HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`CRESTOR safely and effectively. See full prescribing information for
`CRESTOR.
`CRESTOR (rosuvastatin calcium) tablets
`Initial U.S. Approval: 2003
`------------------RECENT MAJOR CHANGES -----------------
`Indications and Usage, Slowing of the Progression
`of Atherosclerosis (1.4)
`11/2007
`Dosage and Administration,
` Slowing of the Progression of Atherosclerosis (2.2)
`11/2007
` Use with Cyclosporine or Lopinavir/Ritonavir (2.5)
`07/2007
`Warnings and Precautions, Skeletal Muscle Effects (5.1)
`07/2007
`
`--------------------INDICATIONS AND USAGE-----------------
`CRESTOR is an HMG Co-A reductase inhibitor indicated for:
`• patients with primary hyperlipidemia and mixed dyslipidemia as an
`adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and
`TG levels and to increase HDL-C (1.1)
`• patients with hypertriglyceridemia as an adjunct to diet (1.2)
`• patients with homozygous familial hypercholesterolemia (HoFH) to reduce
`LDL-C, total-C, and ApoB (1.3)
`• slowing the progression of atherosclerosis as part of a treatment strategy to
`lower total-C and LDL-C as an adjunct to diet (1.4)
`Limitations of use (1.5):
`• Effect of CRESTOR on cardiovascular morbidity and mortality has not
`been determined.
`• CRESTOR has not been studied in Fredrickson Type I, III, and V
`dyslipidemias.
`-------------------------DOSAGE AND ADMINISTRATION---------------------
` • CRESTOR can be taken with or without food, at any time of day. (2.1)
`• Dose range: 5-40 mg once daily. Use 40 mg dose only for patients not
`reaching LDL-C goal with 20 mg. (2.1)
`• Hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, and
`atherosclerosis: Starting dose 10 mg. Consider 20 mg starting dose for
`patients with LDL-C>190 mg/dL and aggressive lipid targets. (2.2)
`• HoFH: Starting dose 20 mg. (2.3)
`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`Tablets: 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)
`• Women who are pregnant or may become pregnant (4, 8.1)
`• Nursing mothers (4, 8.3)
`
`-------------------------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,
`lopinavir/ritonavir, or certain other lipid-lowering drugs. Advise patients to
`promptly report unexplained muscle pain, tenderness, or weakness and
`discontinue CRESTOR if signs or symptoms appear (5.1)
`• Liver enzyme abnormalities and monitoring: Persistent elevations in
`hepatic transaminases can occur. Monitor liver enzymes before and during
`treatment. (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 AstraZeneca
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`-----------------------------------DRUG INTERACTIONS-----------------
`• Cyclosporine: Combination increases rosuvastatin exposure. Limit CRESTOR to 5 mg
`once daily. (2.5, 7.1)
`• Gemfibrozil: Combination should be avoided. If used together, limit
`CRESTOR dose to 10 mg once daily. (2.6, 5.1, 7.2)
`• Lopinavir/Ritonavir: Combination increases rosuvastatin exposure. Limit
`CRESTOR dose to 10 mg once daily. (2.5, 5.1, 7.3)
`• Coumarin anti-coagulants: Combination prolongs INR. Achieve stable
`INR prior to starting CRESTOR. Monitor INR frequently until stable upon
`initiation or alteration of CRESTOR therapy. (5.3, 7.4)
`• Concomitant lipid-lowering therapies: Use with fibrates and niacin
`products may increase the risk of skeletal muscle effects. (2.6, 5.1, 7.5,
`7.6)
`---------------------------USE IN SPECIFIC POPULATIONS--------------------
`• Pediatric use: Safety and effectiveness not established. (8.4)
`• Severe renal impairment (not on hemodialysis): Starting dose is 5 mg,
`not to exceed 10 mg. (2.7, 5.1, 8.6)
`• Asian population: Consider 5 mg starting dose. (2.4, 8.8)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 11/2007
`
`*FULL PRESCRIBING INFORMATION: CONTENTS
`1 INDICATIONS AND USAGE
`1.1 Hyperlipidemia and Mixed Dyslipidemia
`1.2 Hypertriglyceridemia
`1.3 Homozygous Familial Hypercholesterolemia
`1.4 Slowing of the Progression of Atherosclerosis
`1.5 Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`2.2 Hyperlipidemia, Mixed Dyslipidemia,
`Hypertriglyceridemia, and Slowing of the Progression of
`Atherosclerosis
`2.3 Homozygous Familial Hypercholesterolemia
`2.4 Dosage in Asian Patients
`2.5 Use with Cyclosporine or Lopinavir/Rotonavir
`2.6 Concomitant Lipid-Lowering Therapy
`
