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.

BIAXIN XL (NDA-050775)

(CLARITHROMYCIN)

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

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09/18/2019 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

4.5 Lomitapide, Lovastatin, and Simvastatin

(adiitions underlined)

Concomitant administration of BIAXIN with lomitapide is contraindicated due to potential for markedly increased transaminases.

Concomitant administration of BIAXIN with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated, due to the increased risk of myopathy, including rhabdomyolysis.

5 Warnings and Precautions

5.4Serious Adverse Reactions Due to Concomitant Use with Other Drugs

(additions underlined)

Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking BIAXIN concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers

metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older. Use BIAXIN with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of BIAXIN with lomitapide, simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated.

…

Lomitapide: Concomitant use of BIAXIN with lomitapide is contraindicated . Lomitapide is metabolized by CYP3A4, and concomitant treatment with BIAXIN increases the plasma concentration of lomitapide, which increases the risk of elevation in transaminases . If treatment with BIAXIN cannot be avoided, therapy with lomitapide must be suspended during the course of treatment.

…

7 Drug Interactions

(additions to Table 8, please refer to label for more information)

12/19/2018 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Based on findings from animal studies, BIAXIN is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If BIAXIN is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, including fetal malformations, in pregnant animals administered oral clarithromycin.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes- please refer to labeling)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Based on limited human data, clarithromycin and its active metabolite 14-OH clarithromycin are present in human milk at less than 2% of the maternal weight-adjusted dose (see Data). In a separate observational study, reported adverse effects on breast-fed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin. No data are available to assess the effects of clarithromycin or 14-OH clarithromycin on milk production.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for BIAXIN and any potential adverse effects on the breast-fed child from BIAXIN or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Males

Administration of clarithromycin resulted in testicular atrophy in rats, dogs and monkeys.

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

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)

11/25/2018 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 QT Prolongation

Underlined addition of disopyramide to the 3rd bullet following Class 1A

5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs

Drugs metabolized by CYP3A4

Underlined addition of and cardiac arrhythmias (e.g., torsades de pointes) following hypoglycemia in the 3rd line, 1st paragraph.

06/09/2017 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Acute Hypersensitivity Reactions

(Additions and/or revisions are underlined)

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue BIAXIN therapy immediately and institute appropriate treatment.

5.5 All-Cause Mortality in Patients With Coronary Artery Disease 1 to 10 Years After BIAXIN Exposure

(Newly added subsection)

In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality one year or more after the end of treatment was observed in patients randomized to receive clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. The cause of the increased risk has not been established. Other epidemiologic studies evaluating this risk have shown variable results. Consider balancing this potential risk with the treatment benefits when prescribing BIAXIN in patients who have suspected or confirmed coronary artery disease.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following BIAXIN Exposure

In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for several years. A numerically higher number of primary outcome events in patients randomized to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 to 1.14). However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the number of deaths emerged after one year or more after the end of treatment.

The cause of the difference in all-cause mortality has not been established. Other epidemiologic studies evaluating this risk have shown variable results.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne, acute generalized exanthematous pustulosis

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Provide the following instructions or information about BIAXIN to patients:

Advise patients who have coronary artery disease to continue medications and lifestyle modifications for their coronary artery disease because BIAXIN may be associated with increased risk for mortality years after the end of BIAXIN treatment.