimibe tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing rosuvastatin and ezetimibe tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. (5.1, 7, 8.5, 8.6)
    • Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. (5.2)
    • Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme tests before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue rosuvastatin and ezetimibe tablets. (4, 5.3, 8.7)

    ADVERSE REACTIONS

    Most common adverse reactions for:

    • Rosuvastatin (incidence ≥2% and greater than placebo) are headache, nausea, myalgia, arthralgia, dizziness, asthenia, constipation, and abdominal pain. (6.1)
    • Ezetimibe (incidence ≥2% and greater than placebo) are upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza. (6.1)
    • Ezetimibe co-administered with a statin (incidence ≥2% and greater than statin alone) are nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, pain in extremity, and fatigue. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact SCOV3 LLC at 1-888-210-7740 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    • Gemfibrozil or Cyclosporin: Avoid concomitant use with rosuvastatin and ezetimibe tablets. (5.1, 7.1)
    • Antivirals: Avoid concomitant use of rosuvastatin and ezetimibe tablets with certain antivirals and adjust the dose of rosuvastatin and ezetimibe tablets with other antivirals. See Full Prescribing Information for details on concomitant use of rosuvastatin and ezetimibe tablets with antivirals. (2.4, 7.1)
    • Darolutamide: Do not exceed rosuvastatin and ezetimibe tablets 5 mg/10 mg once daily. (5.1, 7.1)
    • Regorafenib: Do not exceed rosuvastatin and ezetimibe tablets 10 mg/10 mg once daily. (5.1, 7.1)
    • Fenofibrates, Niacin, Colchine: Consider the risks and benefits of concomitant use with rosuvastatin and ezetimibe tablets. (5.1, 7.1)
    • Warfarin: Obtain INR before rosuvastatin and ezetimibe tablets initiation and monitor INR during rosuvastatin and ezetimibe tablets dosage initiation or adjustment. (7.3)

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: May cause fetal harm. (8.1)
    • Lactation: Breastfeeding not recommended during treatment with rosuvastatin and ezetimibe tablets. (8.2)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 7/2021

  • Table of Contents

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage and Administration Information

    2.2 Recommended Dosage in Asian Patients

    2.3 Recommended Dosage in Patients with Renal Impairment

    2.4 Dosage and Administration Modifications Due to Drug Interactions

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Myopathy and Rhabdomyolysis

    5.2 Immune-Mediated Necrotizing Myopathy

    5.3 Hepatic Dysfunction

    5.4 Proteinuria and Hematuria

    5.5 Increases in HbA1c and Fasting Serum Glucose Levels

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Postmarketing Experience

    7 DRUG INTERACTIONS

    7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin and Ezetimibe Tablets

    7.2 Drug Interactions that Decrease the Efficacy of Rosuvastatin and Ezetimibe Tablets

    7.3 Rosuvastatin and Ezetimibe Tablets Effects on Other Drugs

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Renal Impairment

    8.7 Hepatic Impairment

    8.8 Asian Population

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.2 Pharmacodynamics

    12.3 Pharmacokinetics

    12.5 Pharmacogenomics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    14 CLINICAL STUDIES

    14.1 Primary Hyperlipidemia

    14.2 HoFH

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
  • 1 INDICATIONS AND USAGE

    Rosuvastatin and ezetimibe tablets 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.
  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage and Administration Information

    • Swallow rosuvastatin and ezetimibe tablets whole at any time of day, with or without food. Do not crush, dissolve, or chew tablets.
    • The dosage range is 5 mg/10 mg to 40 mg/10 mg once daily.
    • The recommended dose of rosuvastatin and ezetimibe tablets depends on a patient’s indication for usage, LDL- C, and individual risk for cardiovascular events.
    • The starting dosage for patients switching to rosuvastatin and ezetimibe tablets from co-administration of a statin and ezetimibe is based on an equivalent dose of rosuvastatin and 10 mg of ezetimibe.
    • Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating rosuvastatin and ezetimibe tablets, and adjust the dosage if necessary.

    2.2 Recommended Dosage in Asian Patients

    Initiate rosuvastatin and ezetimibe tablets at 5 mg/10 mg daily due to increased rosuvastatin plasma concentrations. Consider the risk/benefit when treating Asian patients not adequately controlled at doses up to 20 mg/10 mg once daily [see Warnings and Precautions (5.1), Use in Specific Populations (8.8), and Clinical Pharmacology (12.3)].

    2.3 Recommended Dosage in Patients with Renal Impairment

    In patients with severe renal impairment (CLcr less than 30 mL/min/1.73 m2) not on hemodialysis, the recommended starting dosage is 5 mg/10 mg once daily and should not exceed 10 mg/10 mg once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

    There are no dosage adjustment recommendations for patients with mild and moderate renal impairment.

    2.4 Dosage and Administration Modifications Due to Drug Interactions

    • In patients taking a bile acid sequestrant, administer rosuvastatin and ezetimibe tablets at least 2 hours before or 4 hours after the bile acid sequestrant [see Drug Interactions (7.2)].
    • When taking rosuvastatin and ezetimibe tablets with an aluminum and magnesium hydroxide combination antacid, administer rosuvastatin and ezetimibe tablets at least 2 hours before the antacid [see Drug Interactions (7.2)].
    • Concomitant use of rosuvastatin and ezetimibe tablets with the following drugs requires dosage modifications of rosuvastatin and ezetimibe tablets [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

    Darolutamide
    Do not exceed rosuvastatin and ezetimibe tablets 5 mg/10 mg once daily.

    Regorafenib
    Do not exceed rosuvastatin and ezetimibe tablets 10 mg/10 mg once daily.

    Antiviral Medications
    Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and ledipasvir/sofosbuvir with rosuvastatin and ezetimibe tablets is not recommended.

    In patients taking simeprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, atazanavir/ritonavir, and lopinavir/ritonavir initiate rosuvastatin and ezetimibe tablets at 5 mg/10 mg once daily. Do not exceed rosuvastatin and ezetimibe tablets 10 mg/10 mg once daily.

    No dose adjustment is needed for concomitant use with fosamprenavir/ritonavir or tipranavir/ritonavir.

  • 3 DOSAGE FORMS AND STRENGTHS

    Rosuvastatin and ezetimibe tablets are available as follows:

    StrengthContentsDescription
     5 mg/10 mg rosuvastatin 5 mg/ezetimibe 10 mg round pink biconvex tablets with “5” embossed on one side
     10 mg/10 mg rosuvastatin 10 mg/ezetimibe 10 mg round pink biconvex tablets with “AL” embossed on one side
     20 mg/10 mg rosuvastatin 20 mg/ezetimibe 10 mg round pink biconvex tablets with “II” embossed on one side
     40 mg/10 mg rosuvastatin 40 mg/ezetimibe 10 mg round pink biconvex tablets with “77” embossed on one side

  • 4 CONTRAINDICATIONS

    Rosuvastatin and ezetimibe tablets is contraindicated in patients with:

    • Acute liver failure or decompensated cirrhosis.
    • Hypersensitivity to rosuvastatin, ezetimibe, or any excipients in rosuvastatin and ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, and erythema multiforme have been reported [see Adverse Reactions (6)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Myopathy and Rhabdomyolysis

    Rosuvastatin and ezetimibe tablets 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
    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 rosuvastatin and ezetimibe tablets dosage; Asian patients on rosuvastatin and ezetimibe tablets may be at higher risk for myopathy [see Drug Interactions (7.1) and Use in Specific Populations (8.8)]. The myopathy risk is greater in patients taking rosuvastatin and ezetimibe tablets 40 mg/10 mg daily compared with lower rosuvastatin and ezetimibe tablets dosages.

    Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
    The concomitant use of rosuvastatin and ezetimibe tablets with cyclosporine or gemfibrozil is not recommended. Rosuvastatin and ezetimibe tablets dosage modifications are recommended for patients taking certain antiviral medications, darolutamide, and regorafenib [see Dosage and Administration (2.4)]. Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

    Discontinue rosuvastatin and ezetimibe tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if rosuvastatin and ezetimibe tablets is discontinued. Temporarily discontinue rosuvastatin and ezetimibe tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

    Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the rosuvastatin and ezetimibe tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

    5.2 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. Additional neuromuscular and serologic testing may be necessary. 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.

    5.3 Hepatic Dysfunction

    Increases in serum transaminases have occurred with rosuvastatin [see Adverse Reactions (6.1)]. In most cases, the elevations appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to more than three times the ULN occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo. Marked persistent increases of hepatic transaminases have also occurred with rosuvastatin. There have been rare postmarketing 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.

    Consider liver enzyme testing before rosuvastatin and ezetimibe tablets initiation and thereafter, when clinically indicated. Rosuvastatin and ezetimibe tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue rosuvastatin and ezetimibe tablets.

    5.4 Proteinuria and Hematuria

    In the rosuvastatin clinical trial program, 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 rosuvastatin and ezetimibe tablets therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

    5.5 Increases in HbA1c and Fasting Serum Glucose Levels

    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. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [See Adverse Reactions (6.1)].

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are discussed in greater detail in other sections of the label:

    • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]
    • Hepatic Dysfunction [see Warnings and Precautions (5.3)]

    6.1 Clinical Trials Experience

    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

    Rosuvastatin
    In double-blind, controlled (placebo- or active-controlled) clinical trials of rosuvastatin, 5394 patients with primary hyperlipidemia were treated for a duration of up to 12 weeks. Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1.

    Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with Rosuvastatin and Greater than Placebo in Placebo-Controlled Trials

    Adverse

    Reactions

    Placebo

    (N=382)

    %

    Total Rosuvastatin 5 mg-40 mg

    (N=744)

    %

     Headache 5.0 5.5
     Nausea  3.1 3.4
     Myalgia  1.3 2.8
     Asthenia  2.6 2.7
     Constipation  2.4 2.4

    Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema), and pancreatitis.

    In a double-blind, placebo-controlled trial with mean treatment duration of 1.7 years, 981 participants were treated with rosuvastatin 40 mg (n=700) or placebo (n=281). The most common adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

    Table 2. Adverse Reactions Occurring in ≥2% of Patients Treated with Rosuvastatin and Greater than Placebo

    Adverse Reactions

    Placebo

    (N=281)

    %

    Rosuvastatin 40 mg

    (N=700)

    %

     Myalgia 12.1 12.7
     Arthralgia 7.1 10.1
     Headache  5.3 6.4
     Dizziness 2.8 4.0
     Increased CPK 0.7 2.6
     Abdominal pain 1.8  2.4
     ALT >3x ULN1 0.7 2.2

    1 Frequency recorded as abnormal laboratory value.

    In a double-blind, placebo-controlled trial with mean treatment duration of 2 years, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901). There was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c >6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients.

    Laboratory Tests
    The following laboratory abnormalities have been reported in clinical studies of rosuvastatin: dipstick- positive proteinuria and microscopic hematuria; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.

    Ezetimibe Monotherapy
    In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary hyperlipidemia (50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ezetimibe for a median treatment duration of 12 weeks. Adverse reactions reported in ≥2% of patients treated with ezetimibe and at an incidence greater than placebo are shown in Table 3.

    Table 3: Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Greater than Placebo in Placebo-Controlled Trials

    Adverse Reactions

    Placebo

    (N=1159)

    %

    Ezetimibe

    (N=2396)

    %

     Upper respiratory tract infection2.54.3
     Diarrhea3.7 4.1 
     Arthralgia2.2 3.0 
     Sinusitis2.2 2.8 
     Pain in extremity2.5 2.7 
     Fatigue1.5 2.4 
     Influenza1.5 2.0 

    The incidence of consecutive elevations (≥3x ULN) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).

    Ezetimibe Combination with Statins
    In 28 double-blind, controlled (placebo- or active-controlled) clinical trials, 11,308 patients with primary hyperlipidemia (48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with ezetimibe concurrently with or added to ongoing statin therapy for a median treatment duration of 8 weeks. Clinical adverse reactions reported in ≥2% of patients treated with ezetimibe + statin and at an incidence greater than statin are shown in Table 4.

    Table 4: Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe Coadministered with a Statin and at an Incidence Greater than Statin

    Adverse Reactions

    All Statins1

    (N=9361)

    %

    Ezetimibe + All Statins1

    (N=2396)

    %

     Nasopharyngitis3.33.7 
     Myalgia 2.7 3.2 
     Upper respiratory tract infection2.8 2.9 
     Arthralgia2.4 2.6 
     Diarrhea2.2 2.5 
     Back pain 2.3 2.4 
     Influenza2.1 2.2 
     Pain in extermity1.9 2.1 
     Fatigue1.6 2.0 

    1 All Statins = all doses of statins

    The incidence of consecutive increased transaminases (≥3x ULN) was higher in patients receiving ezetimibe administered with statins (1.3%) than in patients treated with statins alone (0.4%). These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of rosuvastatin and ezetimibe. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Rosuvastatin
    Arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease and gynecomastia. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. There have been rare post marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

    Ezetimibe
    Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis; elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis; nausea; dizziness; paresthesia; depression; headache; cholelithiasis; cholecystitis.

  • 7 DRUG INTERACTIONS

    7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin and Ezetimibe Tablets

    Rosuvastatin is a substrate of CYP2C9 and transporters (such as OATP1B1, BCRP). Rosuvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP2C9 and transporters. Table 5 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with rosuvastatin and ezetimibe tablets and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

    Table 5: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Rosuvastatin and Ezetimibe Tablets

     Cyclosporine or Gemfibrozil 
    Clinical Impact:Cyclosporine increased rosuvastatin exposure 7-fold. In addition, ezetimibe and cyclosporine used concomitantly can increase exposure to both ezetimibe and cyclosporine. Gemfibrozil significantly increased rosuvastatin exposure and gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with rosuvastatin and ezetimibe tablets.
    Intervention:Avoid concomitant use of cyclosporine or gemfibrozil with rosuvastatin and ezetimibe tablets.
     Anti-Viral Medications 
    Clinical Impact:Rosuvastatin plasma levels were significantly increased with concomitant administration of many anti-viral drugs, which increases the risk of myopathy and rhabdomyolysis.
    Intervention:

    Avoid concomitant use of sofosbuvir/velpatasvir/voxilaprevir and ledipasvir/sofosbuvir with rosuvastatin and ezetimibe tablets.

    In patients taking simeprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, atazanavir/ritonavir, and lopinavir/ritonavir initiate with a dose of rosuvastatin and ezetimibe tablets 5 mg/10 mg once daily, and do not exceed a dose of rosuvastatin and ezetimibe tablets 10 mg/10 mg once daily [see Dosage and Administration (2.4)].

    No dose adjustment is needed for concomitant use with fosamprenavir/ritonavir or tipranavir/ritonavir.

    Monitor all patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward titration of either drug.

     Darolutamide 
    Clinical Impact:Darolutamide increased rosuvastatin exposure more than 5-fold. The risk of myopathy and rhabdomyolysis is increased with concomitant use.
    Intervention:In patients taking darolutamide, do not exceed a dose of rosuvastatin and ezetimibe tablets 5 mg/10 mg once daily [see Dosage and Administration (2.4)].
     Regorafenib 
    Clinical Impact:Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy.
    Intervention:In patients taking regorafenib, do not exceed a dose of rosuvastatin and ezetimibe tablets 10 mg/10 mg once daily [see Dosage and Administration (2.4)].
     Fenofibrates (e.g., fenofibrate and fenofibric acid) 
    Clinical Impact:Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with rosuvastatin and ezetimibe tablets.
    Intervention:Consider if the benefit of using fibrates concomitantly with rosuvastatin and ezetimibe tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
     Niacin 
    Clinical Impact:Cases of myopathy and rhabdomyolysis have occurred with concomitant use of niacin with rosuvastatin.
    Intervention:Consider if the benefit of using niacin concomitantly with rosuvastatin and ezetimibe tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
     Colchicine
    Clinical Impact:Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with rosuvastatin and ezetimibe tablets
    Intervention:Consider if the benefit of using colchicine concomitantly with rosuvastatin and ezetimibe tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

    7.2 Drug Interactions that Decrease the Efficacy of Rosuvastatin and Ezetimibe Tablets

    Table 6 presents drug interactions that may decrease the efficacy of rosuvastatin and ezetimibe tablets and instructions for preventing or managing them.

    Table 6: Drug Interactions that Decrease the Efficacy of Rosuvastatin and Ezetimibe Tablets

     Bile Acid Sequestrants
    Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe approximately 55%. The incremental   LDL-C reduction due to adding ezetimibe may be attenuated by coadminstration with cholestyramine. [see Clinical  Pharmacology (12.3)].
    Intervention: In patients taking a bile acid sequestrant, administer rosuvastatin and ezetimibe tablets at least 2 hours before or at least 4 hours after the bile acid sequestrant [see Dosage and Administration (2.4)].
     Antacid
    Clinical Impact: Concomitant aluminum and magnesium hydroxide combination antacid administration decreased the mean exposure of rosuvastatin 50% and total ezetimibe 4%. The incremental LDL-C reduction due to adding rosuvastatin and ezetimibe tablets may be attenuated by coadministration with antacid. [see Clinical Pharmacology (12.3)].
    Intervention: In patients taking antacid, administer rosuvastatin and ezetimibe tablets 2 hours after the antacid [see Dosage and Administration (2.4)].

    7.3 Rosuvastatin and Ezetimibe Tablets Effects on Other Drugs

    Table 7 presents rosuvastatin and ezetimibe tablets effect on other drugs and instructions for preventing or managing them.

    Table 7: Rosuvastatin and Ezetimibe Tablets Effects on Other Drugs

      Warfarin
    Clinical Impact:Rosuvastatin significantly increased the INR in patients receiving coumarin anticoagulants [see Clinical Pharmacology (12.3)].
    Intervention: In patients taking warfarin, obtain an INR before starting rosuvastatin and ezetimibe tablets and frequently enough after initiation, dose titration or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary
    Discontinue rosuvastatin and ezetimibe tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Rosuvastatin and ezetimibe tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, rosuvastatin and ezetimibe tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

    Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with rosuvastatin use in pregnant women are insufficient to determine if there is a drug- associated risk of miscarriage (see Data). In animal reproduction studies, oral administration of rosuvastatin to pregnant rats and rabbits during organogenesis at doses equivalent to the maximum recommended human dose (MRHD) of 40 mg/day resulted in no adverse developmental effects (see Data).

    There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of ezetimibe to pregnant rats and rabbits during organogenesis at doses 10 and 150 times, respectively, the MRHD resulted in no adverse developmental effects (see Data).

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

    Data
    Human Data
    A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

    Animal Data

    Rosuvastatin
    Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively).

    In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC).

    In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area).

    In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area).

    Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18.

    Ezetimibe
    In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats (gestation days 6-15) and rabbits (gestation days 7-19), there was no evidence of maternal toxicity or embryolethality at any dose tested (250, 500, 1000 mg/kg/day) at exposures equivalent to 10 and 150 times the clinical exposure, based on AUC, in rats and rabbits. In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). The animal-to-human exposure multiple for total ezetimibe at the no observed effect level was 6 times for rat and 134 times for rabbit. Fetal exposure to ezetimibe (conjugated and unconjugated) was confirmed in subsequent placental transfer studies conducted using a maternal dose of 1000 mg/kg/day. The fetal maternal plasma exposure ratio (total ezetimibe) was 1.5 for rats on gestation day 20 and 0.03 for rabbits on gestation day 22.

    The effect of ezetimibe on prenatal and postnatal development and maternal function was evaluated in pregnant rats at doses of 100, 300 or 1000 mg/kg/day (gestation day 6 through lactation day 21). No maternal toxicity or adverse developmental outcomes were observed up to and including the highest dose tested (17 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

    Multiple dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis resulted in higher ezetimibe and statin exposures. Reproductive findings occurred at lower doses in combination therapy compared to monotherapy.

    8.2 Lactation

    Risk Summary
    Limited data from case reports in published literature indicate that rosuvastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including rosuvastatin and ezetimibe tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

    There is no information about the presence of ezetimibe in human milk. Ezetimibe is present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. There is no information about the effects of ezetimibe on the breastfed infant or the effects of ezetimibe on milk production.

    Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with rosuvastatin and ezetimibe tablets [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

    Data
    Ezetimibe was present in the milk of lactating rats. The pup to maternal plasma ratio for total ezetimibe was 0.5 on lactation day 12.

    8.4 Pediatric Use

    The safety and effectiveness of rosuvastatin and ezetimibe tablets have not been established in pediatric patients.

