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.

FUSILEV (NDA-020140)

(LEVOLEUCOVORIN CALCIUM)

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

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01/08/2020 (SUPPL-24)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:
Fusilev is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions (6.2)].

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Increased Gastrointestinal Toxicities with Fluorouracil

Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions (7)]. Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l-leucovorin and fluorouracil.

Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with Fusilev and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until resolved, as rapid deterioration leading to death can occur.

Additions and/or revisions underlined:

5.3 Drug Interaction with Trimethoprim-Sulfamethoxazole

The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity [see Drug Interactions (7)].

6 Adverse Reactions

Newly added information:

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypercalcemia [see Warnings and Precautions (5.1)]
Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions (5.2)]
Additions and/or revisions underlined:
6.1 Clinical Trials Experience

Table 2 Adverse Reactions with High-Dose Methotrexate Therapy

Presentation of Data in Table has changed; please refer to label for complete information.

Combination with Fluorouracil in Colorectal Cancer

Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l-leucovorin. Patients were randomized to fluorouracil 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.

Table 3 Adverse Reactions Occurring in greater than or equal to 10% of Patients in Either Arm

Presentation of Data in Table has changed; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reaction have been identified during postapproval use of levoleucovorin products. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: pruritus, rash

Respiratory: dyspnea

Other: temperature change, rigors, allergic reactions

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Effects of Leucovorin Products on Other Drugs

Antiepileptic Drugs

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs.

Fluorouracil

Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with Fusilev and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur [see Warnings and Precautions (5.2)].

Trimethoprim-Sulfamethoxazole

The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study [see Warnings and Precautions (5.3)].

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are limited data with Fusilev use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin.

Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information.

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.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production.

Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.

Newly added subsection:

8.4 Pediatric Use

The safety and effectiveness of Fusilev have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies (14.1)].

The safety and effectiveness of Fusilev have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

Additions and/or revisions underlined:

… In the NCCTG clinical trial of Fusilev in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.