HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EZALLOR SPRINKLE safely and effectively. See full prescribing information for EZALLOR SPRINKLE. EZALLOR SPRINKLETM (rosuvastatin) capsules, for oral use Initial U.S. Approval: 2003

INDICATIONS AND USAGE

EZALLOR Sprinkle is an HMG Co-A reductase inhibitor indicated for:

  • adult patients with hypertriglyceridemia as an adjunct to diet (1.1)
  • adult patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet (1.2)
  • adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total-C, and ApoB (1.3)

Limitations of use (1.4):

  • EZALLOR Sprinkle has not been studied in Fredrickson Type I and V dyslipidemias.

DOSAGE AND ADMINISTRATION

  • EZALLOR Sprinkle can be taken with or without food, at any time of day. (2.1)
  • Dose range: 5 mg to 40 mg once daily. Use 40 mg dose only for patients not reaching LDL-C goal with 20 mg. (2.1)
  • Adult HoFH: Starting dose 20 mg once daily. (2.1)

DOSAGE FORMS AND STRENGTHS

EZALLOR Sprinkle capsules: 5 mg, 10 mg, 20 mg, and 40 mg (3)

    CONTRAINDICATIONS

    • Known hypersensitivity to product components (4)
    • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4)
    • Pregnancy (4, 8.1, 8.3)
    • Lactation (4, 8.2)

    WARNINGS AND PRECAUTIONS

    • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue EZALLOR Sprinkle if signs or symptoms appear. (5.1, 7.5, 7.6)
    • Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.2)

    ADVERSE REACTIONS

    Most frequent adverse reactions (rate > 2%) are headache, myalgia, abdominal pain, asthenia, and nausea. (6.1)

      To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

      DRUG INTERACTIONS

      • Cyclosporine: Combination increases rosuvastatin exposure. Limit EZALLOR Sprinkle dose to 5 mg once daily. (2.4, 5.1, 7.1, 12.3)
      • Gemfibrozil: Combination should be avoided. If used together, limit EZALLOR Sprinkle dose to 10 mg once daily. (2.4, 5.1, 7.2)
      • Atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir: Combination increases rosuvastatin exposure. Limit EZALLOR Sprinkle dose to 10 mg once daily. (2.4, 5.1, 7.3, 12.3)
      • Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting EZALLOR Sprinkle. Monitor INR frequently until stable upon initiation or alteration of EZALLOR Sprinkle therapy. (5.3, 7.4)
      • Concomitant lipid-lowering therapies: Use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with EZALLOR Sprinkle. (5.1, 7.5, 7.6)

      USE IN SPECIFIC POPULATIONS

      • Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with EZALLOR Sprinkle (8.3)
      • Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg. (2.5, 5.1, 8.6) Asian population: Consider 5 mg starting dose. (2.3, 8.8)

      See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Revised: 04/2020

      FULL PRESCRIBING INFORMATION: CONTENTS*

      1 INDICATIONS AND USAGE

      • 1.1 Hypertriglyceridemia
      • 1.2 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
      • 1.3 Adult Patients with Homozygous Familial Hypercholesterolemia
      • 1.4 Limitations of Use

      2 DOSAGE AND ADMINISTRATION

      • 2.1 General Dosing Information
      • 2.2 Dosing in Asian Patients
      • 2.3 Use with Concomitant Therapy
      • 2.4 Dosing in Patients with Severe Renal Impairment
      • 2.5 Administration Options

      3 DOSAGE FORMS AND STRENGTHS

      4 CONTRAINDICATIONS

      5 WARNINGS AND PRECAUTIONS

      • 5.1 Skeletal Muscle Effects
      • 5.2 Liver Enzyme Abnormalities
      • 5.3 Concomitant Coumarin Anticoagulants
      • 5.4 Proteinuria and Hematuria
      • 5.5 Endocrine Effects

      6 ADVERSE REACTIONS

      • 6.1 Clinical Studies Experience
      • 6.2 Postmarketing Experience

      7 DRUG INTERACTIONS

      • 7.1 Cyclosporine
      • 7.2 Gemfibrozil
      • 7.3 Protease Inhibitors
      • 7.4 Coumarin Anticoagulants
      • 7.5 Niacin
      • 7.6 Fenofibrate
      • 7.7 Colchicine

      8 USE IN SPECIFIC POPULATIONS

      • 8.1 Pregnancy
      • 8.2 Lactation
      • 8.3 Females and Males of Reproductive Potential
      • 8.4 Pediatric Use
      • 8.5 Geriatric Use
      • 8.6 Renal Impairment
      • 8.7 Hepatic Impairment
      • 8.8 Asian Patients

      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
      • 13.2 Animal Toxicology and/or Pharmacology

      14 CLINICAL STUDIES

      • 14.1 Hypertriglyceridemia
      • 14.2 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
      • 14.3 Homozygous Familial Hypercholesterolemia

      16 HOW SUPPLIED/STORAGE AND HANDLING

      17 PATIENT COUNSELING INFORMATION

      * Sections or subsections omitted from the full prescribing information are not listed.

        FULL PRESCRIBING INFORMATION

        1 INDICATIONS AND USAGE

        Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

          1.1 Hypertriglyceridemia

          EZALLOR Sprinkle is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia.

            1.2 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

            EZALLOR Sprinkle is indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).

              1.3 Adult Patients with Homozygous Familial Hypercholesterolemia

              EZALLOR Sprinkle is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.

                1.4 Limitations of Use

                EZALLOR Sprinkle has not been studied in Fredrickson Type I and V dyslipidemias.

                  2 DOSAGE AND ADMINISTRATION

                  2.1 General Dosing Information

                  The dose range for EZALLOR Sprinkle in adults is 5 mg to 40 mg orally once daily. The usual starting dose is 10 mg to 20 mg once daily. The usual starting dose in adult patients with homozygous familial hypercholesterolemia is 20 mg once daily. The maximum EZALLOR Sprinkle dose of 40 mg should be used only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose [see Warnings and Precautions (5.1)]. EZALLOR Sprinkle can be administered as a single dose at any time of day, with or without food. Swallow capsules whole. Do not crush or chew. For patients who cannot swallow capsules, the capsules can be opened for administration [see Dosage and Administration (2.5)]. When initiating EZALLOR Sprinkle therapy or switching from another HMG-CoA reductase inhibitor therapy, the appropriate EZALLOR Sprinkle starting dose should first be utilized, and only then titrated according to the patient’s response and individualized goal of therapy. After initiation or upon titration of EZALLOR Sprinkle, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

                    2.2 Dosing in Asian Patients

                    In Asian patients, consider initiation of EZALLOR Sprinkle therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg once daily [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

                      2.3 Use with Concomitant Therapy

                      Patients taking cyclosporine The dose of EZALLOR Sprinkle should not exceed 5 mg once daily [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Patients taking gemfibrozil Avoid concomitant use of EZALLOR Sprinkle with gemfibrozil. If concomitant use cannot be avoided, initiate EZALLOR Sprinkle at 5 mg once daily. The dose of EZALLOR Sprinkle should not exceed 10 mg once daily [see Warnings and Precautions (5.1), Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir Initiate EZALLOR Sprinkle therapy with 5 mg once daily. The dose of EZALLOR Sprinkle should not exceed 10 mg once daily [see Warnings and Precautions (5.1), Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

                        2.4 Dosing in Patients with Severe Renal Impairment

                        For patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) not on hemodialysis, dosing of EZALLOR Sprinkle should be started at 5 mg once daily and not exceed 10 mg once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

                          2.5 Administration Options

                          EZALLOR Sprinkle capsule should be swallowed whole. For patients unable to swallow an intact capsule, alternative administration options are available. Oral Administration Directions for use with soft food (applesauce or pudding For patients with swallowing difficulty, EZALLOR Sprinkle capsule can be opened and contents can be sprinkled over soft food. The contents of the capsules should be swallowed along with a small amount (teaspoonful) of soft food (such as applesauce or chocolate/vanilla flavored pudding). The drug/food mixture should be swallowed within 60 minutes and not be stored for future use. If it is not used in its entirety, the remaining contents should be discarded immediately. Nasogastric Tube (≥16 French) Administration For patients who have a nasogastric tube in place, the EZALLOR Sprinkle capsule can be opened and the intact granules emptied into a 60 mL catheter tipped syringe and add 40 mL of water. Replace the plunger and shake the syringe vigorously for 15 seconds. The granules in EZALLOR Sprinkle may start dissolving which is acceptable. Attach the syringe to a nasogastric tube (≥16-French) and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with 20 mL of additional water. The mixture must be used immediately after preparation and not be stored for future use. If it is not used in its entirety, the remaining mixture should be discarded immediately. Use with any other liquids is not recommended.