`2.7 Dosage in Patients With Severe Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Skeletal Muscle Effects
`5.2 Liver Enzyme Abnormalities and Monitoring
`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 Lopinavir/Ritonavir
`7.4 Coumarin Anticoagulants
`7.5 Niacin
`7.6 Fenofibrate
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`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
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Hyperlipidemia and Mixed Dyslipidemia
`14.2 Heterozygous Familial Hypercholesterolemia
`14.3 Hypertriglyceridemia
`14.4 Homozygous Familial Hypercholesterolemia
`14.5 Slowing of the Progression of Atherosclerosis
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Skeletal Muscle Effects
`17.2 Concomitant Use of Antacids
`17.3 Pregnancy
`17.4 Liver Enzymes
`*Sections or subsections omitted from the full prescribing
`information are not listed
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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`1.1 Hyperlipidemia and Mixed Dyslipidemia
`
`CRESTOR is indicated as adjunctive therapy to diet to reduce elevated Total-C, LDL-C,
`ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with primary
`hyperlipidemia or mixed dyslipidemia. Lipid-altering agents should be used in addition to a
`diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological
`interventions alone has been inadequate.
`
`1.2 Hypertriglyceridemia
`
`CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with
`hypertriglyceridemia.
`
`1.3 Homozygous Familial Hypercholesterolemia
`
`CRESTOR 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 Slowing of the Progression of Atherosclerosis
`
`CRESTOR is indicated as adjunctive therapy to diet to slow the progression of
`atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to
`target levels.
`
`1.5 Limitations of Use
`
`The effect of CRESTOR on cardiovascular morbidity and mortality has not been determined.
`
`CRESTOR has not been studied in Fredrickson Type I, III, and V dyslipidemias.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`
`The dose range for CRESTOR is 5 to 40 mg orally once daily.
`
`CRESTOR can be administered as a single dose at any time of day, with or without food.
`
`When initiating CRESTOR therapy or switching from another HMG-CoA reductase inhibitor
`therapy, the appropriate CRESTOR starting dose should first be utilized, and only then
`titrated according to the patient’s response and individualized goal of therapy.
`
`The 40 mg dose of CRESTOR 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)].
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`2.2 Hyperlipidemia, Mixed Dyslipidemia, Hypertriglyceridemia and Slowing of the
`Progression of Atherosclerosis
`
`The recommended starting dose of CRESTOR is 10 mg once daily. For patients with marked
`hyperlipidemia (LDL-C > 190 mg/dL) and aggressive lipid targets, a 20 mg starting dose may
`be considered.
`
`After initiation or upon titration of CRESTOR, lipid levels should be analyzed within 2 to 4
`weeks and the dosage adjusted accordingly.
`
`2.3 Homozygous Familial Hypercholesterolemia
`
`The recommended starting dose of CRESTOR is 20 mg once daily. Response to therapy
`should be estimated from pre-apheresis LDL-C levels.
`
`2.4 Dosage in Asian Patients
`
`Initiation of CRESTOR therapy with 5 mg once daily should be considered for Asian
`patients. [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].
`
`2.5 Use with Cyclosporine or Lopinavir/Ritonavir
`
`In patients taking cyclosporine, the dose of CRESTOR should be limited to 5 mg once daily
`[see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. In patients taking a
`combination of lopinavir and ritonavir, the dose of CRESTOR should be limited to 10 mg
`once daily [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
`
`
`2.6 Concomitant Lipid-Lowering Therapy
`
`The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination
`with niacin or fenofibrate; a reduction in CRESTOR dosage should be considered in this
`setting. [see Warnings and Precautions (5.1) and Drug Interactions (7.5, 7.6)]
`
`Combination therapy with gemfibrozil should be avoided because of an increase in
`CRESTOR exposure with concomitant use; if CRESTOR is used in combination with
`gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily [see Warnings and
`Precautions (5.1) and Drug Interactions (7.2)].
`
`2.7 Dosage in Patients With Severe Renal Impairment
`
`For patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) not on hemodialysis,
`dosing of CRESTOR 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)].
`
`3 DOSAGE FORMS AND STRENGTHS
`5 mg: Yellow, round, biconvex, coated tablets. Debossed “CRESTOR” and “5” on one side
`of the tablet.
`
`10 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “10” on one side of
`the tablet.
`
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`20 mg: Pink, round, biconvex, coated tablets. Debossed “CRESTOR” and “20” on one side of
`the tablet.
`
`40 mg: Pink, oval, biconvex, coated tablets. Debossed “CRESTOR” on one side and “40” on
`the other side of the tablet.
`
`4 CONTRAINDICATIONS
`CRESTOR 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
`CRESTOR [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)].
`
`• Women who are pregnant or may become pregnant. Because HMG-CoA reductase
`inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically
`active substances derived from cholesterol, CRESTOR may cause fetal harm when
`administered to pregnant women. Additionally, there is no apparent benefit to therapy
`during pregnancy, and safety in pregnant women has not been established. If the patient
`becomes pregnant while taking this drug, the patient should be apprised of the potential
`hazard to the fetus and the lack of known clinical benefit with continued use during
`pregnancy. [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.2)]
`
`• Nursing mothers. Because another drug in this class passes into breast milk, and because
`HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in
`nursing infants, women who require CRESTOR treatment should be advised not to nurse
`their infants. [see Use in Specific Populations (8.3)].
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 5
`
`
`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 CRESTOR. These risks
`can occur at any dose level, but are increased at the highest dose (40 mg).
`
`CRESTOR 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 CRESTOR may be increased with concurrent
`administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil,
`cyclosporine, or lopinavir/ritonavir. [see Dosage and Administration (2) and Drug
`Interactions (7)].
`
`CRESTOR therapy should be discontinued if markedly elevated creatinine kinase levels
`occur or myopathy is diagnosed or suspected. CRESTOR therapy should also be temporarily
`withheld in any patient with an acute, serious condition suggestive of myopathy or
`
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`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). All patients should be advised to promptly
`report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by
`malaise or fever.
`
`5.2 Liver Enzyme Abnormalities and Monitoring
`It is recommended that liver enzyme tests be performed before and at 12 weeks following
`both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually)
`thereafter.
`
`Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with
`HMG-CoA reductase inhibitors, including CRESTOR. 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 CRESTOR 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 CRESTOR versus 0.5% of
`patients treated with placebo.
`
`Patients who develop increased transaminase levels should be monitored until the
`abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist,
`reduction of dose or withdrawal of CRESTOR is recommended.
`
`CRESTOR 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 CRESTOR. [see Contraindications (4)]
`
`5.3 Concomitant Coumarin Anticoagulants
`
`Caution should be exercised when anticoagulants are given in conjunction with CRESTOR
`because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin
`time/INR. In patients taking coumarin anticoagulants and CRESTOR concomitantly, INR
`should be determined before starting CRESTOR 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 CRESTOR clinical trial program, dipstick-positive proteinuria and microscopic
`hematuria were observed among CRESTOR treated patients. This finding was more frequent
`in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR 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 CRESTOR therapy with
`unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.
`
`5.5 Endocrine Effects
`
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`Although clinical studies have shown that CRESTOR alone does not reduce basal plasma
`cortisol concentration or impair adrenal reserve, caution should be exercised if CRESTOR 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)]
`
`In the CRESTOR 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 CRESTOR
`controlled clinical trial database of 5,394 patients were:
`
`• headache
`
`• myalgia
`
`•
`
`•
`
`abdominal pain
`
`asthenia
`
`• nausea
`
`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.
`
`Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a
`rate greater than or equal to placebo are shown in Table 1. These studies had a treatment
`duration of up to 12 weeks.
