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.

ZOCOR (NDA-019766)

(SIMVASTATIN)

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

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08/09/2023 (SUPPL-104)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… 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.

…

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

PATIENT INFORMATION

Additions and/or revisions underlined:

Before you take ZOCOR, tell your healthcare provider about all of your medical conditions, including if you:

…

have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing), ocular myasthenia (a disease causing eye muscle weakness).
…

03/14/2023 (SUPPL-103)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myopathy and Rhabdomyolysis

Additions and/or revisions underlined:
…

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 ZOCOR dosage; Chinese patients on ZOCOR may be at higher risk for myopathy [see Contraindications (4), Drug Interactions (7.1), and Use in Specific Populations (8.8)]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking an 80 mg daily dosage of ZOCOR compared with patients taking lower ZOCOR dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see Adverse Reactions (6.1)].
…

Use the 80 mg daily dosage of ZOCOR only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see Dosage and Administration (2.1)]. If patients treated with an 80 mg daily dosage of ZOCOR are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [see Drug Interactions (7.1)].
…

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ZOCOR dosage and advise patients receiving an 80 mg daily dosage of ZOCOR of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

7 Drug Interactions

Additions and/or revisions underlined:

…

Lomitapide

…

Intervention: Reduce the dose of ZOCOR by 50% if initiating lomitapide. Do not exceed ZOCOR 20 mg daily (or ZOCOR 40 mg daily for patients who have previously taken an 80 mg daily dosage of ZOCOR chronically) while taking lomitapide [see Dosage and Administration (2.1, 2.5)].

…

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

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 (CLcr 15 – 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. The 5 mg strength of ZOCOR is no longer marketed. Use another simvastatin product to initiate dosing in such patients.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Myopathy and Rhabdomyolysis
Advise patients that ZOCOR may cause myopathy and rhabdomyolysis. Inform patients taking an 80 mg daily dose of ZOCOR that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking ZOCOR. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)].

…

Missed Dose
Instruct patients to take ZOCOR only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose.

PATIENT INFORMATION

Newly added; please refer to label

05/31/2022 (SUPPL-102)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

Additions and/or 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 without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of ZOCOR. 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.

…

Skin and Subcutaneous Tissue Disorders: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens- Johnson syndrome

…

03/07/2022 (SUPPL-99)

Approved Drug Label (PDF)

Other

(Extensive changes throughout label, including Pregnancy and Lactation Labeling Rule (PLLR) requirements; please refer to label)

09/25/2020 (SUPPL-101)

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.

10/04/2019 (SUPPL-100)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myopathy/Rhabdomyolysis

(additions and/or revisions are underlined)

(addition of Daptomycin to the Interacting Agents of table; please refer to labeling for complete information)

…

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice. Combination of these drugs with simvastatin is contraindicated. If short- term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated.

Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered.

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.

The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fibrates or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine.

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products.

Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin.

Temporarily suspend ZOCOR in patients taking daptomycin.

…

7 Drug Interactions

7.8 Daptomycin

(newly added subsection)

Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Temporarily suspend ZOCOR in patients taking daptomycin.

03/01/2019 (SUPPL-92)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myopathy/Rhabdomyolsis

Addition of the following to the end of the first paragraph:

Chinese patients may be at increased risk for myopathy.

For Table 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis: Addition of Niacin (? 1g/day) to interacting agents and corresponding prescribing recommendation of For Chinese patients, not recommended with simvastatin.

7 Drug Interactions

7.4 Niacin

Additions and/or revisions underlined:

… lipid-modifying doses (?1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (?1 g/day) of niacin. Coadministration of ZOCOR with lipid-modifying doses (?1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patient

8 Use in Specific Populations

Newly added subsection:
8.8 Chinese Patients

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non- Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). The incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%.

Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Coadministration of ZOCOR with lipid-modifying doses (?1 g/day niacin) of niacin-containing products is not recommended in Chinese patients.

02/28/2018 (SUPPL-98)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myopathy/Rhabdomyolysis

Additions and/or revisions underlined:

… The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid …

Drug Interactions

The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid …