Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Hemorrhage
(Additions and revisions underlined)
An increased risk of bleeding may occur following
NEXAVAR administration. In the SHARP (HCC) study, an excess of bleeding
regardless of causality was not apparent and the rate of bleeding from
esophageal varices was 2.4% in NEXAVAR-treated patients and 4% in
placebo-treated patients. Bleeding with a fatal outcome from any site
was reported in 2.4% of NEXAVAR-treated patients and 4% in placebo-treated
patients. In the TARGET (RCC) study, bleeding regardless of causality was
reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients
in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was
2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%,
respectively, in placebo-treated patients. There was one fatal hemorrhage in
each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study,
bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of
placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was
1% in NEXAVAR-treated patients and 1.4% in placebo- treated patients. There
was no Grade 4 bleeding reported and there was one fatal hemorrhage in a
placebo-treated patient.
…
5.5 Gastrointestinal Perforation
(Additions underlined)
Gastrointestinal perforation is an uncommon adverse reaction
and has been reported in less than 1% of patients taking NEXAVAR. In some
cases this was not associated with apparent intra-abdominal tumor. In the event
of a gastrointestinal perforation, permanently discontinue NEXAVAR.
5.7 Wound Healing Complications
(Newly added subsection on 07/09, corrected on 07/15)
No formal studies of the effect of NEXAVAR on wound healing have been conducted. Temporary interruption of NEXAVAR is recommended in patients undergoing surgical procedures. There is limited clinical experience regarding the timing of reinitiation of NEXAVAR following major surgical intervention. Therefore, the decision to resume NEXAVAR following a major surgical intervention should be based on clinical judgment of adequate wound healing.
5.11 Embryo-Fetal Toxicity
(Additions underlined)
… Verify the pregnancy
status of females of reproductive potential prior to initiation of NEXAVAR.
…
6
Adverse Reactions
(Additions
underlined)
The
following serious adverse reactions are discussed elsewhere in the labeling:
…
Hand-foot skin reaction, rash, Stevens-Johnson syndrome,
and toxic epidermal necrolysis [see Warnings and
Precautions (5.4)]
…
6.1 Clinical
Trials Experience
(Extensive
additions, please refer to label for complete information)
6.2 Postmarketing
Experience
(Additions underlined)
…
Vascular: Arterial
(including aortic) aneurysms, dissections, and rupture
8
Use in Specific Populations
8.6 Patients with Hepatic Impairment
(Additions underlined)
In
a trial of HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B)
hepatic impairment, the systemic exposure (AUC) of sorafenib was within the range
observed in patients without hepatic impairment. In another trial in subjects
without HCC, the mean AUC was similar for subjects with mild (n=15) and
moderate (n=14) hepatic impairment compared to subjects (n=15) with normal
hepatic function.
No dose adjustment is necessary for patients with mild or moderate hepatic
impairment. The pharmacokinetics of sorafenib have not been studied in patients
with severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3)].
8.7 Patients with Renal Impairment
(Additions underlined)
No
correlation between sorafenib exposure and renal function was observed
following administration of a single oral dose of NEXAVAR 400 mg to subjects
with normal renal function and subjects with mild (CLcr 50–80 mL/min), moderate
(CLcr 30–<50 mL/min), or severe (CLcr <30 mL/min) renal impairment who
are not on dialysis.
No dose adjustment is necessary for patients with mild, moderate or severe
renal impairment who are not on dialysis. The pharmacokinetics of sorafenib
have not been studied in patients who are on dialysis [see Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined on 07/09, corrected on 07/15)
…
Wound
Healing Complications
Inform
patients that temporary interruption of NEXAVAR is recommended in patients undergoing
major surgical procedures [see Warnings and Precautions (5.7)].
…
PATIENT INFORMATION
(Additions and/or
revisions underlined on 07/09, corrected on 07/15)
…
- possible wound healing
problems. If
you need to have a surgical procedure, tell your healthcare provider that you are
taking NEXAVAR. NEXAVAR may need to be stopped until your wound heals after some
types of surgery.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
(Extensive changes; please refer to label)
6
Adverse Reactions
(Extensive changes; please refer to label)
7
Drug Interactions
(Extensive changes; please refer to label)
8
Use in Specific Populations
8.3 Females and Males of Reproductive Potential
(Newly added information)
NEXAVAR may cause fetal harm when
administered to a pregnant
woman [see Use
in Specific Populations
(8.1)].
8.4 Pediatric Use
(Additions and/or revisions underlined)
The safety and effectiveness
of NEXAVAR
have not been
established in pediatric patients.
8.7 Hepatic Impairment
(Additions and/or revisions underlined)
No
dose adjustment is
necessary for patients
with mild or moderate
hepatic impairment. The pharmacokinetics of sorafenib have not been
studied in patients with severe (Child-Pugh
C)
hepatic impairment [see Clinical Pharmacology
(12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling Information
(Additions and/or revisions underlined)
Risk of Impaired
Wound Healing
Advise patients that NEXAVAR
may impair wound
healing. Advise patients to inform their healthcare provider of any planned
surgical procedure [see Warnings
and Precautions (5.7)].