`
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`Table 1. Adverse Reactions* Reported by ≥ 2% of Patients Treated with CRESTOR
`and ≥ Placebo in Placebo-Controlled Trials (% of Patients)
`
`Adverse
`Reactions
`
`Total
`CRESTOR
`5 mg
`–
`40mg
`N=744
`
`Placebo
`
`N=382
`
`CRESTOR
`5 mg
`
`CRESTOR
`10 mg
`
`CRESTOR
`20 mg
`
`CRESTOR
`40 mg
`
`N=291
`
`N=283
`
`N=64
`
`N=106
`
`Headache
`
`Nausea
`
`Myalgia
`
`Asthenia
`
`5.5
`
`3.8
`
`3.1
`
`2.4
`
`Constipation 2.1
`
`4.9
`
`3.5
`
`2.1
`
`3.2
`
`2.1
`
`3.1
`
`6.3
`
`6.3
`
`4.7
`
`4.7
`
`8.5
`
`0
`
`1.9
`
`0.9
`
`2.8
`
`5.5
`
`3.4
`
`2.8
`
`2.7
`
`2.4
`
`5.0
`
`3.1
`
`1.3
`
`2.6
`
`2.4
`
`* 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
`[see Warnings and Precautions
`microscopic hematuria
`(5.4)]; elevated creatine
`phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and
`bilirubin; and thyroid function abnormalities.
`
`In the METEOR study, 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 CRESTOR-treated
`subjects 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 [see Clinical Studies (14.5)]
`
`Adverse reactions reported in ≥ 2% of patients and at a rate greater than or equal to placebo
`are shown in Table 2.
`
`Table 2. Adverse Reactions* Reported by ≥ 2% of Patients Treated with CRESTOR
`and ≥ Placebo in the METEOR Trial (% of Patients)
`
`Adverse Reactions
`
`CRESTOR 40 mg
`
`Placebo
`
`N=700
`
`12.7
`
`10.1
`
`6.4
`
`Myalgia
`
`Arthralgia
`
`Headache
`
`
`
`N=281
`
`12.1
`
`7.1
`
`5.3
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`Dizziness
`
`Blood CPK
`
`Abdominal pain
`
`ALT >3x ULN
`
`4.0
`
`2.6
`
`2.4
`
`2.2
`
`2.8
`
`0.7
`
`1.8
`
`0.7
`
`* Adverse reactions by MedDRA preferred term.
`
`
`6.2 Postmarketing Experience
`
`The following adverse reactions have been identified during post-approval use of CRESTOR:
`arthralgia, hepatitis, jaundice and memory loss. 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.
`
`7 DRUG INTERACTIONS
`7.1 Cyclosporine
`
`Cyclosporine significantly increased rosuvastatin exposure. Therefore, in patients taking
`cyclosporine, therapy should be limited to CRESTOR 5 mg once daily. [see Dosage and
`Administration (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
`
`7.2 Gemfibrozil
`
`Gemfibrozil significantly increased rosuvastatin exposure. Therefore, combination therapy
`with CRESTOR and gemfibrozil should be avoided. If used, do not exceed CRESTOR 10
`mg once daily. [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
`
`7.3 Lopinavir/Ritonavir
`
`The combination of lopinavir and ritonavir significantly increased rosuvastatin exposure.
`Therefore, in patients taking a combination of lopinavir and ritonavir, the dose of CRESTOR
`should be limited to 10 mg once daily. The effect of other protease inhibitors on rosuvastatin
`pharmacokinetics has not been examined. [see Dosage and Administration (2.5), Warnings
`and Precautions (5.1) and Clinical Pharmacology (12.3)]
`
`7.4 Coumarin Anticoagulants
`
`CRESTOR significantly increased INR in patients receiving coumarin anticoagulants.
`Therefore, caution should be exercised when coumarin anticoagulants are given in
`conjunction with CRESTOR. In patients taking coumarin anticoagulants and CRESTOR
`concomitantly, INR should be determined before starting CRESTOR 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)]
`
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`7.5 Niacin
`
`The risk of skeletal muscle effects may be enhanced when CRESTOR is used in combination
`with niacin; a reduction in CRESTOR dosage should be considered in this setting [see
`Warnings and Precautions (5.1)]
`
`7.6 Fenofibrate
`When CRESTOR was coadministered with fenofibrate no clinically significant increase in
`the AUC of rosuvastatin or fenofibrate was observed. The benefit of further alterations in
`lipid levels by the combined use of CRESTOR with fibrates should be carefully weighed
`against the potential risks of this combination. [see Warnings and Precautions (5.1) and
`Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Teratogenic effects: Pregnancy Category X.