                            3 DOSAGE FORMS AND STRENGTHS

                            5 mg: Hard gelatin capsule, Size “3” pink cap/off white body, imprinted axially with “984” on cap and body in black ink filled with yellow colored granules. 10 mg: Hard gelatin capsule, Size “3” purple cap/off white body, imprinted axially with “985” on cap and body in black ink filled with yellow colored granules. 20 mg: Hard gelatin capsule, Size “1” blue cap/off white body, imprinted axially with “986” on cap and body in black ink filled with yellow colored granules. 40 mg: Hard gelatin capsule, Size “0el” green cap/white body, imprinted axially with “987” on cap and body in black ink filled with yellow colored granules.

                              4 CONTRAINDICATIONS

                              EZALLOR Sprinkle is contraindicated in the following conditions:

                              • Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin [see Adverse Reactions (6.1)].
                              • Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.2)].
                              • Pregnancy [see Use in Specific Populations (8.1, 8.3)].
                              • Lactation. Limited data indicate that rosuvastatin is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require EZALLOR Sprinkle treatment should not breastfeed their infants [see Use in Specific Populations (8.2)].

                              5 WARNINGS AND PRECAUTIONS

                              5.1 Skeletal Muscle Effects

                              Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg). EZALLOR Sprinkle should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with EZALLOR Sprinkle may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir [see Dosage and Administration (2) and Drug Interactions (7)]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing EZALLOR Sprinkle with colchicine [see Drug Interactions (7.7)]. EZALLOR Sprinkle therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. EZALLOR Sprinkle therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). 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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing EZALLOR Sprinkle.

                                5.2 Liver Enzyme Abnormalities

                                It is recommended that liver enzyme tests be performed before the initiation of EZALLOR Sprinkle, and if signs or symptoms of liver injury occur. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to > 3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin versus 0.5% of patients treated with placebo. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with EZALLOR Sprinkle, promptly interrupt therapy. If an alternate etiology is not found, do not restart EZALLOR Sprinkle. EZALLOR Sprinkle should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of EZALLOR Sprinkle [see Contraindications (4)].

                                  5.3 Concomitant Coumarin Anticoagulants

                                  Caution should be exercised when anticoagulants are given in conjunction with EZALLOR Sprinkle because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and EZALLOR Sprinkle concomitantly, INR should be determined before starting EZALLOR Sprinkle and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Drug Interactions (7.4)].

                                    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 HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on EZALLOR Sprinkle therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

                                      5.5 Endocrine Effects

                                      Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1)]. Although clinical studies have shown that rosuvastatin alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if EZALLOR Sprinkle is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine.

                                        6 ADVERSE REACTIONS

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

                                        • Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and Precautions (5.1)]
                                        • Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

                                        6.1 Clinical Studies 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.

                                          In the rosuvastatin controlled clinical trials database (placebo or active-controlled) of 5,394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:

                                          • myalgia
                                          • abdominal pain
                                          • nausea

                                          The most commonly reported adverse reactions (incidence ≥ 2%) in the rosuvastatin controlled clinical trial database of 5,394 patients were:

                                          • headache
                                          • myalgia
                                          • abdominal pain
                                          • asthenia
                                          • nausea

                                          Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.

                                            Table 1. Adverse Reactions1 Reported in ≥ 2% of Patients Treated with Rosuvastatin and > Placebo in Placebo-Controlled Trials (% of Patients)

                                            Adverse Reactions
                                            Rosuvastatin 5 mg N=291
                                            Rosuvastatin 10 mg N=283
                                            Rosuvastatin 20 mg N=64
                                            Rosuvastatin 40 mg N=106
                                            Total Rosuvastatin 5 mg to 40 mg N=744
                                            Placebo N=382
                                            Headache5.54.93.18.55.55
                                            Nausea3.83.56.303.43.1
                                            Myalgia3.12.16.31.92.81.3
                                            Asthenia2.43.24.70.92.72.6
                                            Constipation2.12.14.72.82.42.4

                                            1 Adverse reactions by COSTART preferred term. Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see Warnings and Precautions (5.4)]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In a clinical trial, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea. Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

                                              Table 2. Adverse Reactions1 Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)

                                              Adverse ReactionsRosuvastatin 40 mg N=700Placebo N=281
                                              Myalgia12.712.1
                                              Arthralgia10.17.1
                                              Headache6.45.3
                                              Dizziness4.02.8
                                              Increased CPK2.60.7
                                              Abdominal pain2.41.8
                                              ALT >3x ULN22.20.7

                                              1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8,901) or placebo (n=8,901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation. 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 [see Warnings and Precautions (5.5)]. Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3.