    8.5 Geriatric Use

    Advanced age (≥65 years) is a risk factor for rosuvastatin and ezetimibe tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease or other drug therapy; and the higher risk of myopathy. Monitor geriatric patients receiving rosuvastatin and ezetimibe tablets for the increased risk of myopathy [see Warnings and Precautions (5.1)].

    Rosuvastatin
    Of the 10,275 patients in clinical studies with rosuvastatin, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older.

    Ezetimibe
    Of the 2396 patients who received ezetimibe monotherapy in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Of the 11,308 patients who received ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients. In a multiple-dose study with ezetimibe, plasma concentrations for ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects [See Clinical Pharmacology (12.3)].

    8.6 Renal Impairment

    Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor patients with renal impairment for development of myopathy. In patients with severe renal impairment not on hemodialysis, the recommended starting dosage is 5 mg/10 mg daily and should not exceed 10 mg/10 mg daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

    Rosuvastatin
    Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr≥30 mL/min/1.73 m2 ). Exposure to rosuvastatin is increased to a clinically significant extent in patients with severe renal impairment (CLcr<30 mL/min/1.73 m2) who are not receiving hemodialysis [see Clinical Pharmacology (12.3)].

    Ezetimibe
    In a trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years.

    8.7 Hepatic Impairment

    Rosuvastatin and ezetimibe tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

    8.8 Asian Population

    Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. Adjust the rosuvastatin and ezetimibe tablets dosage in Asian patients [see Dosage and Administration (2.2)]

  • 10 OVERDOSAGE

    No specific treatments of over dosage with rosuvastatin and ezetimibe tablets are known. Hemodialysis does not significantly enhance clearance of rosuvastatin. Contact Poison Control (1-800-222-1222) for latest recommendations.

  • 11 DESCRIPTION

    Rosuvastatin and ezetimibe tablets contain rosuvastatin calcium and ezetimibe. Rosuvastatin is a 3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. Ezetimibe is a dietary cholesterol absorption inhibitor.
    The chemical name of ezetimibe is (3R,4S)-1-(p-Fluorophenyl)-3-[(3S)-3-(p-fluorophenyl)-3- hydroxypropyl]-4-(p-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.43 g.mol-1. Ezetimibe is a white, crystalline powder, which is insoluble in water. Its structural formula is:

    ezetimibe-structure

    The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2[methyl(methyl sulfonyl)amino] pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt to [S-[R*,S*-(E)]]-7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1). The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular weight is 1001.14 g.mol-1. Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0. Its structural formula is:

    rosuvastatin-calcium-structure

    Rosuvastatin and ezetimibe tablets 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg, and 40 mg/10 mg contain the equivalent of 5, 10, 20, and 40 mg rosuvastatin (provided as rosuvastatin calcium 5.2, 10.4, 20.8, and 41.7 mg) and 10 mg ezetimibe. Each film-coated tablet of rosuvastatin and ezetimibe tablets contains the following inactive ingredients: pregelatinized starch, microcrystalline cellulose, meglumine, dibasic calcium phosphate dihydrate , crospovidone, colloidal silicon dioxide, sodium stearyl fumarate, mannitol, sodium lauryl sulfate, croscarmellose sodium, povidone, ferric oxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, polyethylene glycol, and ferric oxide.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Rosuvastatin
    Rosuvastatin is an inhibitor of HMG CoA-reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

    Ezetimibe
    The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. 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. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

    12.2 Pharmacodynamics

    The maximum therapeutic response of rosuvastatin is usually achieved by 4 weeks and is maintained after that. The maximum therapeutic response of ezetimibe is generally achieved within 2 weeks and is maintained during chronic therapy.

    12.3 Pharmacokinetics

    Absorption
    Rosuvastatin
    In clinical pharmacology studies in man, 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 mean 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 highly bound (>90%) to human plasma proteins.

    Elimination
    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.

    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
    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.

    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.

    Specific Populations
    Geriatric Patients
    Rosuvastatin
    There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥65 years).

    Ezetimibe
    In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.

    Gender
    Rosuvastatin
    There were no differences in plasma concentrations of rosuvastatin between men and women.

    Ezetimibe
    In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.

    Race
    Rosuvastatin
    A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups. However, pharmacokinetic studies, including one conducted in the US, have demonstrated an approximate 2-fold elevation in median exposure (AUC and Cmax) in Asian subjects when compared with a Caucasian control group. [See Dosage and Administration (2.1) and Specific Populations (8.8).]

    Ezetimibe
    Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.

    Hepatic Impairment
    Rosuvastatin
    In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child-Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function [see Contraindications (4) and Warnings and Precautions (5.2)].

    Ezetimibe
    After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6- fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child- Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold on both Day 1 and Day 14 when compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.2), and Specific Populations (8.7)].

    Renal Impairment
    Rosuvastatin
    Mild to moderate renal impairment (CLcr ≥30 mL/min/1.73 m2) had no influence on plasma concentrations of rosuvastatin. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not receiving hemodialysis compared with healthy subjects (CLcr>80 mL/min/1.73 m2). Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function.

    Ezetimibe
    After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CLcr≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).

    Drug Interactions
    No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with rosuvastatin. Specific pharmacokinetic drug interaction studies with rosuvastatin and ezetimibe tablets have not been performed.

    Cytochrome P450
    Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter organic anion-transporting polyprotein 1B1 (OATP1B1) and efflux transporter breast cancer resistance protein (BCRP) [see Dosage and Administration (2.3) and Drug Interactions (7.1, 7.3)].

    Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes.

    Rosuvastatin
    Table 8: Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

    Coadministered drug and dosing regimenRosuvastatin
    Mean Ratio (ratio with/without coadministered drug) No Effect=1.0 
    Dose (mg)1Change in AUCChange in Cmax

    Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg)

    + Voxilaprevir (100 mg) QD for 15 days

    10 mg single dose7.392
    (6.68-8.18)3
    18.882
    (16.23-21.96)3
    Cyclosporine – stable dose required
    (75 mg – 200 mg BID)
    10 mg QD for 10 days 7.12112
    Darolutamide 600 mg BID, 5 days5 mg, single dose5.22~52
    Regorafenib 160 mg OD, 14 days5 mg single dose3.824.62
    Atazanavir/ritonavir combination
    300 mg/100 mg QD for 8 days
    10 mg3.1272
    Simeprevir 150 mg QD, 7 days10 mg, single dose

