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.

VARUBI (NDA-208399)

(ROLAPITANT HYDROCHLORIDE)

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

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08/19/2020 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:
… VARUBI is contraindicated in pediatric patients less than 2 years of age because of irreversible impairment of sexual development and fertility observed in juvenile rats at clinically relevant dosages [see Use in Specific Populations (8.4)].

5 Warnings and Precautions

5.1 Interaction with CYP2D6 Substrates

Additions and/or revisions underlined:

Rolapitant is a moderate inhibitor of CYP2D6. Exposure to dextromethorphan, a CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan (CYP2D6 substrate) concentrations, the last time point measured.

6 Adverse Reactions

Newly added information:

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Interaction with CYP2D6 Substrates [see Contraindications (4), Warnings and Precautions (5.1)]

7 Drug Interactions

Additions and/or revisions underlined:

Rolapitant, given as a single oral dose, is not an inhibitor or inducer of CYP3A4 [see Clinical Pharmacology (12.3)]. Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with VARUBI [see Dosage and Administration (2)].

Table 4 and Table 5 include drugs with clinically important drug interactions when administered concomitantly with VARUBI and instructions for preventing or managing them.

Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with VARUBI

Table 5: Clinically Relevant Interactions Affecting Rolapitant When Co-Administered with Other Drugs

Tables 4 and 5 are newly added; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Statistics in section revised from ‘1.3 times and 3 times’ to ‘1.2 times and 2.9 times’

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of VARUBI have not been established in pediatric patients. VARUBI is contraindicated in pediatric patients less than 2 years of age [see Contraindications (4)]. Rolapitant administration in juvenile rats (human age equivalent of birth to 2 years) resulted in abnormal ovarian and uterine development, early sexual development in females, delayed sexual development in males, and impaired fertility.

Juvenile Animal Toxicity Data

A toxicity study in juvenile rats at rolapitant doses approximately 1.2 and 2.5 times the approved adult body surface area (BSA)-based dose from postnatal day (PND) 7 through PND 70 (approximate human age equivalent of birth to 16 years) identified reproductive toxicity. A subsequent toxicity study in juvenile rats was conducted to identify the critical window of exposure for reproductive toxicity. A rolapitant dose of 50 mg/kg/day (approximately 2.7 times the approved adult BSA-based dose) was administered daily from PNDs 7 through 70, 7 to 21, 21 to 42 and 42 to 70 (approximate human age equivalent of birth to 16 years, birth to 2 years, 2 years to 12 years, and 12 years to 16 years, respectively). Female juvenile rats treated with rolapitant beginning on PND 7 developed adverse effects including partial or irreversible lower uterine weights that correlated with decreased endometrial glands of the uterus, decreases in the numbers of corpora lutea, implantation sites and live embryos and increases in pre- and post-implantation loss, and early resorptions. These adverse effects were observed in female juvenile rats administered rolapitant prior to PND 21 (approximate human age equivalent of 2 years). Additionally, juvenile rats treated with rolapitant beginning on either PND 7 or PND 21 developed slight changes in the onset of sexual maturation (including earlier attainment of vaginal opening in females and delay in preputial separation in males).

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

PATIENT INFORMATION

Additions and/or revisions underlined:

Do not take VARUBI if you:

are a child less than 2 years of age.

Before taking VARUBI, tell your doctor about all of your medical conditions, including if you:

are breastfeeding or plan to breastfeed. It is not known if VARUBI passes into your breast milk or could harm your baby. Talk to your doctor about the best way to feed your baby if you take VARUBI.

Other

Varubi Injectable Emulsion is no longer being marketed.