                                                Table 3. Adverse Reactions1 Reported in ≥2% of Patients Treated with Rosuvastatin and > Placebo in a Trial (% of Patients)

                                                Adverse ReactionsRosuvastatin 20 mg N=8,901Placebo N=8,901
                                                Myalgia7.66.6
                                                Arthralgia3.83.2
                                                Constipation3.33.0
                                                Dizziness4.02.8
                                                Diabetes mellitus2.82.3
                                                Nausea2.42.3

                                                1 Treatment-emergent adverse reactions by MedDRA preferred term.

                                                  6.2 Postmarketing Experience

                                                  The following adverse reactions have been identified during postapproval use of 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and 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).

                                                    7 DRUG INTERACTIONS

                                                    7.1 Cyclosporine

                                                    Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of EZALLOR Sprinkle should not exceed 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

                                                      7.2 Gemfibrozil

                                                      Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with EZALLOR Sprinkle and gemfibrozil should be avoided. If used together, the dose of EZALLOR Sprinkle should not exceed 10 mg once daily [see Clinical Pharmacology (12.3)].

                                                        7.3 Protease Inhibitors

                                                        Coadministration of rosuvastatin with certain protease inhibitors has differing effects on rosuvastatin exposure and may increase risk of myopathy. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase rosuvastatin exposure [see Table 4 – Clinical Pharmacology (12.3)]. For these protease inhibitors, the dose of EZALLOR Sprinkle should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in rosuvastatin exposure. Caution should be exercised when EZALLOR Sprinkle is coadministered with protease inhibitors [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

                                                          7.4 Coumarin Anticoagulants

                                                          Rosuvastatin significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with EZALLOR Sprinkle. In patients taking coumarin anticoagulants and EZALLOR Sprinkle concomitantly, INR should be determined before starting EZALLOR Sprinkle and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

                                                            7.5 Niacin

                                                            The risk of skeletal muscle effects may be enhanced when EZALLOR Sprinkle is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with EZALLOR Sprinkle [see Warnings and Precautions (5.1)].

                                                              7.6 Fenofibrate

                                                              When rosuvastatin was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with EZALLOR Sprinkle [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

                                                                7.7 Colchicine

                                                                Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing EZALLOR Sprinkle with colchicine [see Warnings and Precautions (5.1)].

                                                                  8 USE IN SPECIFIC POPULATIONS

                                                                  8.1 Pregnancy

                                                                  Risk Summary

                                                                  EZALLOR Sprinkle is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with EZALLOR Sprinkle during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, EZALLOR Sprinkle may cause fetal harm when administered to pregnant women. EZALLOR Sprinkle should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [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 Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Animal Data 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. 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).

                                                                      8.2 Lactation

                                                                      Risk Summary EZALLOR Sprinkle use is contraindicated during breastfeeding [see Contraindications (4)]. Limited data 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. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with EZALLOR Sprinkle.

                                                                        8.3 Females and Males of Reproductive Potential

                                                                        Contraception EZALLOR Sprinkle may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with EZALLOR Sprinkle.

                                                                          8.4 Pediatric Use

                                                                          Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

                                                                            8.5 Geriatric Use

                                                                            Of the 10,275 patients in clinical studies with rosuvastatin, 3,159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and EZALLOR Sprinkle should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

                                                                              8.6 Renal Impairment

                                                                              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 and dose adjustment is required [see Dosage and Administration (2.5), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

                                                                                8.7 Hepatic Impairment

                                                                                EZALLOR Sprinkle is contraindicated in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels. Chronic alcohol liver disease is known to increase rosuvastatin exposure; EZALLOR Sprinkle should be used with caution in these patients [see Contraindications (4), Warning and Precautions (5.2) and Clinical Pharmacology (12.3)].

                                                                                  8.8 Asian Patients

                                                                                  Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. EZALLOR Sprinkle dosage should be adjusted in Asian patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

                                                                                    10 OVERDOSAGE

                                                                                    There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.