    2.82

    (2.3-3.4)3

    3.22
    (2.6-3.9)3
    Velpatasvir 100 mg once daily10 mg single dose2.692
    (2.46-2.94)3
    2.612
    (2.32-2.92)3
    Ombitasvir 25 mg/paritaprevir 150 mg/
    ritonavir 100 mg + dasabuvir 400 mg BID
    5 mg single dose2.592
    (2.09-3.21)3
    7.132
    (5.11-9.96)3
    Elbasvir 50 mg/grazoprevir 200 mg QD10 mg single dose2.262
    (1.89-2.69)3
    5.492
    (4.29-7.04)3
    Glecaprevir 400 mg/pibrentasvir 120 mg QD5 mg once daily2.152
    (1.88-2.46)3
    5.622
    (4.80-6.59)3
    Lopinavir/ritonavir combination
    400 mg/100 mg BID for 17 days
    20 mg QD for 7 days2.12
    (1.7-2.6)3
    52
    (3.4-6.4)3
    Gemfibrozil 600 mg BID for 7 days80 mg1.92
    (1.6-2.2)3
    2.22
    (1.8-2.7)3
    Eltrombopag 75 mg QD, 5 days10 mg1.6
    (1.4-1.7)3
    2
    (1.8-2.3)3
    Darunavir 600 mg/ritonavir 100 mg BID, 7 days10 mg QD for 7 days1.5
    (1.0-2.1)3
    2.4
    (1.6-3.6)3
    Tipranavir/ritonavir combination
    500 mg/200 mg BID for 11 days
    10 mg1.4
    (1.2-1.6)3
    2.2
    (1.8-2.7)3
    Dronedarone 400 mg BID10 mg1.4
    Itraconazole 200 mg QD, 5 days10 mg or 80 mg1.4
    (1.2-1.6)3
    1.3
    (1.1-1.4)3
    1.4
    (1.2-1.5)3
    1.2
    (0.9-1.4)3
    Ezetimibe 10 mg QD, 14 days10 mg QD for 14 days1.2
    (0.9-1.6)3
    1.2
    (0.8-1.6)3
    Fosamprenavir/ritonavir
    700 mg/100 mg BID for 7 days
    10 mg1.11.5
    Fenofibrate 67 mg TID for 7 days10 mg↔ 1.2
    (1.1-1.3)3
    Rifampicin 450 mg QD, 7 days20 mg

    Aluminum & magnesium hydroxide

    combination antacid

    Administered simultaneously

    40 mg

    0.52
    (0.4-0.5)3

    0.52
    (0.4-0.6)3

    Administered 2 hours apart40 mg0.8
    (0.7-0.9)3
    0.8
    (0.7-1.0)3
    Ketoconazole 200 mg BID for 7 days80 mg1.0
    (0.8-1.2)3
    1.0
    (0.7-1.3)3
    Fluconazole 200 mg QD for 11 days80 mg1.1
    (1.0-1.3)3
    1.1
    (0.9-1.4)3
    Erythromycin 500 mg QID for 7 days80 mg0.8
    (0.7-0.9)3
    0.7
    (0.5-0.9)3

    QD= Once daily, BID= Twice daily, TID= Three times daily, QID= Four times daily
    1 Single dose unless otherwise noted.
    2 Clinically significant [See Dosage and Administration (2), Warnings and Precautions (5), and Drug Interactions (7)]

    3 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7 = 30% decrease, 11=11 fold increase in exposure)

    Table 9: Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs

    Rosuvastatin Dosage RegimenCoadministered Drug  

    Mean Ration (ratio with/without coadministered drug)

    No Effect=1.0

    Name and DoseChange in AUCChange in Cmax
    40 mg QD for 10 daysWarfarin1
    25 mg single dose
    R- Warfarin
    1.0
    (1.0-1.1)2
    S-Warfarin
    1.1
    (1.0-1.1)2
    R-Warfarin
    1.0
    (0.9-1.0)2
    S-Warfarin
    1.0
    (0.9-1.1)2
    40 mg QD for 12 daysDigoxin
    0.5 mg single dose
    1.0
    (0.9-1.2)2
    1.0
    (0.9-1.2)2
    40 mg QD for 28 daysOral Contraceptive
    (ethinyl estradiol 0.035 mg & norgestrel 0.180,
    0.215 and 0.250 mg) QD for 21 Days
    EE 1.3
    (1.2-1.3)2
    NG 1.3
    (1.3-1.4)2
    EE 1.3
    (1.2-1.3)2
    NG 1.2
    (1.1-1.3)2

     EE = ethinyl estradiol, NG = norgestrel, QD= Once daily

    1 Clinically significant pharmacodynamic effects [see Drug Interactions (7)]
    2 Mean ratio with 90% CI (with/without coadministered drug, e.g., 1= no change, 0.7=30% decrease, 11=11-fold increase in exposure)

    Ezetimibe
    Table 10: Effect of Co-Administered Drugs on Total Ezetimibe

    Coadministered Drug and Dosing RegimenTotal Ezetimibe* 
    Change in AUCChange in Cmax
    Cyclosporine-stable dose required (75-150 mg BID)1,2↑240%↑290%
    Fenofibrate, 200 mg QD, 14 days2↑48%↑64%
    Gemfibrozil, 600 mg BID, 7 days2↑64%↑91%
    Cholestyramine, 4 g BID, 14 days2↓55%↓4%
    Aluminum & magnesium hydroxide combination antacid, single dose3↓4%↓30%
    Cimetidine, 400 mg BID, 7 days↑6%↑22%
    Glipizide, 10 mg, single dose↑4%↓8%
    Statins
         Lovastatin 20 mg QD, 7 days
         Pravastatin 20 mg QD, 14 days
         Atorvastatin 10 mg QD, 14 days
         Rosuvastatin 10 mg QD, 14 days
         Fluvastatin 20 mg QD, 14 days

    ↑9%
    ↑7%
    ↓2%
    ↑13%
    ↓19%

    ↑3%
    ↑23%
    ↑12%
    ↑18%
    ↑7%

    * Based on 10-mg dose of ezetimibe
    1 Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal impairment (creatinine clearance of 13.2 mL/min/1.73m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects.
    2 See Drug Interactions (7)
    3 Supralox®, 20 mL

    Table 11: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs

    Coadministered Drug and its Dosage RegimenEzetimibe Dosage Regimen Change in AUC of Coadministered DrugChange in Cmax of Coadministered Drug 
    Warfarin, 25 mg single dose on Day 710 mg QD, 11 days↓2% (R-warfarin)
    ↓4% (S-warfarin)
    ↓3% (R-warfarin)
    ↓1% (S-warfarin)
    Digoxin, 0.5 mg single dose10 mg QD, 8 days↑2%↓7%
    Gemfibrozil, 600 mg BID, 7 days*10 mg QD, 7 days↓1%↓11%
    Ethinyl estradiol and levonorgestrel, QD, 21 days10 mg QD, Days 8-14 of 21 day oral contraceptive cycleEthinyl estradiol
    0%
    Levonorgestrel
    0%

    Ethinyl estradiol
    ↓9%

    Levonorgestrel
    ↓5%

    Glipizide, 10 mg on Days 1 and 910 mg QD, Days 2-9↓3%↓5%
    Fenofibrate, 200 mg QD, 14 days*10 mg QD, 14 days↑11%↑7%
    Cyclosporine, 100 mg single dose Day 7*20 mg QD, 8 days↑15%↑10%
    Statins
         Lovastatin 20 mg QD, 7 days10 mg QD, 7 days↑19%↑3%
         Pravastatin 20 mg QD, 14 days10 mg QD, 14 days↓20%↓24%
         Atorvastatin 10 mg QD, 14 days10 mg QD, 14 days↓4%↑7%
         Rosuvastatin 10 mg QD, 14 days10 mg QD, 14 days↑19%↑17%
         Fluvastatin 20 mg QD, 14 days10 mg QD, 14 days↓39%↓27%

    * See Drug Interactions (7)

    12.5 Pharmacogenomics

    Disposition of statins, including rosuvastatin, involves OATP1B1 and other transporter proteins. Higher plasma concentrations of rosuvastatin have been reported in very small groups of patients (n=3 to 5) who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T > C). The frequency of this genotype (i.e., SLCO1B1 521T>C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on rosuvastatin is unknown.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No animal carcinogenicity or fertility studies have been conducted with the combination of rosuvastatin and ezetimibe.

