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:
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:
Before taking
VARUBI, tell your doctor about all of your medical conditions, including if
you:
Other
Varubi Injectable Emulsion is no longer being
marketed.
Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
VARUBI is contraindicated in patients taking CYP2D6
substrates with a narrow therapeutic index, such as thioridazine and
pimozide. VARUBI can significantly increase the plasma
concentrations of thioridazine and pimozide, which may result in QT
prolongation and Torsades de Pointes.
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 concentrations, the last time point measured. The inhibitory
effect of rolapitant on CYP2D6 is expected to persist beyond 28 days
for an unknown duration following administration of VARUBI.
Narrow Therapeutic Index Drugs
(Thioridazine and Pimozide)
VARUBI is
contraindicated in patients taking CYP2D6 substrates with a narrow
therapeutic index such as thioridazine and pimozide. Increased
plasma concentrations of thioridazine and pimozide are associated with
serious and/or life-threatening events of QT prolongation and Torsades de
Pointes.
Before starting
treatment with VARUBI, consider whether patients require treatment with
thioridazine or pimozide. If patients require these drugs, use an alternative
antiemetic to VARUBI or an alternative to thioridazine or pimozide that is not
metabolized by CYP2D6.
Other Drugs
VARUBI can also
increase plasma concentrations of other CYP2D6 substrates for at least 28 days
following administration of VARUBI and may result in adverse reactions.
Before starting
treatment with VARUBI, consult the prescribing information for CYP2D6
substrates to obtain additional information about interactions with CYP2D6
inhibitors.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Tablets
In 4 controlled
clinical trials in patients receiving emetogenic cancer chemotherapy, VARUBI tablets
were given in combination with a 5-HT3 receptor antagonist and
dexamethasone … The remainder of this
paragraph references tablets.
7
Drug Interactions
Addition of the following subsections; please refer to
label for complete information:
7.1 CYP2D6 Substrates
7.2 Strong CYP3A4 Inducers
7.3 BCRP Substrates with a Narrow Therapeutic Index
7.4 P-gp Substrates with a Narrow Therapeutic Index
7.5 Warfarin
7.6 CYP3A4 Substrates
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
The limited data with
VARUBI use in pregnant women are insufficient to inform a drug
associated risk of adverse developmental outcomes. In animal
reproduction studies, there were no adverse developmental effects
observed with oral administration of rolapitant …
The estimated
background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. In the U.S. general population …
Data
Animal Data
he potential
embryo-fetal toxicity of rolapitant was assessed in pregnant rats administered
oral doses up to 22.5 mg/kg per day throughout the period of
organogenesis … a concomitant decrease in food consumption during the first
week of dosing. No adverse embryo-fetal developmental effects
were observed at doses up to 22.5 mg/kg per day rolapitant (approximately 1.3
times the recommended intravenous human dose on a body surface area
basis). In rabbits administered rolapitant throughout the period of
organogenesis, oral doses up to 27 mg/kg per day (approximately 3 times
the recommended intravenous human dose on a body surface area basis) …
… and increased
number of unaccounted for implantation sites at a dose of 22.5 mg/kg per day
(approximately 1.3 times the recommended intravenous human dose
on a body surface area basis). Effects on offspring … (approximately 0.5 times
the recommended intravenous human dose on a body surface area basis …
8.3 Females and Males of Reproductive Potential
Newly created subsection:
Infertility
Females
In animal
fertility studies, rolapitant impaired the fertility in females in a reversible
fashion.
8.4 Pediatric Use
Newly added information following Safety &
efficacy of VARUBI have not been established in pediatric patients:
In non-clinical
studies, sexual development and fertility of juvenile rats (human age
equivalent of birth to 16 years) were affected following oral administration of
VARUBI, as described below in Juvenile Animal Toxicity Data.
Juvenile Animal
Toxicity Data
In an oral
juvenile toxicity study in rats, at rolapitant doses of 11.3, 22.5 and 45
mg/kg/day from postnatal (PND) Day 7 through PND 70 (equivalent human age of
newborn to 16 years), there was a delay in the attainment of balanopreputial
separation in males and an acceleration of the attainment of vaginal patency in
females with rolapitant doses of 22.5 and 45 mg/kg/day (approximately 1.3 and
2.6 times,
respectively, the recommended intravenous human dose on a body surface area
basis). Treated males and females were mated following a 2-week wash-out period
after the last dose. There were lower mean numbers of implantation sites,
corpora lutea, and mean number of viable embryos at 22.5 and 45 mg/kg/day
(approximately 1.3 and 2.6 times, respectively, the recommended intravenous
human dose on a body surface area basis) when compared to control.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Addition of the following:
Infertility
Advise females of
reproductive potential that VARUBI may impair fertility.
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