                                                                                      11 DESCRIPTION

                                                                                      Rosuvastatin calcium is a synthetic lipid-lowering agent for oral administration. The chemical name for rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with the following structural formula:

                                                                                        The molecular formula for rosuvastatin calcium is (C22H27FN3O6S)2•Ca and the molecular weight is 1,001.14. Rosuvastatin calcium is off-white to light yellow amorphous powder that is slightly soluble in water and methanol, and insoluble in ethanol. Rosuvastatin calcium is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7. Each rosuvastatin capsule for oral administration contains 5 mg, 10 mg, 20 mg, or 40 mg of rosuvastatin (present as 5.198 mg, 10.395 mg, 20.790 mg, or 41.580 mg of rosuvastatin calcium) in the form of granules with the following inactive ingredients: microcrystalline cellulose, crospovidone, mannitol, magnesium oxide, ferric oxide, sodium citrate, hypromellose, polyethylene glycol 4000, and silicon dioxide. The capsule shells have the following inactive ingredients: gelatin, titanium dioxide, water, and sodium lauryl sulfate. Additionally following colorants are used in capsules: FD&C Red 40 (5 mg), FD&C Blue 1 (5 mg, 10 mg, 20 mg), D&C Red 28 (5 mg, 10 mg), FD&C Red 3 (20 mg), and FD&C Green 3 (40 mg). The imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, purified water, and potassium hydroxide.

                                                                                          12 CLINICAL PHARMACOLOGY

                                                                                          12.1 Mechanism of Action

                                                                                          Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for, action in the liver, the target organ for cholesterol lowering. 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.

                                                                                            12.2 Pharmacodynamics

                                                                                            Rosuvastatin dose dependently reduces elevated LDL-cholesterol and reduces total cholesterol and triglycerides and increases HDL-cholesterol [see Clinical Studies (14)]. A therapeutic response to rosuvastatin is evident within 1 week of commencing therapy and 90% of maximum response is usually achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that. Individualization of drug dosage should be based on the therapeutic response [see Dosage and Administration (2)].

                                                                                              12.3 Pharmacokinetics

                                                                                              Absorption 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%. Administration of rosuvastatin with food did not affect the AUC of rosuvastatin. The AUC of rosuvastatin does not differ following evening or morning drug administration. Distribution 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. Elimination Rosuvastatin is primarily eliminated by excretion in the feces. The elimination half-life of rosuvastatin is approximately 19 hours. Metabolism 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. Excretion Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. Specific Populations Racial or Ethnic Groups 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. Male and Female Patients There were no differences in plasma concentrations of rosuvastatin between men and women. Geriatric Patients There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age ≥ 65 years). Patients with Renal Impairment 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). Hemodialysis Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function. Patients with Hepatic Impairment 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. Drug Interaction Studies 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 organic anion-transporting polyproteins (OATP1B1, OATP1B3) and efflux transporter breast cancer resistance protein (BCRP). Concomitant administration of rosuvastatin with medications that are inhibitors of these transporter proteins (e.g., cyclosporine, certain HIV protease inhibitors) may result in increased rosuvastatin plasma concentrations [see Dosage and Administration (2.3) and Drug Interactions (7.1, 7.3)].