    Rosuvastatin
    In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses.

    In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses.

    Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test.

    In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class.

    Ezetimibe
    A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
    No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

    In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

  • 14 CLINICAL STUDIES

    14.1 Primary Hyperlipidemia

    Rosuvastatin and ezetimibe tablets reduces total-C, LDL-C, Apo B, and non-HDL-C in adults with hyperlipidemia.

    Rosuvastatin monotherapy
    In a multicenter, double-blind, placebo-controlled, dose-ranging study in patients with hyperlipidemia, rosuvastatin given as a single daily dose for 6 weeks significantly reduced Total-C, LDL-C, non-HDL- C, and Apo B, across the dose range (Table 12).

    Table 12. Dose-Response of Rosuvastatin Monotherapy in Patients with Hyperlipidemia (Adjusted Mean % Change from Baseline at Week 6)

     DoseNTotal-CLDL-C Non-HDL-CApo BTGHDL-C
     Placebo 13 -5 -7-7 -3 -33
     Rosuvastatin 5 mg 17 -33 -45-44 -38 -35 13
     Rosuvastatin 10 mg 17 -36 -52 -48 -42 -10 14
     Rosuvastatin 20 mg 17 -40 -55 -51 -46 -23 8
     Rosuvastatin 40 mg 18 -46 -63 -60 -54 -28 10

    Ezetimibe added to ongoing statin therapy
    In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ezetimibe or placebo in addition to their ongoing statin.

    Ezetimibe, added to ongoing statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (Table 13). LDL-C reductions induced by ezetimibe were generally consistent across all statins.

    Table 13: Response to Addition of Ezetimibe to Ongoing Statin Therapy1 in Patients with Hyperlipidemia (Mean2 % Change from Treated Baseline3)

     Treatment (Daily Dose)NTotal-C LDL-C Apo B Non-HDL-C TG HDL-C 
     Ongoing Statin + Placebo4390 -2 -4 -3 -3 -3 +1 
     Ongoing Statin + Ezetimibe4379 -17 -25 -19 -23 -14 +3 

    1 Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)
    2 For triglycerides, median % change from baseline
    3 Baseline – on a statin alone
    4 Ezetimibe + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG and increased HDL-C compared to statin alone

    14.2 HoFH

    Rosuvastatin monotherapy
    Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40) were evaluated for their response to rosuvastatin 20 to 40 mg titrated at a 6-week interval. In the overall population, the mean LDL-C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL-C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL-C reduction of <15%, 3 had no change or an increase in LDL-C. Reductions in LDL-C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.

    Ezetimibe monotherapy
    A study was conducted to assess the efficacy of ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups: atorvastatin or simvastatin (80 mg), ezetimibe administered with atorvastatin or simvastatin (40 mg), or ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ezetimibe plus 80 mg atorvastatin or with ezetimibe plus 80 mg simvastatin, LDL-C was reduced by 27%.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Rosuvastatin and ezetimibe tablets are supplied as follows:

     Strength (Contents) Description Container  NDC 
     5 mg/10 mg (rosuvastatin 5 mg and ezetimibe 10 mg)  round pink biconvex tablets with “5” embossed on one side  Bottle of 30 tablets and two 1 g desiccants  82120-125-30
     10 mg/10 mg (rosuvastatin 10 mg and ezetimibe 10 mg)  round pink biconvex tablets with “AL” embossed on one side  Bottle of 30 tablets and two 1 g desiccants 82120-126-30
     20 mg/10 mg (rosuvastatin 20 mg and ezetimibe 10 mg)  round pink biconvex tablets with “II” embossed on one side Bottle of 30 tablets and two 1 g desiccants 82120-127-30
     40 mg/10 mg (rosuvastatin 40 mg and ezetimibe 10 mg)  round pink biconvex tablets with “77” embossed on one side  Bottle of 30 tablets and two 1 g desiccants 82120-128-30

    Store at controlled room temperature (USP), 20°C to 25 ºC (68°F to 77 ºF) [see USP Controlled Room Temperature]. Store in the original container to protect from light. Protect from moisture. Once the bottle has been opened, use the tablets within 30 days.

    Dispense in original container to protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Patient Information).

    Myopathy and Rhabdomyolysis
    Advise patients that rosuvastatin and ezetimibe tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

    Hepatic Dysfunction
    Inform patients that rosuvastatin and ezetimibe tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].

    Increases in HbA1c and Fasting Serum Glucose Levels
    Inform patients that increases in HbA1c and fasting serum glucose levels may occur with rosuvastatin and ezetimibe tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.5)].

    Pregnancy
    Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if rosuvastatin and ezetimibe tablets should be discontinued [see Use in Specific Populations (8.1)].

    Lactation
    Advise patients that breastfeeding is not recommended during treatment with rosuvastatin and ezetimibe tablets [see Use in Specific Populations (8.2)].

    Concomitant Use of Antacids
    When taking rosuvastatin and ezetimibe tablets with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin and ezetimibe tablets administration.

    Administration Instructions
    Advise patients to swallow tablets whole. Do not crush, dissolve, or chew tablets. If a dose is missed, advise patients not take an extra dose. Just resume the usual schedule.

    Manufactured by:
    Piramal Pharma Limited,
    Plot No. 67-70, Sector 2, Dist. Dhar, Pithampur, Madhya Pradesh 454775, India

    Distributed by:
    SCOV3 LLC
    1201 N Orange St,
    Wilmington, DE 19801
    USA
    Ref: AL-320-001-3

  • PATIENT PACKAGE INSERT

    Patient Information

    ROSUVASTATIN AND EZETIMIBE

    tables, for oral use

    What is rosuvastatin and ezetimibe tablets?
    Rosuvastatin and ezetimibe tablets contain two medicines, rosuvastatin and ezetimibe, to lower cholesterol. Rosuvastatin and ezetimibe tablets is used:

    • Along with diet in adults with high blood cholesterol levels to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol.
    • Alone or together with other LDL-lowering medicines in adults with a type of high cholesterol called homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.
    It is not known if rosuvastatin and ezetimibe tablets is safe and effective in children.

