Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Risks of Substitution with Other Azacitidine Products
Newly added
subsection:
Due to substantial differences in the
pharmacokinetic parameters [see Clinical Pharmacology (12.3)], the recommended
dose and schedule for VIDAZA are different from those of oral azacitidine
products. Treatment of patients using VIDAZA at the recommended dosage of oral
azacitidine may result in a fatal adverse reaction. Treatment of patients using
oral azacitidine at the doses recommended for VIDAZA may not be effective.
Do not substitute
VIDAZA for oral azacitidine [see Dosage and Administration (2.1)].
5.2 Anemia, Neutropenia and Thrombocytopenia
Additions and/or revisions underlined:
VIDAZA causes anemia, neutropenia and thrombocytopenia
in adult patients with MDS and in pediatric patients with JMML. Monitor
complete blood counts frequently for response and/or toxicity, at a minimum,
prior to each dosing cycle.
In adult patients with MDS, after administration of the recommended dosage for the first cycle, adjust
dosage for subsequent cycles based on nadir counts and hematologic response [see Dosage and Administration (2.5)].
In pediatric patients with JMML, dose reductions due
to hematological toxicity are not recommended within the first 3 cycles as hematological
toxicity will be difficult to assess and to differentiate from the natural
course of the underlying disorder [see
Dosage and Administration (2.5)]
5.3 Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment
Additions and/or
revisions underlined:
…
Safety and effectiveness of VIDAZA in patients with MDS
or in pediatric
patients with JMML and hepatic impairment have not been studied as these patients
were excluded from the clinical trials.
5.4 Renal Toxicity
Additions and/or revisions underlined:
…
Patients with renal impairment
may be at increased risk for renal toxicity. Also, azacitidine and its
metabolites are primarily excreted by the kidney. Therefore, monitor these
patients closely for toxicity [see Dosage and Administration (2.6, 2.7)]. Patients
with MDS or pediatric patients with JMML and renal impairment were
excluded from the clinical studies.
5.6 Embryo-Fetal Toxicity
Subsection title
revised; Additions and/or revisions underlined:
…
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with VIDAZA and for 6 months after the last
dose. Advise males with female partners of reproductive potential to use
effective contraception during treatment with VIDAZA and for 3 months after the
last dose [see Use in Specific Populations (8.1, 8.3)].
6
Adverse Reactions
6.1 Clinical Trials Experience
Subsection title
revised
Extensive changes;
please refer to label
8
Use in Specific Populations
8.2 Lactation
Additions and/or
revisions underlined:
Risk Summary
There is no information regarding the presence of
azacitidine in human milk, the effects of VIDAZA on the breastfed infant, or the
effects of VIDAZA on milk production. Because many drugs are excreted in human
milk and because of the potential for tumorigenicity shown for azacitidine in
animal studies [see Nonclinical Toxicology (13.1)] and the potential for
serious adverse reactions in nursing infants from VIDAZA, advise patients not
to breastfeed during treatment with VIDAZA and for 1 week after the last
dose .
8.3 Females and Males of Reproductive Potential
Additions and/or
revisions underlined:
…
Contraception
Females
Advise
pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during treatment with VIDAZA
and for 6 months after the last dose.
Males
Advise
males with
female partners of reproductive potential to use effective contraception during
treatment with VIDAZA and for 3 months after the last dose.
…
8.4 Pediatric Use
Additions and/or
revisions underlined:
Safety
and effectiveness of VIDAZA in pediatric patients with MDS have not
been established.
The
safety and effectiveness of VIDAZA have been established in pediatric patients with
newly diagnosed JMML aged 1 month and older and the information on this use is
discussed throughout the labeling. The safety and effectiveness of VIDAZA have
not been established in pediatric patients younger than 1 month old [see Clinical Studies (14.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Hepatotoxicity
in Patients with Severe Pre-Existing Hepatic Impairment
Instruct
patients to inform their physician about any underlying liver disease [see Warnings
and Precautions (5.3)].
Renal
Toxicity
Instruct
patients to inform their physician about any underlying renal disease [see Warnings
and Precautions (5.4)].
Embryo-Fetal
Toxicity
Advise
pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations
(8.1)].
Advise
females of reproductive potential to use effective contraception during
treatment with VIDAZA and for 6 months after the last dose. Advise males
with female partners of reproductivepotential to use effective contraception during
treatment with VIDAZA and for 3 months after the last dose. Advise patients
to report known or suspected pregnancy to their physicians immediately [see Warnings and Precautions (5.6) and Use
in Specific Populations (8.3)].
Lactation
Advise
patients to avoid breastfeeding while receiving VIDAZA and for 1 week after the
last dose [see Use in Specific
Populations (8.2)].
