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.

REBETOL (NDA-020903)

(RIBAVIRIN)

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

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03/16/2022 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

REBETOL capsules and oral solution may cause birth defects, miscarriage or stillbirth. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Female patients should use effective contraception and have periodic monitoring with pregnancy tests during treatment and during the 9-month period after treatment has been stopped. Male patients and their female partners should use effective contraception during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. REBETOL has demonstrated significant teratogenic and embryocidal effects in all animal species tested. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. [see Boxed Warning, Contraindications (4), and Use in Specific Populations (8.1, 8.3)].

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Pregnancy Testing

REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of treatment. Patients should have periodic pregnancy tests during treatment and during the 9-month period after treatment has been stopped [see Warnings and Precautions (5.1)].

Contraception

Female patients of reproductive potential should use effective contraception during treatment and for 9 months post-therapy.

Male patients and their female partners should use effective contraception during treatment with REBETOL and for the 6-month post-therapy period

[see Warnings and Precautions (5.1)].

Infertility

Based on animal data, REBETOL may impair male fertility. In animal studies, these effects were mostly reversible within a few months after drug cessation [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with REBETOL/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the observed safety findings.

Long-term follow-up data in pediatric subjects indicates that REBETOL in combination with PegIntron or with INTRON A may induce a growth inhibition that results in reduced height in some patients [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see Warnings and Precautions (5.10)]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see Warnings and Precautions (5.2)].

Juvenile Animal Toxicity Data

In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.

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

MEDICATION GUIDE

Extensive changes; please refer to label

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Advise female patients of reproductive potential to use effective contraception during treatment with REBETOL and for 9 months post therapy and male patients with female partners of reproductive potential to use effective contraception during treatment with REBETOL and for 6 months post therapy.

Advise patients to notify the physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

…

01/28/2020 (SUPPL-56)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pregnancy

(Additions and/or revisions underlined)

Data

Human Data

Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects (9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system.

05/02/2019 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Ophthalmologic Disorders

(subsection revised, additions underlined)

Ribavirin is used in combination therapy with INTRON A or PegIntron. Refer to labeling for PegIntron for additional information.

6 Adverse Reactions

(section revised)

The following serious adverse drug reactions are discussed in other sections of the labeling:

Embryo-Fetal Toxicity
Anemia
Pancreatitis
Pulmonary Disorders
Ophthalmic Disorders
Dental and Periodontal Disorders
Impact on Growth in Pediatric Patients

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of ribavirin in human milk or the effects on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REBETOL and any potential adverse effects on the breastfed infant from REBETOL or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

REBETOL may cause fetal harm when administered to a pregnant woman .

Pregnancy Testing

Contraception

Females of reproductive potential should use effective contraception during treatment and during 6 months post-therapy based on a multiple-dose half-life (t1/2 ) of ribavirin of 12 days (e.g., 15 half-lives for ribavirin clearance from the body).

Male patients and their female partners should use effective contraception during treatment with REBETOL and for the 6-month post-therapy period

Infertility

Based on animal data, REBETOL may impair male fertility. In animal studies, these effects were mostly reversible within a few months after drug cessation.

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

MEDICATION GUIDE

(additions and revisions, please refer to label)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Embryo-Fetal Toxicity

Inform females of reproductive potential and pregnant women that REBETOL capsules and oral solution may cause birth defects, miscarriage, and stillbirth. Advise females of reproductive potential that they must have a pregnancy test prior to initiating treatment and periodically during therapy.

Advise females of reproductive potential and male patients with female partners of reproductive potential to use effective contraception during treatment with REBETOL and for 6 months post therapy. Advise patients to notify the physician immediately in the event of a pregnancy .

Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to REBETOL during pregnancy. Patients may enroll in the Ribavirin Pregnancy Registry by calling 1-800-593-2214.

Missed Dose

Inform patients that in the event a dose is missed, the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Advise patients to contact their healthcare provider if they have questions.

Dental and Periodontal Disorders

Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards.