Approved Drug Label (PDF)
5
Warnings and Precautions
5.11 Embryo-Fetal Toxicity
(Additions and/or revisions underlined)
Based on findings from animal
studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic
and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose. Advise pregnant
women of the potential
risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with ZALTRAP and for 3 months following
the last dose [see Use in Specific Populations (8.1, 8.3)].
8
Use in Specific Populations
8.3 Females and Males
of Reproductive Potential
(Additions and/or revisions underlined)
ZALTRAP can cause fetal harm when administered to a pregnant
woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status in females
of reproductive potential
prior to initiating ZALTRA![]()
[see Use in Specific
Populations (8.1)].
Contraception
Females
Based on data from animal studies
and its mechanism
of action, ZALTRAP
can cause fetal
harm when administered to pregnant women [see Use in Specific
Populations (8.1)].
Females
Advise female patients of reproductive potential
to use effective contraception during treatment
with ZALTRAP and for 3 months following the last dose…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
…
Advise females
of reproductive potential:
- to use effective contraception during treatment with ZALTRAP and for 3 months following the last dose [see Use in
Specific Populations (8.3)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.11 Embryo-Fetal Toxicity
(Newly added
subsection)
Based
on findings from animal studies and its mechanism of action, ZALTRAP can cause
fetal harm when administered to pregnant women. Administration of
Ziv-aflibercept during the period of organogenesis was embryotoxic and
teratogenic in rabbits at exposure levels approximately 0.3
times the human exposure at the 4 mg per kg dose. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with ZALTRAP and for 1 month following
the last dose.
6
Adverse Reactions
(Additions and/or revisions underlined)
The
following clinically significant adverse reactions are described
elsewhere in the labeling:
Hemorrhage
Gastrointestinal
Perforation
Compromised
Wound Healing
Fistula
Formation
Hypertension
Arterial
Thromboembolic Events
Proteinuria
Neutropenia
and Neutropenic Complications
Diarrhea
and Dehydration
Reversible
Posterior Leukoencephalopathy Syndrome
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Because
clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
The
safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR
(EFC102621). Patients received
ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two
weeks (one cycle) in combination with FOLFIRI. Patients received a
median of 9 cycles of ZALTRAP/FOLFIRI.
The
most common Grade 3-4 adverse reactions (greater than or equal to 5%) in the ZALTRAP/FOLFIRI arm were
neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue,
proteinuria, and asthenia.
The
most frequent adverse reactions leading to permanent discontinuation in greater than or equal to 1% of
patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue,
infections, diarrhea, dehydration, hypertension, stomatitis, venous
thromboembolic events, neutropenia, and proteinuria.
The
ZALTRAP dose was reduced and/or omitted in 17% of patients. Cycle delays >7
days occurred in 60% of patients treated with ZALTRAP/FOLFIRI.
The
most common adverse reactions (greater than or equal to 20%) in the ZALTRAP/FOLFIRI arm were
leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis,
fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased,
decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine
increased, and headache.
Adverse
reactions
and laboratory abnormalities that occurred in greater than or equal to 5% (all grades) of
patients receiving ZALTRAP in combination with FOLFIRI and which occurred at
greater than or equal to 2% higher frequency in patients who received ZALTRAP/FOLFIRI compared
to those who received placebo/FOLFIRI in VELOUR are shown in
Table 1. VELOUR was not designed to demonstrate a statistically significant
difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to
placebo/FOLFIRI for any adverse reactions listed below.
Table
1: Selected Adverse Reactions and Laboratory Findings in VELOUR
…
6.2 Immunogenicity
(Additions and/or revisions underlined)
As
with all therapeutic proteins, there is a 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 in the studies described below with the incidence of antibodies in
other studies or to other products may be misleading.
In
patients with various cancers across 15 studies, 1.4% (41/2862) of patients
tested positive for antiproduct antibody (APA) at baseline. The incidence of
APA development was 3.1% (53/1687) in patients receiving intravenous
ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among
patients who tested positive for APA and had sufficient samples for further
testing, neutralizing antibodies were detected in 17 of 48
ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.
The
mean free ziv-aflibercept trough concentrations were lower in patients with
positive neutralizing antibodies than in the overall population. The impact of
neutralizing antibodies on efficacy and safety could not be assessed based on
limited available data.
7
Drug Interactions
(Additions and/or revisions underlined)
No
dedicated drug-drug interaction studies have been conducted for ZALTRAP. No
clinically important pharmacokinetic interactions were found between
ziv-aflibercept and irinotecan/SN-38 or fluorouracil.
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion)
Risk
Summary
Based
on findings from animal reproduction studies and its mechanism of action,
ZALTRAP can cause fetal harm when administered to pregnant women. There is
insufficient data in pregnant women exposed to ZALTRAP to assess
the risks.