    Do not take rosuvastatin and ezetimibe tablets if you:

    • have liver problems or repeated blood tests showing possible liver problems.
    • are allergic to ezetimibe or rosuvastatin or any of the ingredients in rosuvastatin and ezetimibe tablets. See the end of this leaflet for complete list of ingredients in rosuvastatin and ezetimibe tablets.

    Before you take rosuvastatin and ezetimibe tablets, tell your healthcare provider about all of your medical conditions, including if you:

    • have unexplained muscle aches or weakness.
    • have thyroid problems.
    • have kidney problems.
    • drink more than 2 glasses of alcohol daily or have had liver problems.
    • have diabetes.
    • are pregnant or plan to become pregnant. Rosuvastatin and ezetimibe tablets may harm your unborn baby. If you become pregnant, stop taking rosuvastatin and ezetimibe tablets and call your healthcare provider right away.
    • are breast feeding. Rosuvastatin and ezetimibe tablets can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take rosuvastatin and ezetimibe tablets. Do not breastfeed while taking rosuvastatin and ezetimibe tablets.
    • are 65 years of age or older.
    • are of Asian descent.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines.
    Taking rosuvastatin and ezetimibe tablets with certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your healthcare provider if you take medicines for:
         • heartburn (such as antacids that contain aluminum and magnesium hydroxide)
         • your immune system (such as cyclosporine)
         • cholesterol (such as niacin or nicotinic acid, gemfibrozil, fibrates)
         • infections or anti-fungals (such as itraconazole, ketoconazole, and fluconazole)
         • heart failure including coumarin anticoagulants (such as warfarin)
         • gout (such as colchicine)
         • darolutamide (a medicine for the treatment of prostate cancer)
         • regorafenib (a medicine used to treat cancer of the colon and rectum)
         • anti-viral medicines including certain HIV or hepatitis C virus drugs such as:
              o lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, simeprevir
              o combination of
                    ■ sofosbuvir/velpatasvir/voxilaprevir
                    ■ dasabuvir/ombitasvir/paritaprevir/ritonavir
                    ■ elbasvir/grazoprevir
                    ■ sofosbuvir/velpatasvir
                    ■ glecaprevir/pibrentasvir and
              • all other combinations with ledipasvir including ledipasvir/sofosbuvir
    Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know all of the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get new medicine.

    How should I take rosuvastatin and ezetimibe tablets?

    • Take rosuvastatin and ezetimibe tablets exactly as your healthcare provider tells you to take it.
    • Take rosuvastatin and ezetimibe tablets 1 time each day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime.
    • Tablets should be swallowed whole. Do not crush, dissolve, or chew tablets.
    • Keep taking rosuvastatin and ezetimibe tablets unless your healthcare provider tells you to stop. If you stop taking rosuvastatin and ezetimibe tablets, your cholesterol may rise again.
    • If you miss a dose, do not take an extra dose. Take the next dose at the usual time. Do not take 2 doses of rosuvastatin and ezetimibe tablets within 12 hours of each other.
    • If you take too much rosuvastatin and ezetimibe tablets, call the Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.
    • See your healthcare provider regularly to check your cholesterol level and to check for side effects. Your healthcare provider may do blood tests to check your liver before you start taking rosuvastatin and ezetimibe tablets and during treatment.

    What are the possible side effects of rosuvastatin and ezetimibe tablets?
    Rosuvastatin and ezetimibe tablets may cause serious side effects, including:
    Allergic reactions, including a severe reaction known as anaphylaxis. Tell your healthcare provider right away if you have any of the following symptoms:
         o swelling of the face, lips, tongue, and/or throat which makes it difficult to swallow or breathe
         o breathing problems or wheezing
         o feeling dizzy or fainting
         o rash or hives
         o itching
    Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely causes kidney damage that can lead to death. You have a higher chance for muscle problems if you are taking certain other medicines with rosuvastatin and ezetimibe tablets. Tell your healthcare provider right away if:
         o you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take rosuvastatin and ezetimibe tablets.
         o you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking rosuvastatin and ezetimibe tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.
    Your chances of getting muscle problems are higher if you:
         o are taking certain other medicines while you take rosuvastatin and ezetimibe tablets (see “Especially tell your healthcare provider if you take medicines”)
         o are 65 years of age or older
         o are of Asian descent
         o have thyroid problems (hypothyroidism) that are not controlled
         o have kidney problems
         o are taking higher doses of rosuvastatin and ezetimibe tablets
    Liver problems. Your healthcare provider may do blood tests to check your liver before you start taking rosuvastatin and ezetimibe tablets and if you have symptoms of liver problems while you take rosuvastatin and ezetimibe tablets. Call your healthcare provider right away if you have the following symptoms of liver problems:
         o feel tired or weak                                              o loss of appetite
         o upper belly pain                                                o dark urine
         o yellowing of your skin or the whites of your eyes
    The most common side effects of rosuvastatin and ezetimibe tablets include:
         o headache                     o nausea                           o muscle aches and pains
         o weakness                     o constipation                 o common cold and flu
         o diarrhea                       o joint pain                     o runny nose and sore throat
         o dizziness                      o stomach pain                o tiredness
         o pain (back, hands, legs)
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
    These are not all the possible side effects of rosuvastatin and ezetimibe tablets.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store rosuvastatin and ezetimibe tablets?

    • Store rosuvastatin and ezetimibe tablets at room temperature between 68°F to 77°F (20°C to 25°C).
    • Protect rosuvastatin and ezetimibe tablets bottle from moisture or humidity.
    • Remove a tablet from bottle only when you are ready to take it.
    • Replace the cap on the bottle and close it tightly after removing the tablet from the bottle.
    • After opening the bottle, use the tablets within 30 days.

    Keep rosuvastatin and ezetimibe tablets and all medicines out of the reach of children.

    General information about the safe and effective use of rosuvastatin and ezetimibe tablets.
    Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use rosuvastatin and ezetimibe tablets for a condition for which it was not prescribed. Do not give rosuvastatin and ezetimibe tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about rosuvastatin and ezetimibe tablets that is written for health professionals.

    What are the ingredients in rosuvastatin and ezetimibe tablets?
    Active ingredients: ezetimibe and rosuvastatin
    Inactive ingredients:
    Pregelatinized starch, microcrystalline cellulose, meglumine, dibasic calcium phosphate dihydrate, crospovidone, colloidal silicon dioxide, sodium stearyl fumarate, mannitol, sodium lauryl sulfate, croscarmellose sodium, povidone, ferric oxide, and magnesium stearate. In addition, the tablet film coating contains the following inactive ingredients: hypromellose, titanium dioxide, polyethylene glycol and ferric oxide.


