Drug Safety-related Labeling Changes (SrLC)

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CRESTOR (NDA-021366)

(ROSUVASTATIN CALCIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/13/2023 (SUPPL-43)

4 Contraindications

Additions and revisions underlined:

CRESTOR is contraindicated in the following conditions:

• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].

• Hypersensitivity to rosuvastatin or any excipients in CRESTOR. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR [see Adverse Reactions (6.1)].

5 Warnings and Precautions

5.1 Myopathy and Rhabdomyolysis

Section title revised

Additions and revisions underlined:

CRESTOR may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including CRESTOR.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher CRESTOR dosage. Asian patients on CRESTOR may be at higher risk for myopathy [see Drug Interactions (7.1) and Use in Specific Populations (8.8)]. The myopathy risk is greater in patients taking CRESTOR 40 mg daily compared with lower CRESTOR dosages.

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

The concomitant use of CRESTOR with cyclosporine or gemfibrozil is not recommended. CRESTOR dosage modifications are recommended for patients taking certain antiviral medications, darolutamide, and regorafenib [see Dosage and Administration (2.6)]. Niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

Discontinue CRESTOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if CRESTOR is discontinued.

Temporarily discontinue CRESTOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

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

5.2 Immune-Mediated Necrotizing Myopathy

Additions and revisions underlined:

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue CRESTOR if IMNM is suspected.

5.3 Hepatic Dysfunction

Section title revised

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

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7)].

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

5.5 Increases in HbA1c and Fasting Serum Glucose Levels

Section title revised

Additions and revisions underlined:

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including CRESTOR. Based on clinical trial data with CRESTOR, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1)].

Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6 Adverse Reactions

Additions and revisions underlined:

The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]

Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]

Hepatic Dysfunction [see Warnings and Precautions (5.3)]

Proteinuria and Hematuria [see Warnings and Precautions (5.4)]

Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.5)]

7 Drug Interactions

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTOR

Section title revised

Newly added information:

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

Newly added table: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTOR

7.2 Drug Interactions that Decrease the Efficacy of CRESTOR

Newly added subsection

7.3 CRESTOR Effects on Other Drugs

Newly added subsection

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes; please refer to label

8.2 Lactation

Extensive changes; please refer to label

8.4 Pediatric Use

Extensive changes; please refer to label

8.5 Geriatric Use

Newly added information:

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

8.6 Renal Impairment

Newly added information:

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

8.7 Hepatic Impairment

Additions and revisions underlined:

CRESTOR is contraindicated in patients with acute liver failure or decompensated cirrhosis. Chronic alcohol liver disease is known to increase rosuvastatin exposure. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Contraindications (4), Warning and Precautions (5.3) and Clinical Pharmacology (12.3)].

8.8 Asian Patients

Additions and revisions underlined:

Pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects when compared with White controls. Adjust the CRESTOR dosage in Asian patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label

PATIENT INFORMATION

Extensive changes; please refer to label

01/13/2023 (SUPPL-44)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and revisions underlined:

The following adverse reactions have been identified during postapproval use of CRESTOR. 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.

Blood Disorders: thrombocytopenia

Hepatobiliary Disorders: hepatitis, jaundice, fatal and non-fatal hepatic failure

Musculoskeletal Disorders: arthralgia, rare reports of immune-mediated necrotizing myopathy associated with statin use

Nervous System Disorders: peripheral neuropathy, rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with the use of 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).

Psychiatric Disorders: depression, sleep disorders (including insomnia and nightmares)

Reproductive System and Breast Disorders: gynecomastia

Respiratory Disorders: interstitial lung disease

Skin and Subcutaneous Tissue Disorders: drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid drug eruption

09/25/2020 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

(New subsection added)

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

05/21/2020 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Skeletal Muscle Effects

(Additions and/or revisions underlined)

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 gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir). 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 CRESTOR with colchicine.

…

7 Drug Interactions

7.3 Anti-viral Medications

(Subsection title revised)

(Additions and/or revisions underlined)

Coadministration of rosuvastatin with certain anti-viral drugs has differing effects on rosuvastatin exposure and may increase risk of myopathy.

The combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti- HCV) drugs, increases rosuvastatin exposure. Similarly, the combination of ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For these combinations of anti-HCV drugs, concomitant use with CRESTOR is not recommended.

Simeprevir and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which are anti-HCV drugs, increase rosuvastatin exposure. Combinations of atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs, increase rosuvastatin exposure. For these anti-viral drugs, the dose of CRESTOR should not exceed 10 mg once daily.

The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure. No dose adjustment is needed for concomitant use with these combinations.

7.5 Regorafenib

(Newly added subsection)

Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. If used together, the dose of CRESTOR should not exceed 10 mg once daily.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Talk to your doctor before you start taking any new medicines.

Taking CRESTOR with certain other medicines may affect each other causing side effects. CRESTOR may affect the way other medicines work, and other medicines may affect how CRESTOR works.

Especially tell your doctor if you take:

• cyclosporine (a medicine for your immune system)

• gemfibrozil (a fibric acid medicine for lowering cholesterol)

• darolutamide (a medicine for the treatment of prostate cancer)

• regorafenib (a medicine used to treat cancer of the colon and rectum)

• anti-viral medicines including certain HIV or hepatitis C virus drugs such as:

• lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, simeprevir

• combination of

• sofosbuvir/velpatasvir/voxilaprevir

• dasabuvir/ombitasvir/paritaprevir/ritonavir

• elbasvir/grazoprevir

• sofosbuvir/velpatasvir

• glecaprevir/pibrentasvir and

• all other combinations with ledipasvir including ledipasvir/sofosbuvir

• certain anti-fungal medicines (such as itraconazole, ketoconazole and fluconazole)

• coumarin anticoagulants (medicines that prevent blood clots, such as warfarin)

• niacin or nicotinic acid

• fibric acid derivatives (such as fenofibrate)

• colchicine (a medicine used to treat gout)

Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know all of the medicines you take. Keep a list of them to show your doctor and pharmacist when you get new medicine.

…

05/21/2020 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Skeletal Muscle Effects

(Additions and/or revisions underlined)

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 gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir). 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 CRESTOR with colchicine.

…

7 Drug Interactions

7.4 Darolutamide

(Newly added subsection)

Darolutamide increased rosuvastatin exposure more than 5 fold. Therefore, in patients taking darolutamide, the dose of CRESTOR should not exceed 5 mg once daily.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Talk to your doctor before you start taking any new medicines.

Taking CRESTOR with certain other medicines may affect each other causing side effects. CRESTOR may affect the way other medicines work, and other medicines may affect how CRESTOR works.

Especially tell your doctor if you take:

• cyclosporine (a medicine for your immune system)

• gemfibrozil (a fibric acid medicine for lowering cholesterol)

• darolutamide (a medicine for the treatment of prostate cancer)

• regorafenib (a medicine used to treat cancer of the colon and rectum)

• anti-viral medicines including certain HIV or hepatitis C virus drugs such as:

• lopinavir, ritonavir, fosamprenavir, tipranavir, atazanavir, simeprevir

• combination of

• sofosbuvir/velpatasvir/voxilaprevir

• dasabuvir/ombitasvir/paritaprevir/ritonavir

• elbasvir/grazoprevir

• sofosbuvir/velpatasvir

• glecaprevir/pibrentasvir and

• all other combinations with ledipasvir including ledipasvir/sofosbuvir

• certain anti-fungal medicines (such as itraconazole, ketoconazole and fluconazole)

• coumarin anticoagulants (medicines that prevent blood clots, such as warfarin)

• niacin or nicotinic acid

• fibric acid derivatives (such as fenofibrate)

• colchicine (a medicine used to treat gout)

Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know all of the medicines you take. Keep a list of them to show your doctor and pharmacist when you get new medicine.

…

11/09/2018 (SUPPL-38)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Cyclosporine

(additions underlined)

Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of CRESTOR should not exceed 5 mg once daily.

7.3 Protease Inhibitors

(additions underlined)

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.

…

08/04/2017 (SUPPL-37)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following to the adverse reactions identified during postapproval use of CRESTOR:

interstitial lung disease

05/27/2016 (SUPPL-33)

Approved Drug Label (PDF)

4 Contraindications

Replace bullets 3 and 4 with the following:

• Pregnancy

• Lactation. Limited data indicate that CRESTOR is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require CRESTOR treatment should not breastfeed their infants.

6 Adverse Reactions

Clinical Studies Experience

• In the CRESTOR controlled clinical trials database (placebo or active-controlled) of 5394 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 greater than or equal to 2%) in the CRESTOR controlled clinical trial database of 5394 patients were:
  • headache
  • myalgia
  • abdominal pain
  • asthenia
  • nausea
• Adverse reactions reported in (greater than or equal to 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - What is CRESTOR?

CRESTOR is used to treat:

• adults who cannot control their cholesterol levels by diet and exercise alone
• children 8 to 17 years of age with heterozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL)
• children 7 to 17 years of age with homozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL).

CRESTOR is not approved for use in children with heterozygous familial hypercholesterolemia younger than 8 years of age or for use in children with homozygous familial hypercholesterolemia younger than 7 years of age.

PCI - Embryofetal Toxicity (add new section)

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.

PCI - Lactation (add new section)

Advise women not to breastfeed during treatment with CRESTOR.