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.

OTREXUP (NDA-204824)

(METHOTREXATE)

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

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12/26/2019 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Otrexup is contraindicated in the following:

• Pregnancy

Otrexup can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].

5 Warnings and Precautions

Organ System Toxicity

Hepatic:

(Newly added subsection; see label for complete information)

Embryo-Fetal Toxicity

(Extensive changes; please refer to label)

Effects on Reproduction

(Extensive changes; please refer to label)

7 Drug Interactions

Hepatotoxins

(Newly added subsection)

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with Otrexup and other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

Mercaptopurine

(Additions and/or revisions underlined)

Methotrexate increases the plasma levels of mercaptopurine. The combination of Otrexup and mercaptopurine may therefore require dose adjustment.

Nitrous Oxide

(Newly added subsection)

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

Other Drugs

(Newly added subsection)

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides.

Renal tubular transport is also diminished by probenecid; use of Otrexup with this drug should be carefully monitored.

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

8 Use in Specific Populations

Females and Males of Reproductive Potential

(PLLR conversion. Please refer to label for complete information.)

Lactation

(PLLR conversion. Please refer to label for complete information.)

Pregnancy

(PLLR conversion. Please refer to label for complete information.)

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

PATIENT COUNSELING INFORMATION

(Newly added information)

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Otrexup is intended for use under the guidance and supervision of a physician. Patients should not self-administer until they receive training from a healthcare professional. The patient’s or caregiver’s ability to administer Otrexup should be assessed.

Instruct patients not to administer Otrexup to the arms or any other areas of the body, as delineated in the Otrexup Instructions for Use [see Instructions for Use].

Embryo-Fetal Toxicity

· Advise females of reproductive potential that Otrexup can cause fetal harm and is contraindicated in pregnancy. Advise women of childbearing potential that Otrexup 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 Otrexup therapy 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 Otrexup therapy and for 3 months after the final dose [see Use in Specific Populations (8.3)].

Infertility

Advise patients of reproductive potential that Otrexup may cause impairment of fertility, oligospermia, and menstrual dysfunction [see Warnings and Precautions (5.2), Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with Otrexup and for one week after the final dose [see Use in Specific Populations (8.3)].

Ability to Drive or Operate Machinery

Inform patients that adverse reactions such as dizziness and fatigue may affect their ability to drive or operate machinery.

Proper Storage and Disposal

Advise patients to store Otrexup at room temperature (68 to 77°F or 20 to 25°C). Inform patients and caregivers of the need for proper disposal after use, including the use of a sharps disposal container.

PATIENT INFORMATION

(Additions and/or revisions underlined)

Otrexup is a single-dose auto-injector containing a prescription medicine, methotrexate.

Otrexup is available in doses of 10, 12.5, 15, 17.5, 20, 22.5 and 25 mg.

Pregnancy should be avoided if either partner is receiving Otrexup:

• for a minimum of 3 months after treatment with Otrexup for males.

• during and for 6 months after treatment with Otrexup for females.

06/19/2019 (SUPPL-9)

Approved Drug Label (PDF)

Other

Proprietary Name Revision

(Otrexup has been revised to read Otrexup PFS throughout entire label; please refer to label for complete information)

03/15/2018 (SUPPL-8)

Approved Drug Label (PDF)

7 Drug Interactions

7.8 Nitrous Oxide

(new subsection added)