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.

RITUXAN HYCELA (BLA-761064)

(RITUXIMAB; HYALURONIDASE (HUMAN RECOMBINANT))

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

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06/10/2021 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

(Additions and/or revisions underlined)

There are no data on the presence of hyaluronidase human in human milk or the effect of rituximab on milk production, and there is limited data on the effect of rituximab on the breastfed child. However, rituximab is detected in the milk of lactating cynomolgus monkeys and maternal IgG is present in human breast milk.

Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RITUXAN HYCELA and for 6 months after the last dose due to the potential for serious adverse reactions in breastfed children.

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

MEDICATION GUIDE

(Extensive changes; please refer to label)

05/05/2020 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA.

6 Adverse Reactions

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In the SABRINA study, where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP, the incidence of treatment- induced/enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group (2.0% RITUXAN HYCELA vs. 1.9% rituximab). The incidence of treatment- induced/enhanced anti-recombinant human hyaluronidase antibodies was 15% in the RITUXAN HYCELA group compared with 8% in the rituximab group, and the overall proportion of patients found to have anti- recombinant human hyaluronidase antibodies remained generally constant over the follow-up period in both cohorts. All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies.

In the SAWYER study, where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC, the incidence of treatment-induced/enhanced anti-rituximab antibodies was 12% in the RITUXAN HYCELA group and 15% in the rituximab group. The incidence of treatment- induced/enhanced anti- recombinant human hyaluronidase antibodies was 11% in the RITUXAN HYCELA treatment arm. None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. There are no available data on RITUXAN HYCELA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, intravenous administration of a rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at a dose > 2700 times higher than the human dose. Comparable systemic exposure levels could occur in a pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA. Advise pregnant women of the potential risk to a fetus.

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

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Rituximab-containing products can cause fetal harm.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RITUXAN HYCELA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

05/05/2020 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

6 Adverse Reactions

6.2 Immunogenicity

(Additions and/or revisions underlined)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Rituximab-containing products can cause fetal harm.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RITUXAN HYCELA.

Contraception

Females

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

12/18/2019 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(addition underlined)

…

Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).

…