Administration
of Ziv-aflibercept during the period of organogenesis was embryotoxic and
teratogenic in rabbits at exposure levels approximately 0.3 times the
human exposure at the 4 mg per kg dose. Advise pregnant women
of the potential risk to a fetus.
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.
Data
Animal Data
In
pregnant rabbits, administration of ziv-aflibercept during the period of
organogenesis resulted in an increase in post-implantation loss and
external (including anasarca, umbilical hernia, diaphragmatic hernia and
gastroschisis, cleft palate, ectrodactyly, and anal atresia), visceral
(heart, great vessels, and arteries), and skeletal fetal malformations
(including fused vertebrae, sternebrae, and ribs, supernumerary arches and
ribs, and incomplete ossification) at doses greater than or equal to 3
mg per kg, administered once every 3 days (approximately 0.3 times
the human exposure at the 4 mg per kg dose based on AUC).
8.2 Lactation
(PLLR conversion)
Risk
Summary
There
are no data on the presence of ziv-aflibercept in human milk, or the effects of
ziv- aflibercept on the breastfed infant or on milk production. Because of the
potential for serious adverse reactions in breastfed infants, advise women not
to breastfeed during treatment with ZALTRAP and for 1 month following the last
dose.
8.3 Females and Males of Reproductive Potential
(PLLR conversion)
Pregnancy
Testing
Verify
the pregnancy status in females of reproductive potential prior to initiating
ZALTRAP. Contraception
Based
on data from animal studies and its mechanism of action, ZALTRAP can cause
fetal harm when administered to pregnant women.
Females
Advise
female patients of reproductive potential to use effective contraception during
treatment with ZALTRAP and for 1 month following the last dose.
Infertility
Advise
female and male patients of reproductive potential that ZALTRAP may impair
reproductive function and fertility.
8.4 Pediatric Use
(Additions and/or revisions underlined)
The
safety and effectiveness in pediatric patients have not been established. Safety
and efficacy were assessed, but not established in a dose-escalation,
safety, and tolerability study (NCT00622414) in 21 patients with
solid tumors 2 to 21 years of age (median age 12.9). The mean
elimination half-life of free ziv-aflibercept determined after the first
dose in 8 pediatric patients aged 5 to 17 years was within
the range of values previously observed in adults. The maximum tolerated
dose based on body weight in these pediatric patients was lower than the
dose known to be safe and effective in adults with mCRC.
Juvenile
Animal Toxicity Data
Weekly/every-two-weeks
intravenous administration of ziv-aflibercept at dose of 3 mg per kg
(approximately 0.6 times the human exposure at the 4 mg per kg dose based on
AUC) to growing young adult (sexually mature) cynomolgus monkeys for up to 6
months resulted in changes in the bone (effects on growth plate and the axial
and appendicular skeleton), nasal cavity (atrophy/loss of the septum and/or
turbinates), kidney (glomerulopathy with inflammation), ovary (decreased number of maturing follicles,
granulosa cells, and/or theca cells), and adrenal gland (decreased vacuolation
with inflammation). In another study in sexually immature cynomolgus monkeys
(treated intravenously for 3 months), there were similar effects. The skeletal
and nasal cavity effects were not reversible after a post-dosing recovery
period.
8.6 Renal Impairment
(Additions and/or revisions underlined)
No
dosage modification is recommended for patients with renal impairment.
8.7 Hepatic Impairment
(Additions and/or revisions underlined)
No
dosage modification is recommended for patients with mild (total
bilirubin >1 to 1.5 times upper limit normal [ULN] and any aspartate
transaminase [AST]) and moderate (total bilirubin >1.5
to 3 times ULN and any AST) hepatic impairment. ZALTRAP has not been studied
in patients with severe hepatic impairment (total bilirubin >3 times
ULN and any AST).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Hemorrhage
Gastrointestinal
Perforation and Fistula Formation
Compromised
Wound Healing
Hypertension
Inform patients that ZALTRAP can cause or exacerbate
existing hypertension. Advise patients to undergo routine blood pressure
monitoring and to contact their health care provider if blood pressure is
elevated or if symptoms from hypertension occur including severe headache,
lightheadedness, or neurologic symptoms.
Arterial
Thromboembolic Events
Inform patients of an increased risk of ATE.
Proteinuria
Advise patients that they will need to undergo regular
laboratory tests to monitor protein in their urine.
Neutropenia
and Neutropenic Complications
Advise patients to notify their health care provider
of fever or other signs of infection.
Diarrhea
and Dehydration
Advise patients to notify the health care provider of
severe diarrhea, vomiting, or severe abdominal pain.
Posterior
Reversible Leukoencephalopathy Syndrome
Advise patients to immediately contact their health care
provider for new onset or worsening neurological function.
Embryo-Fetal
Toxicity
Advise pregnant women and females of reproductive
potential
of the potential risk to a fetus. Advise females to inform
their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use
effective contraception during treatment with ZALTRAP and for 1 month
following the last dose.
Lactation
Get Email Alerts |
Guide