Drug-Induced Liver Injury
(Section renamed)
Inform patients that NEXAVAR
can cause hepatitis which may result in
hepatic failure and death.
Advise patients that liver function tests should
be monitored
regularly during treatment and
to report signs and symptoms
of hepatitis [see Warnings and Precautions (5.10)].
Patient Information
(Additions and/or revisions underlined)
Do not take NEXAVAR if you:
plan to have surgery or have had a recent surgery. You
should stop taking NEXAVAR at least 2
weeks before planned surgery. See “What are the possible
side effects of NEXAVAR?”
NEXAVAR may cause serious side effects, including:
• risk of wound healing problems. Wounds may not
heal properly during NEXAVAR treatment. Tell
your healthcare provider if you plan to have any surgery
before starting or during treatment with
NEXAVAR.
o You should stop taking NEXAVAR at least 10 days before
planned surgery.
o Your healthcare provider should tell you when you may
start taking NEXAVAR again after
surgery.
Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or
revisions underlined)
The
following adverse drug reactions have been identified during post-approval use
of NEXAVAR. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Blood and
lymphatic disorders: Thrombotic microangiopathy (TMA)
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Cardiovascular Events
(additions
underlined)
In the SHARP (HCC) study, the incidence of cardiac
ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% in
the placebo-treated group, in the TARGET (RCC) study, the
incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated
group (2.9%) compared with the placebo-treated group (0.4%), and in the DECISION
(DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the
NEXAVAR-treated group compared with 0% in the placebo-treated group. Patients
with unstable coronary artery disease or recent myocardial infarction were
excluded from this study. In multiple clinical trials, congestive heart
failure has been reported in 1.9% of Nexavar-treated patients (N=2276).
Temporary or permanent discontinuation of
NEXAVAR should be considered in patients who develop cardiovascular events.
5.11 Embryo-Fetal Toxicity
(additions
underlined)
Based on its mechanism of action and findings in animals,
NEXAVAR may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in
animals at maternal exposures that were significantly lower than the human
exposures at the recommended dose of 400 mg twice daily. Advise pregnant
women and females of reproductive potential of the potential risk
to a fetus. Verify the pregnancy status of females of reproductive potential
prior to initiation of NEXAVAR. Advise females of reproductive potential to use
effective contraception during treatment and for 6 months following the last
dose of NEXAVAR. Advise male patients with female partners of reproductive
potential and pregnant partners to use effective contraception during treatment
and for 3 months following the last dose of NEXAVAR.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
Cardiovascular Events
Discuss with patients that cardiac ischemia and/or
infarction and congestive heart failure, have been reported during
NEXAVAR treatment, and that they should immediately report any episodes of
chest pain or other symptoms of cardiac ischemia or congestive heart
failure.
…
Embryo-Fetal
Toxicity
Advise females to inform their healthcare
provider if they are pregnant or become pregnant.
Inform female patients of the risk to a fetus and potential loss of
pregnancy.Advise females of
reproductive potential to use effective contraception during treatment
with NEXAVAR and for 6 months after the last dose. Advise male patients with
female partners of reproductive potential or who are pregnant to use
effective contraception during treatment with NEXAVAR and for months after
receiving the last dose of NEXAVAR.
Lactation
Advise patients not to breastfeed while taking
NEXAVAR and for 2 weeks after receiving the last dose of NEXAVAR.
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(PLLR
conversion, please refer to label for more information)
8.2 Lactation
(PLLR
conversion)
Risk
Summary
There are no data on the presence of sorafenib or its
metabolites in human milk, or its effects on the breast-fed child or on milk
production. Sorafenib was present in milk of lactating rats [see Data]. Because of the potential for
serious adverse reactions in a breastfed child from NEXAVAR, advise lactating
women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the
last dose.
Data
Following administration of radiolabeled sorafenib to
lactating Wistar rats, approximately 27% of the radioactivity was secreted into
milk. The milk to plasma AUC ratio was approximately 5:1.
8.3 Females and Males of Reproductive Potential
(PLLR
conversion)
Pregnancy
Testing
Verify the pregnancy status of females of reproductive
potential prior to the initiation of NEXAVAR.
Contraception
Females
NEXAVAR may cause fetal harm when administered to a
pregnant woman. Advise females of
reproductive potential to use effective contraception during treatment and for
6 months following the last dose of NEXAVAR.
Males
Based on genotoxicity and findings in animal reproduction
studies, advise male patients with female partners of reproductive potential
and pregnant partners to use effective contraception during treatment with
NEXAVAR and for 3 months after the last dose of NEXAVAR.
Infertility
Males
Based on findings in animal studies, NEXAVAR may impair
fertility in males of reproductive potential.
Other
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