Infertility
Advise males and females
that VIDAZA may impair fertility [see Use
in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Approved Drug Label (PDF)
5
Warnings and Precautions
Embryo-Fetal Risk replaces Use in Pregnancy and Use in Males
- Based on the mechanism of action and
findings in animals, VIDAZA can cause fetal harm when administered to a
pregnant woman. Azacitidine administered to pregnant rats via a single
intraperitoneal (IP) dose approximating 8% of the recommended human daily dose
caused fetal death and anomalies.
- Advise females with reproductive
potential to avoid pregnancy during treatment with VIDAZA. Men should be advised
to not father a child while receiving treatment with VIDAZA.
Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment replaces VIDAZA Toxicity in Patients with Severe Pre-existing Hepatic Impairment
- …Azacitidine is contraindicated in
patients with advanced malignant hepatic tumors. Monitor liver chemistries
prior to initiation of therapy and with each cycle (bolded sentence added).
Renal Toxicity
- …developed in 5 patients with CML
treated with azacitidine and etoposide. Monitor serum creatinine and
electrolytes prior to initiation of therapy and with each cycle. If
unexplained … (bolded sentence added)
Tumor Lysis Syndrome (additional section)
- VIDAZA may cause fatal or serious tumor
lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur
despite concomitant use of allopurinol. Assess baseline risk and monitor and
treat as appropriate.
6
Adverse Reactions
The following adverse reactions are
described in other labeling sections: (revised)
Anemia,
Neutropenia and Thrombocytopenia
Hepatotoxicity
in Patients with Severe Pre-existing Hepatic Impairment
Renal
Toxicity
Tumor
Lysis Syndrome
Embryo-Fetal
Risk
8
Use in Specific Populations
Females and Males of Reproductive Potential (PLLR Conversion)
Based on its mechanism of action and
findings in animals, VIDAZA can cause fetal harm when administered to a pregnant
woman.
Pregnancy Testing
Verify the pregnancy status of females
of reproductive potential prior to initiating VIDAZA.
Contraception
Females
- Advise females of reproductive potential
to avoid pregnancy during treatment with VIDAZA.
Males
- Males with female sexual partners of
reproductive potential should not father a child and should use effective
contraception during treatment with VIDAZA.
Infertility
- Based on animal data, azacitidine could have an
effect on male or female fertility.
Lactation (PLLR Conversion)
Risk Summary
- There is no information regarding the
presence of azacitidine in human milk, the effects of VIDAZA on the breastfed
infant, or the effects of VIDAZA on milk production. Because many drugs are
excreted in human milk and because of the potential for tumorigenicity shown
for azacitidine in animal studies and the potential for serious adverse
reactions in nursing infants from VIDAZA, advise patients not to breastfeed
during treatment with VIDAZA.
Pregnancy (PLLR Conversion)
Risk Summary
- Based on its mechanism of action and
findings in animals, VIDAZA can cause fetal harm when administered to a
pregnant woman. There are no data on the use of azacitidine in pregnant women.
Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than
the recommended human daily dose. Advise pregnant women of the potential risk to
the fetus.
- The background rate of major birth
defects and miscarriage is unknown for the indicated population. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
- Early embryotoxicity studies in mice
revealed a 44% frequency of intrauterine embryonal death (increased resorption)
after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of
the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day
10. Developmental abnormalities in the brain have been detected in mice given
azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2
(approximately 4%-16% the recommended human daily dose on a mg/m2 basis).
- In rats, azacitidine was clearly
embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of
6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2
basis), although treatment in the preimplantation period (on gestation days
1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal
abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8%
the recommended human daily dose on a mg/m2 basis) given on gestation day 9,
10, 11 or 12. In this study azacitidine caused fetal death when administered at
3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was
reduced to 9% of control at the highest dose on gestation day 9. Fetal
anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies
(micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia,
gastroschisis, edema, and rib abnormalities).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PCI
Hepatotoxicity in Patients with Severe
Pre-Existing Hepatic Impairment
- Instruct patients to inform their
physician about any underlying liver disease.
Renal Toxicity
- Instruct patients to inform their
physician about any underlying renal disease.
Embryo-Fetal Risk
- Advise pregnant women of the potential
risk to a fetus.
- Advise females of reproductive potential
to avoid pregnancy during treatment with VIDAZA.
- Advise males with female sexual partners
of reproductive potential to not father a child and to use effective
contraception during treatment with VIDAZA. Advise patients to report pregnancy
to their physicians immediately.
Lactation
- Advise patients to avoid breastfeeding
while receiving VIDAZA.
Get Email Alerts |
Guide