                                                                                                Table 4. Effect of Coadministered Drugs on Rosuvastatin Systemic Exposure

                                                                                                Coadministered drug and dosing regimenRosuvastatin
                                                                                                  Mean Ratio (ratio with/without coadministered drug) No Effect = 1
                                                                                                 Dose (mg)1Change in AUCChange in Cmax
                                                                                                Cyclosporine - stable dose required (75 mg to 200 mg BID)10 mg QD for 10 days7.12112
                                                                                                Atazanavir/ritonavir combination 300 mg/100 mg QD for 8 days10 mg3.1272
                                                                                                Simeprevir 150 mg QD, 7 days10 mg, single dose2.82 (2.3 to 3.4)33.22 (2.6 to 3.9)3
                                                                                                Lopinavir/ritonavir combination 400 mg/100 mg BID for 17 days20 mg QD for 7 days2.12 (1.7 to 2.6)352 (3.4 to 6.4)3
                                                                                                Gemfibrozil 600 mg BID for 7 days80 mg1.92 (1.6 to 2.2)32.22 (1.8 to 2.7)3
                                                                                                Eltrombopag 75 mg QD, 5 days10 mg1.6 (1.4 to 1.7)32 (1.8 to 2.3)3
                                                                                                Darunavir 600 mg/ritonavir 100 mg BID, 7 days10 mg QD for 7 days1.5 (1 to 2.1)32.4 (1.6 to 3.6)3
                                                                                                Tipranavir/ritonavir combination 500 mg/200mg BID for 11 days10 mg1.4 (1.2 to 1.6)32.2 (1.8 to 2.7)3
                                                                                                Dronedarone 400 mg BID10 mg1.4 
                                                                                                Itraconazole 200 mg QD, 5 days10 mg or 80 mg1.4 (1.2 to 1.6)3 1.3 (1.1 to 1.4)31.4 (1.2 to 1.5)3 1.2 (0.9 to 1.4)3
                                                                                                Ezetimibe 10 mg QD, 14 days10 mg QD for 14 days1.2 (0.9 to 1.6)31.2 (0.8 to 1.6)3
                                                                                                Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 days10 mg1.11.5
                                                                                                Fenofibrate 67 mg TID for 7 days10 mg1.2 (1.1 to 1.3)3
                                                                                                Rifampicin 450 mg QD, 7 days20 mg 
                                                                                                Aluminum & magnesium hydroxide combination antacid Administered simultaneously40 mg0.520.52
                                                                                                Administered 2 hours apart40 mg(0.4 to 0.5)3 0.8 (0.7 to 0.9)3(0.4 to 0.6)3 0.8 (0.7 to 1)3
                                                                                                Ketoconazole 200 BID for 7 days80 mg1 (0.8 to 1.2)31 (0.7 to 1.3)3
                                                                                                Fluconazole 200 mg QD for 11 days80 mg1.1 (1 to 1.3)31.1 (0.9 to 1.4)3
                                                                                                Erythromycin 500 mg QID for 7 days80 mg0.8 (0.7 to 0.9)30.7 (0.5 to 0.9)3

                                                                                                1 Single dose unless otherwise noted. 2 Clinically significant [see Dosage and Administration (2) and Warnings and Precautions (5)] 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) QD: Once daily BID: 2 times a day TID: 3 times a day QID: 4 times a day

                                                                                                  Table 5. Effect of Rosuvastatin Coadministration on Systemic Exposure to Other Drugs

                                                                                                  Rosuvastatin Dosage RegimenCoadministered Drug
                                                                                                    Mean Ratio (ratio with/without coadministered drug) No Effect = 1
                                                                                                   Name and DoseChange in Change in Name and Dose AUCChange in Cmax
                                                                                                  40 mg QD for 10 daysWarfarin1 25 mg single doseR-Warfarin 1 (1 to 1.1)2 S-Warfarin 1.1 (1 to 1.1)2R-Warfarin1 (0.9 to 1)2 S-Warfarin 1 (0.9 to 1.1)2
                                                                                                  40 mg QD for 12 daysDigoxin 0.5 mg single dose1 (0.9 to 1.2)21 (0.9 to 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 DaysEE 1.3 (1.2 to 1.3)2 NG 1.3 (1.3 to 1.4)2EE 1.3 (1.2 to 1.3)2 NG 1.2 (1.1 to 1.3)2

                                                                                                  EE = ethinyl estradiol, NG = norgestrel 1 Clinically significant pharmacodynamic effects [see Warnings and Precautions (5.3)] 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) QD: Once daily

                                                                                                    12.5 Pharmacogenomics

                                                                                                    Disposition of HMG-CoA reductase inhibitors, 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 521 C/C) is generally lower than 5% in most racial/ethnic groups. The impact of this polymorphism on efficacy and/or safety of rosuvastatin has not been clearly established.

                                                                                                      13 NONCLINICAL TOXICOLOGY

                                                                                                      13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

                                                                                                      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.

                                                                                                        13.2 Animal Toxicology and/or Pharmacology

                                                                                                        Central Nervous System Toxicity CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with several other members of this drug class. A chemically similar drug in this class produced dose-dependent optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in dogs, at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. Edema, hemorrhage, and partial necrosis in the interstitium of the choroid plexus was observed in a female dog sacrificed moribund at day 24 at 90 mg/kg/day by oral gavage (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Corneal opacity was seen in dogs treated for 52 weeks at 6 mg/kg/day by oral gavage (systemic exposures 20 times the human exposure at 40 mg/day based on AUC). Cataracts were seen in dogs treated for 12 weeks by oral gavage at 30 mg/kg/day (systemic exposures 60 times the human exposure at 40 mg/day based on AUC). Retinal dysplasia and retinal loss were seen in dogs treated for 4 weeks by oral gavage at 90 mg/kg/day (systemic exposures 100 times the human exposure at 40 mg/day based on AUC). Doses ≤30 mg/kg/day (systemic exposures ≤ 60 times the human exposure at 40 mg/day based on AUC) did not reveal retinal findings during treatment for up to one year. Juvenile Toxicology Study In a juvenile study, rats were dosed by oral gavage with 10 or 50 mg/kg/day from weaning for 9 weeks prior to pairing, throughout pairing and up to the day before necropsy for males or up to gestation day 7 for females. No effects on sexual development, testicular and epididymal appearance or fertility were observed at either dose level. Pediatric information is approved for AstraZeneca's CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