    Manufactured by:
    Piramal Pharma Limited,
    Plot No. 67-70, Sector 2, Dist. Dhar, Pithampur, 
    Madhya Pradesh 454775, India

    Distributed by:
    SCOV3 LLC
    1201 N Orange St,
    Wilmington, DE 19801
    USA
    Ref: AL-320-001-3

    This Patient Information has been approved by the U.S. Food and Drug Administration

    Issued: 07/2021

  • PACKAGE LABEL/DISPLAY PANEL - 5 mg / 10 mg

    NDC 82120-125-30

    Rosuvastatin and Ezetimibe Tablets

    5 mg/10 mg

    Rx Only

    30 Tablets

    Each tablet contains the equivalent of 5 mg rosuvastatin (provided as rosuvastatin calcium 5.2 mg) and 10 mg ezetimibe

    RECOMMENDED DOSAGE:

    See Prescribing Information.

    Store at 20 to 25°C (68 to 77°F).

    Protect from moisture.

    WARNING: As with all medications, keep out of the reach of children.

    Distributed by: SCOV3 LLC

    Wilmington, DE 19801

    CODE: MP/DRUGS/25/10/92

    Made in India

    Issue 07/2021

    rosuvastatin-ezetimibe-5mg-10mg

  • PACKAGE LABEL/DISPLAY PANEL - 10 mg / 10 mg

    NDC 82120-126-30

    Rosuvastatin and Ezetimibe Tablets

    10 mg/10 mg

    Rx Only

    30 Tablets

    Each tablet contains the equivalent of 10 mg rosuvastatin (provided as rosuvastatin calcium 10.4 mg) and 10 mg ezetimibe

    RECOMMENDED DOSAGE:

    See Prescribing Information.

    Store at 20 to 25°C (68 to 77°F).

    Protect from moisture.

    WARNING: As with all medications, keep out of the reach of children.

    Distributed by: SCOV3 LLC

    Wilmington, DE 19801

    CODE: MP/DRUGS/25/10/92

    Made in India

    Issue 07/2021

    rosuvastatin-ezetimibe-10mg-10mg.jpg

  • PACKAGE LABEL/DISPLAY PANEL - 20 mg / 10 mg

    NDC 82120-127-30

    Rosuvastatin and Ezetimibe Tablets

    20 mg/10 mg

    Rx Only

    30 Tablets

    Each tablet contains the equivalent of 20 mg rosuvastatin (provided as rosuvastatin calcium 20.8 mg) and 10 mg ezetimibe

    RECOMMENDED DOSAGE:

    See Prescribing Information.

    Store at 20 to 25°C (68 to 77°F).

    Protect from moisture.

    WARNING: As with all medications, keep out of the reach of children.

    Distributed by: SCOV3 LLC

    Wilmington, DE 19801

    CODE: MP/DRUGS/25/10/92

    Made in India

    Issue 07/2021

    rosuvastatin-ezetimibe-20mg-10mg

  • PACKAGE LABEL/DISPLAY PANEL - 40 mg/10 mg

    NDC 82120-128-30

    Rosuvastatin and Ezetimibe Tablets

    40 mg/10 mg

    Rx Only

    30 Tablets

    Each tablet contains the equivalent of 40 mg rosuvastatin (provided as rosuvastatin calcium 41.7 mg) and 10 mg ezetimibe

    RECOMMENDED DOSAGE:

    See Prescribing Information.

    Store at 20 to 25°C (68 to 77°F).

    Protect from moisture.

    WARNING: As with all medications, keep out of the reach of children.

    Distributed by: SCOV3 LLC

    Wilmington, DE 19801

    CODE: MP/DRUGS/25/10/92

    Made in India

    Issue 07/2021

    rosuvastatin-ezetimibe-40mg-10mg

  • INGREDIENTS AND APPEARANCE
    ROSUVASTATIN AND EZETIMIBE 
    rosuvastatin and ezetimibe tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:82120-125
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ROSUVASTATIN CALCIUM (UNII: 83MVU38M7Q) (ROSUVASTATIN - UNII:413KH5ZJ73) ROSUVASTATIN5.2 mg
    EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24) EZETIMIBE10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    MEGLUMINE (UNII: 6HG8UB2MUY)  
    DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    MANNITOL (UNII: 3OWL53L36A)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    POVIDONE (UNII: FZ989GH94E)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    ColorpinkScoreno score
    ShapeROUNDSize9mm
    FlavorImprint Code 5
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:82120-125-3030 in 1 BOTTLE; Type 0: Not a Combination Product08/15/2021
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21307208/15/2021
    ROSUVASTATIN AND EZETIMIBE 
    rosuvastatin and ezetimibe tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:82120-126
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ROSUVASTATIN CALCIUM (UNII: 83MVU38M7Q) (ROSUVASTATIN - UNII:413KH5ZJ73) ROSUVASTATIN10.4 mg
    EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24) EZETIMIBE10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    MEGLUMINE (UNII: 6HG8UB2MUY)  
    DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    MANNITOL (UNII: 3OWL53L36A)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    POVIDONE (UNII: FZ989GH94E)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    ColorpinkScoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code AL
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:82120-126-3030 in 1 BOTTLE; Type 0: Not a Combination Product08/15/2021
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21307208/15/2021
    ROSUVASTATIN AND EZETIMIBE 
    rosuvastatin and ezetimibe tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:82120-127
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ROSUVASTATIN CALCIUM (UNII: 83MVU38M7Q) (ROSUVASTATIN - UNII:413KH5ZJ73) ROSUVASTATIN20.8 mg
    EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24) EZETIMIBE10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    MEGLUMINE (UNII: 6HG8UB2MUY)  
    DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    MANNITOL (UNII: 3OWL53L36A)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    POVIDONE (UNII: FZ989GH94E)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    ColorpinkScoreno score
    ShapeROUNDSize11mm
    FlavorImprint Code II
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:82120-127-3030 in 1 BOTTLE; Type 0: Not a Combination Product08/15/2021
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21307208/15/2021
    ROSUVASTATIN AND EZETIMIBE 
    rosuvastatin and ezetimibe tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:82120-128
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ROSUVASTATIN CALCIUM (UNII: 83MVU38M7Q) (ROSUVASTATIN - UNII:413KH5ZJ73) ROSUVASTATIN41.7 mg
    EZETIMIBE (UNII: EOR26LQQ24) (EZETIMIBE - UNII:EOR26LQQ24) EZETIMIBE10 mg
    Inactive Ingredients
    Ingredient NameStrength
    STARCH, CORN (UNII: O8232NY3SJ)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    MEGLUMINE (UNII: 6HG8UB2MUY)  
    DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP)  
    CROSPOVIDONE (UNII: 2S7830E561)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    MANNITOL (UNII: 3OWL53L36A)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    POVIDONE (UNII: FZ989GH94E)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    Product Characteristics
    ColorpinkScoreno score
    ShapeROUNDSize13mm
    FlavorImprint Code 77
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:82120-128-3030 in 1 BOTTLE; Type 0: Not a Combination Product08/15/2021
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21307208/15/2021
    Labeler - SCOV3 LLC (118183816)
    Establishment
    NameAddressID/FEIBusiness Operations
    Piramal Pharma Limited862202793manufacture(82120-125, 82120-126, 82120-127, 82120-128)