`
`CRESTOR is contraindicated in women who are or may become pregnant. Serum cholesterol
`and triglycerides increase during normal pregnancy, and cholesterol products are essential for
`fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering
`drugs during pregnancy should have little impact on long-term outcomes of primary
`hyperlipidemia therapy. [see Contraindications (4)]
`
`There are no adequate and well-controlled studies of CRESTOR in pregnant women. There
`have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA
`reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women
`exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies,
`spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the
`general population. However, this study was only able to exclude a three-to-four-fold
`increased risk of congenital anomalies over background incidence. In 89% of these cases,
`drug treatment started before pregnancy and stopped during the first trimester when
`pregnancy was identified.
`
`Rosuvastatin crosses the placenta in rats and rabbits. In rats, CRESTOR was not teratogenic
`at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times
`the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight
`among female pups, and delayed ossification. In rabbits, pup viability decreased and
`maternal mortality increased at doses equivalent to the human dose of 40 mg/day. [see
`Nonclinical Toxicology (13.2)]
`
`CRESTOR may cause fetal harm when administered to a pregnant woman. If the patient
`becomes pregnant while taking CRESTOR, the patient should be apprised of the potential
`risks to the fetus and the lack of known clinical benefit with continued use during pregnancy.
`
`8.3 Nursing Mothers
`
`It is not known whether rosuvastatin is excreted in human milk, but a small amount of
`another drug in this class does pass into breast milk. In rats, breast milk concentrations of
`rosuvastatin are three times higher than plasma levels; however, animal breast milk drug
`levels may not accurately reflect human breast milk levels. Because another drug in this class
`
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`passes into human milk and because HMG-CoA reductase inhibitors have a potential to cause
`serious adverse reactions in nursing infants, women who require CRESTOR treatment should
`be advised not to nurse their infants. [see Contraindication (4)]
`
`8.4 Pediatric Use
`
`The safety and effectiveness of CRESTOR in pediatric patients have not been established.
`
`Treatment experience with CRESTOR in a pediatric population is limited to 8 patients with
`homozygous FH. None of these patients was below 8 years of age.
`
`In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with
`heterozygous FH received single and multiple oral doses of CRESTOR. Both Cmax and AUC
`of rosuvastatin were similar to values observed in adult subjects administered the same doses.
`
`8.5 Geriatric Use
`
`Of the 10,275 patients in clinical studies with CRESTOR, 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 CRESTOR should be prescribed with
`caution in the elderly. [see Warnings and Precautions, (5.1) and Clinical Pharmacology,
`(12.3)]
`
`Renal Impairment
`
`8.6
`
`Rosuvastatin exposure is not influenced by mild to moderate renal impairment (CLcr ≥ 30
`mL/min/1.73 m2); however, exposure to rosuvastatin is increased to a clinically significant
`extent in patients with severe renal impairment who are not receiving hemodialysis.
`CRESTOR dosing should be adjusted in patients with severe renal impairment (CLcr <30
`mL/min/1.73 m2) not requiring hemodialysis. [see Dosage and Administration (2.7) and
`Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
`
`
`8.7 Hepatic Impairment
`
`CRESTOR 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; CRESTOR should be used with caution
`in these patients. [see Contraindications (4) and 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.
`CRESTOR dosage should be adjusted in Asian patients. [see Dosage and Administration
`(2.4) and Clinical Pharmacology (12.3)]
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`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
`CRESTOR (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 empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca and the molecular
`weight is 1001.14. 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.
`
`lactose
`tablet contains: microcrystalline cellulose NF,
`Ingredients: Each
`Inactive
`monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF,
`hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric
`oxide NF.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`CRESTOR 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.
`
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`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 CRESTOR dose. The absolute bioavailability
`of rosuvastatin is approximately 20%.
`
`Administration of CRESTOR 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.
`• 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%). 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