                                                                                                          14 CLINICAL STUDIES

                                                                                                          14.1 Hypertriglyceridemia

                                                                                                          Dose-Response Study: In a double-blind, placebo-controlled dose-response study in patients with baseline TG levels from 273 to 817 mg/dL, rosuvastatin given as a single daily dose (5 mg to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 9).

                                                                                                            Table 9. Dose-Response in Patients with Primary Hypertriglyceridemia over 6 Weeks Dosing Median (Min, Max) Percent Change from Baseline

                                                                                                            DosePlacebo (n=26)Rosuvastatin 5 mg (n=25)Rosuvastatin 10 mg (n=23)Rosuvastatin 20 mg (n=27)Rosuvastatin 40 mg (n=25)
                                                                                                            Triglycerides1 (-40, 72)-21 (-58, 38)-37 (-65, 5)-37 (-72, 11)-43 (-80, -7)
                                                                                                            nonHDL-C2 (-13, 19)-29 (-43, -8)-49 (-59, -20)-43 (-74, 12)-51 (-62, -6)
                                                                                                            VLDL-C2 (-36, 53)-25 (-62, 49)-48 (-72, 14)-49 (-83, 20)-56 (-83, 10)
                                                                                                            Total-C1 (-13, 17)-24 (-40, -4)-40 (-51, -14)-34 (-61, -11)-40 (-51, -4)
                                                                                                            LDL-C5 (-30, 52)-28 (-71, 2)-45 (-59, 7)-31 (-66, 34)-43 (-61, -3)
                                                                                                            HDL-C-3 (-25, 18)3 (-38, 33)8 (-8, 24)22 (-5, 50)17 (-14, 63)

                                                                                                              14.2 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

                                                                                                              In a randomized, multicenter, double-blind crossover study, 32 patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia) entered a 6-week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments in conjunction with the TLC diet for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. Rosuvastatin reduced non HDL-C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.

                                                                                                                Table 10. Lipid-modifying Effects of Rosuvastatin 10 mg and 20 mg in Primary Dysbetalipoproteinemia (Type III hyperlipoproteinemia) After Six Weeks by Median Percent Change (95% CI) from Baseline (N=32)

                                                                                                                 Median at Baseline (mg/dL)Median percent change from baseline (95% CI) Rosuvastatin 10 mgMedian percent change from baseline (95% CI) Rosuvastatin 20 mg
                                                                                                                Total-C342.5-43.3 (-46.9, -37.5)-47.6 (-51.6,-42.8)
                                                                                                                Triglycerides503.5-40.1 (-44.9, -33.6)-43 (-52.5, -33.1)
                                                                                                                NonHDL-C294.5-48.2 (-56.7, -45.6)-56.4 (-61.4, -48.5)
                                                                                                                VLDL-C + IDL-C209.5-46.8 (-53.7, -39.4)-56.2 (-67.7, -43.7)
                                                                                                                LDL-C112.5-54.4 (-59.1, -47.3)-57.3 (-59.4, -52.1)
                                                                                                                HDL-C35.510.2 (1.9, 12.3)11.2 (8.3, 20.5)
                                                                                                                RLP-C82-56.4 (-67.1, -49)-64.9 (-74, -56.6)
                                                                                                                Apo-E16-42.9 (-46.3, -33.3)-42.5 (-47.1, -35.6)

                                                                                                                  14.3 Homozygous Familial Hypercholesterolemia

                                                                                                                  Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8 to 63 years) were evaluated for their response to rosuvastatin 20 mg 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. Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca's CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

