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.

RYTHMOL SR (NDA-021416)

(PROPAFENONE HYDROCHLORIDE)

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

Download Data

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11/02/2018 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Proarrhythmic Effects

(Additions and/or revisions are underlined)

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In the RYTHMOL SR Atrial Fibrillation Trial (RAFT) trial, there were too few deaths to assess the long-term risk to patients. There were 5 deaths, 3 in the pooled group for RYTHMOL SR (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of RYTHMOL SR and immediate-release RYTHMOL, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

...

5.4 Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450

(Additions and/or revisions are underlined)

Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and other demographic groups are deficient to a somewhat lesser extent. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole,erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.

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8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) revisions)

Risk Summary

In the absence of studies in pregnant women, available data from published case reports and several decades of postmarketing experience with use of RYTHMOL in pregnancy have not identified any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. Untreated arrhythmias during pregnancy may pose a risk to the pregnant woman and fetus (see Clinical Considerations). Propafenone and its metabolite, 5-OH-propafenone, cross the placenta in humans. In animal studies, propafenone was not teratogenic. At maternally toxic doses (ranging from 2 to 6 times the maximum recommended human dose [MRHD]), there was evidence of adverse developmental outcomes when administered to pregnant rabbits and rats during organogenesis or when administered to pregnant rats during mid-gestation through weaning of their offspring (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk: The incidence of VT is increased and may be more symptomatic during pregnancy. Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal Adverse Reactions: Propafenone and its metabolite have been shown to cross the placenta. Adverse reactions such as fetal/neonatal arrhythmias have been associated with the use of other antiarrhythmic agents by pregnant women. Fetal/neonatal monitoring for signs and symptoms of arrhythmia is recommended during and after treatment of pregnant women with propafenone.

Labor or Delivery: Risk of arrhythmias may increase during labor and delivery. Patients treated with RYTHMOL should be monitored continuously for arrhythmias during labor and delivery [see Warnings and Precautions (5.1)].

Data

Propafenone has been shown to cause embryo-fetal mortality in rabbits and rats when given orally during organogenesis at maternally toxic doses of 150 mg/kg/day (rabbit: maternal mortality, decreased body weight gain and food consumption at approximately 3 times the MRHD on a mg/m2 basis) and 600 mg/kg/day (rat: maternal decreased body weight gain and food consumption at approximately 6 times the MRHD on a mg/m2 basis). In addition, a maternally toxic dose of 600 mg/kg/day (approximately 6 times the MRHD on a mg/m2 basis) also caused decreased fetal weights in rats. Increased placental weights and delayed ossification occurred in rabbits at a dose of 30 mg/kg/day (less than the MRHD on a mg/m2 basis) in the absence of maternal toxicity. No adverse developmental outcomes in the absence of maternal toxicity were seen following oral doses of 15 mg/kg/day to rabbits or up to 270 mg/kg/day to rats administered during organogenesis (equivalent to 0.3 times or approximately 3 times the MRHD on a mg/m2 basis, respectively). In an oral study, female rats received propafenone up to

500 mg/kg/day from mid-gestation through weaning. At 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), there were no adverse developmental outcomes in the absence of maternal toxicity. However, doses ?180 mg/kg/day (2 or more times the MRHD on a mg/m2 basis) produced increases in maternal deaths and resulted in reductions in neonatal survival, body weight gain, and delayed development in the presence of maternal toxicity.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) revisions)

Risk Summary

Propafenone and its active metabolite, 5-OH-propafenone, are present in human milk, but the levels are likely to be low. There are no data on the effects of propafenone on the breastfed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for propafenone and any potential adverse effects on the breastfed infant from propafenone or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) revisions)

Infertility

Males: Based on human and animal studies, RYTHMOL may transiently impair spermatogenesis in males. Evaluation of the effects on spermatogenesis was performed in 11 healthy males given oral propafenone 300 mg b.i.d. for 4 days, which was then increased to 300 mg t.i.d. for an additional 4 days. Study findings included a 28% reduction in semen sample volume on Treatment Day 8 and a 27% reduction in sperm count 64 days after treatment (both values remained within the laboratories normal reference range). These effects were not seen in follow- up visits up to 120 days after treatment. Reversible decreases in spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after lethal.

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

17 PATIENT COUNSELING INFORMATION

(Subsection has been revised)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instruct patients to notify their healthcare providers of any change in over-the-counter, prescription, and supplement use.

Instruct patients to report symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst.
Instruct patients not to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Other

PATIENT INFORMATION

(Additions and/or revisions are underlined)

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What should I tell my doctor before taking RYTHMOL SR?

Before you take RYTHMOL SR, tell your doctor if you:

have liver or kidney problems
have breathing problems
have symptoms including diarrhea, sweating, vomiting, or loss of appetite or thirst that are severe. These symptoms may be a sign of abnormal electrolyte levels in your blood.
have myasthenia gravis
have lupus erythematosus
have been told you have or had an abnormal blood test called Antinuclear Antibody Test or ANA Test
are pregnant or plan to become pregnant
are breastfeeding or plan to breastfeed. RYTHMOL SR can pass into your milk. You and your doctor should discuss the best way to feed your baby during this time.
have any other medical conditions

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