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.

RASUVO (NDA-205776)

(METHOTREXATE)

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

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03/11/2020 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

Number 1 (beginning with ‘Methotrexate has been reported to cause fetal death and/or congenital abnormalities’ has been replaced with the following:

Methotrexate can cause embryo-fetal toxicity, including fetal death. Use is contraindicated during pregnancy. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Rasuvo [see Warnings and Precautions (5.2) Contraindications (4), and Use in Specific Populations (8.1, 8.3)].

5 Warnings and Precautions

5.2 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on published reports and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman. In pregnant women Rasuvo is contraindicated. Verify the pregnancy status of females of reproductive potential prior to initiating Rasuvo. Advise females of reproductive potential to use effective contraception during treatment with Rasuvo and for 6 months after the final dose. Advise males of reproductive potential to use effective contraception during Rasuvo treatment and for 3 months after the final dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

5.3 Effects on Reproduction

Additions and/or revisions underlined:

Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential [see Use in Specific Populations (8.3)].

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Based on published reports, and methotrexate’s mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1)]. In pregnant women with psoriasis or rheumatoid arthritis, Rasuvo is contraindicated [see Contraindications (4)]. There are no animal data that meet current standards for nonclinical developmental toxicity studies.

The estimated background risk 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 – 4 % and 15 – 20 %, respectively.

Data

Human Data

Published data from cases, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8-29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13-22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03-9.5]) (2.9%).Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Limited published literature report the presence of methotrexate in human breast milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, including myelosuppression advise women not to breastfeed during treatment with Rasuvo and for one week after the final dose.

8.3 Females and Males of Reproductive Potential

PLLR conversion; additions and/or revisions underlined:

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Rasuvo. Contraception

Females

Rasuvo can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Rasuvo.

Males

Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after the final dose of Rasuvo.

Infertility

Females

Based on the published reports of female infertility after treatment with methotrexate, advise females of reproductive potential that Rasuvo can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

Males

Based on published reports of male infertility after treatment with methotrexate, advise males of reproductive potential that Rasuvo can cause infertility or oligospermia during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Embryo-Fetal Toxicity

Advise females of reproductive potential that Rasuvo can cause fetal harm and is contraindicated in pregnancy. Advise women of childbearing potential that Rasuvo should not be started until pregnancy is excluded. Women should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Inform patients to contact their physician if they suspect that they are pregnant [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during Rasuvo treatment and for 6 months after the final dose [see Use in Specific Populations (8.3)].
Advise males of reproductive potential to use effective contraception during Rasuvo treatment and for 3 months after the final dose [see Use in Specific Populations (8.3)].

Infertility

Advise patients of reproductive potential that Rasuvo may cause impairment of fertility, oligospermia and menstrual dysfunction [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with Rasuvo and for one week after the final dose [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Additions and/or revisions underlined:

What is the most important information I should know about Rasuvo? Rasuvo can cause serious side effects that can lead to death, including:

Women who are pregnant are at increased risk for death of the baby and birth defects. Women who are pregnant or who plan to become pregnant must not take Rasuvo. A pregnancy test should be performed before starting Rasuvo.

Contraception should be used by both females and males while taking Rasuvo. Pregnancy should be avoided if either partner is receiving Rasuvo:

for a minimum of 3 months after treatment with Rasuvo for males.
during and for at least 6 months after treatment with Rasuvo for females.

03/15/2018 (SUPPL-2)

Approved Drug Label (PDF)

7 Drug Interactions

7.8 Nitrous oxide

(new subsection added)

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate dependent metabolic pathways, resulting in the potential for increased toxicity. Avoid the simultaneous use of nitrous oxide and methotrexate.