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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
CRESTOR (NDA-021366)
(ROSUVASTATIN CALCIUM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/31/2024 (SUPPL-46)
7 Drug Interactions
7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTORAddition of the following underlined text to Table 5:
Table 5: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with CRESTOR
Ticagrelor
Clinical Impact: Concomitant use of CRESTOR and ticagrelor has been shown to increase rosuvastatin concentrations, which may result in increased risk of myopathy. Cases of myopathy and rhabdomyolysis have been reported in patients using both products concomitantly. Cases have occurred more frequently in patients taking 40 mg of rosuvastatin.
Intervention: In patients taking concomitant ticagrelor, especially those with additional risk factors for myopathy and rhabdomyolysis, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of CRESTOR
Addition of the following underlined text to Table 6:
Antacids
Clinical Impact: Concomitant aluminum and magnesium hydroxide combination antacid
administration decreased the mean exposure of rosuvastatin 50% [see Clinical
Pharmacology (12.3)].
Intervention: In patients taking antacid, administer CRESTOR at least 2 hours before the
antacid.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
…
When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, administer CRESTOR at least 2 hours before the antacid [see Drug Interactions (7.2)].
…
PATIENT INFORMATION
Extensive additions and/or revisions; please refer to label for complete information.
07/27/2023 (SUPPL-45)
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or 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). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.
…
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 RhabdomyolysisSection 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.
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.
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.
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 CRESTORSection 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
Newly added subsection
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)].
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 INFORMATIONExtensive changes; please refer to label
Extensive changes; please refer to label
01/13/2023 (SUPPL-44)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions 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)
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)
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.
(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)
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)
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.
(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)
6 Adverse Reactions
6.2 Postmarketing ExperienceAddition of the following to the adverse reactions identified during postapproval use of CRESTOR:
interstitial lung disease
05/27/2016 (SUPPL-33)
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.