                                                                                                                    16 HOW SUPPLIED/STORAGE AND HANDLING

                                                                                                                    EZALLOR Sprinkle (rosuvastatin) capsules 5 mg are hard gelatin capsule, Size “3” pink cap/off white body, imprinted axially with “984” on cap and body in black ink filled with yellow colored granules. They are available as follows: Bottles of 30’s with Child Resistant Closure ...................... NDC 47335-984-83 Bottles of 90’s with Child Resistant Closure ...................... NDC 47335-984-81 Unit-dose blister pack of 30 (3 × 10) capsules .................... NDC 47335-984-64 EZALLOR Sprinkle (rosuvastatin) capsules 10 mg are hard gelatin capsule, Size “3” purple cap/off white body, imprinted axially with “985” on cap and body in black ink filled with yellow colored granules. They are available as follows: Bottles of 30’s with Child Resistant Closure ...................... NDC 47335-985-83 Bottles of 90’s with Child Resistant Closure ...................... NDC 47335-985-81 Unit-dose blister pack of 30 (3 × 10) capsules .................... NDC 47335-985-64 EZALLOR Sprinkle (rosuvastatin) capsules 20 mg are hard gelatin capsule, Size “1” blue cap/off white body, imprinted axially with “986” on cap and body in black ink filled with yellow colored granules. They are available as follows: Bottles of 30’s with Child Resistant Closure ...................... NDC 47335-986-83 Bottles of 90’s with Child Resistant Closure ...................... NDC 47335-986-81 Unit-dose blister pack of 30 (3 × 10) capsules .................... NDC 47335-986-64 EZALLOR Sprinkle (rosuvastatin) capsules 40 mg are hard gelatin capsule, Size “0el” green cap/white body, imprinted axially with “987” on cap and body in black ink filled with yellow colored granules. They are available as follows: Bottles of 30’s with Child Resistant Closure ...................... NDC 47335-987-83 Bottles of 90’s with Child Resistant Closure ...................... NDC 47335-987-81 Unit-dose blister pack of 30 (3 × 10) capsules .................... NDC 47335-987-64

                                                                                                                      Storage

                                                                                                                      Store EZALLOR Sprinkle (rosuvastatin) capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

                                                                                                                        17 PATIENT COUNSELING INFORMATION

                                                                                                                        Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

                                                                                                                          Skeletal Muscle Effects

                                                                                                                          Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing EZALLOR Sprinkle.

                                                                                                                            Concomitant Use of Antacids

                                                                                                                            When taking EZALLOR Sprinkle with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after EZALLOR Sprinkle administration.

                                                                                                                              Embryofetal Toxicity

                                                                                                                              Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy. [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].

                                                                                                                                Lactation

                                                                                                                                Advise women not to breastfeed during treatment with EZALLOR Sprinkle [see Contraindications (4) and Use in Specific Populations (8.2)].

                                                                                                                                  Liver Enzymes

                                                                                                                                  It is recommended that liver enzyme tests be performed before the initiation of EZALLOR Sprinkle and if signs or symptoms of liver injury occur. All patients treated with EZALLOR Sprinkle should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

                                                                                                                                    Administration Information

                                                                                                                                    Inform patients:

                                                                                                                                    • EZALLOR Sprinkle can be administered as a single dose at any time of day, with or without food.
                                                                                                                                    • Patients should be instructed not to take 2 doses of EZALLOR Sprinkle within 12 hours of each other.
                                                                                                                                    • EZALLOR Sprinkle should not be crushed or chewed.

                                                                                                                                    For Oral Administration Patients with Difficulty Swallowing Capsules Instruct patients that the EZALLOR Sprinkle capsule can be opened, the granules filled in the capsule carefully emptied onto one teaspoonful of soft food (such as applesauce, or chocolate-or vanilla-flavored pudding). The granules with soft food (such as applesauce, or chocolate-or vanilla-flavored pudding) should be swallowed within 60 minutes, without chewing. The mixture should not be stored for future use. If it is not used in its entirety, the remaining mixture should be discarded immediately For Nasogastric Tube (≥16 French) Administration Instruct patients that EZALLOR Sprinkle capsule can be opened and the intact granules emptied into a 60 mL catheter tipped syringe and add 40 mL of water. Replace the plunger and shake the syringe vigorously for 15 seconds. The granules in EZALLOR Sprinkle may start dissolving which is acceptable. Attach the syringe to a nasogastric tube (≥16-French) and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with 20 mL of additional water. The mixture must be used immediately after preparation and not be stored for future use. If it is not used in its entirety, the remaining mixture should be discarded immediately. Use with any other liquids is not recommended.

                                                                                                                                      Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd. Halol-Baroda Highway, Halol-389 350, Gujarat, India. Version: 04/2020