Drug Safety-related Labeling Changes (SrLC)

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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)

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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)

CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ?65 years, inadequately treated hypothyroidism, renal impairment).

…

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.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.