Approved Drug Label (PDF)
4
Contraindications
(Newly
added information)
TEMODAR is contraindicated in patients with a history of hypersensitivity reactions to:
temozolomide or any other ingredients in TEMODAR;
and
dacarbazine, since
both
temozolomide
and
dacarbazine are metabolized to the same active
metabolite
5-(3- methyltriazen-1-yl)-imidazole-4-carboxamide.
Reactions to TEMODAR
have included anaphylaxis [see Adverse Reactions (6.2)].
5
Warnings and Precautions
(Newly
added information)
Myelosuppression
Myelosuppression, including pancytopenia, leukopenia
and anemia, some with fatal outcomes,
have occurred with TEMODAR [see Adverse Reactions (6.1, 6.2)]. Geriatric
patients and women have been shown in clinical
trials to have a higher risk of developing myelosuppression.
Prior to dosing,
patients must have an ANC of 1.5 x 109/L or greater
and a platelet count of 100 x 109/L or greater.
For the concomitant phase with radiotherapy, obtain a complete
blood count prior to initiation of treatment
and weekly during treatment [see Dosage
and Administration (2.1)].
For the 28-day treatment cycles, obtain a complete blood count prior to treatment
on Day 1 and on Day 22 of each cycle. Perform complete blood counts weekly until recovery
if the ANC falls below 1.5 x 109/L and the platelet count falls below 100 x 109/L [see Dosage and Administration (2.1, 2.2)].
Myelodysplastic Syndrome and Secondary Malignancies
(Updated
section title)
(Additions and/or
revisions underlined)
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid
leukemia, have been observed
following TEMODAR
administration.
Pneumocystis Pneumonia
(Newly
added information)
Pneumocystis pneumonia (PCP) can occur in patients receiving TEMODAR. The risk of PCP is increased in patients
receiving steroids
or with longer treatment regimens.
For patients with newly diagnosed
glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue in patients who experience lymphopenia until resolution to grade 1 or less [see Dosage and Administration (2.1)].
Monitor all patients receiving TEMODAR for the development of lymphopenia and PCP.
Embryo-Fetal Toxicity
(Newly added
subsection)
Based on findings
from animal studies and its mechanism of action, TEMODAR can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes
have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted
in embryolethality
and polymalformations at doses less than the maximum
human dose based on body surface area.
Advise pregnant
women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TEMODAR and for at least 6 months after the final dose. Because of potential
risk of genotoxic
effects on sperm, advise male patients with female partners
of reproductive potential to use condoms
during treatment with TEMODAR
and for at least 3 months after the final dose. Advise male patients not to
donate semen during treatment with TEMODAR and for at least 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
6
Adverse Reactions
(Newly
added information)
The following clinically significant adverse reactions are described elsewhere in the labeling:
Myelosuppression [see Warnings and Precautions (5.1)].
Myelodysplastic Syndrome and Secondary
Malignancies [see Warnings and Precautions (5.2)].
Pneumocystis Pneumonia [see Warnings and Precautions (5.3)].
Hepatotoxicity [see Warnings
and Precautions (5.4)].
Clinical Trials Experience
(Extensive
changes; please refer to label for complete information.)
8
Use in Specific Populations
Females and Males of Reproductive Potential
(Newly added section)
Pregnancy Testing
Verify pregnancy status in females
of reproductive potential prior to initiating TEMODAR [see Use in Specific
Populations (8.1)]. Contraception
Females
TEMODAR can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment
with TEMODAR and for at least
6 months after the last dose.
Males
Because of the potential
for embryofetal toxicity and genotoxic
effects on sperm cells, advise male patients with pregnant
partners or female partners of reproductive potential
to use condoms during treatment
with TEMODAR and for at least 3 months after the final dose [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].
Advise male patients
not to donate semen during treatment with TEMODAR and for at least 3 months after the final dose. Infertility
TEMODAR may impair male fertility [see Nonclinical Toxicology (13.1)]. Limited data from male patients show changes in sperm parameters during treatment with TEMODAR; however,
no information is available
on the duration or reversibility of these changes.
Geriatric Use
(Newly
added information)
In the Newly
Diagnosed Glioblastoma trial, Study MK-7365-051, 15% of patients
were 65 years and older. This study did not include sufficient numbers
of patients aged 65 years and older to determine differences in effectiveness from younger patients.
No overall differences in safety were observed
between patients
?65 years and younger
patients. In the Refractory Anaplastic Astrocytoma trial, Study MK-7365-0006, 4% of patients
were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger
patients. Patients 70 years and older had a higher incidence
of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1), Adverse Reactions
(6.1)].
Hepatic Impairment
(Newly
added information)
No dosage
adjustment is recommended for patients with mild to moderate hepatic
impairment (Child Pugh class Aand B) [see Clinical Pharmacology (12.3)]. The recommended dose of TEMODAR has not been established for patients with severe hepatic impairment (Child-Pugh class C).
Lactation
(PLLR
Conversion with extensive changes)
There are no data on the presence of TEMODAR or its metabolites in human milk, the
effects on a breastfed child, or the effects on milk production. Because
of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed
children, advise women not to breastfeed during treatment with TEMODAR
and for at least 1 week after the final dose.
Pediatric Use
(Additions and/or
revisions underlined)
Safety
and effectiveness of TEMODAR
have not been established in pediatric
patients. Safety and effectiveness of TEMODAR capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to18 years.
In one study, 29 patients with recurrent brain stem glioma
and 34 patients with recurrent
high-grade astrocytoma were enrolled. In a second study conducted by the Children’s Oncology Group (COG), 122 patients were enrolled, including patients
with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS
tumors (9). The adverse reaction profile
in pediatric patients was similar to adults.
Pregnancy
(PLLR
Conversion with extensive changes)
Risk Summary
Based on its mechanism of action [see Clinical
Pharmacology (12.1)] and
findings from animal studies,
TEMODAR can cause fetal harm when administered to a pregnant
woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central
nervous system,
facial, cardiac,
skeletal, and genitourinary system anomalies with exposure
to TEMODAR during pregnancy. These cases report similar adverse
developmental outcomes to those observed in animal studies.
Administration of TEMODAR
to rats and rabbits during the period
of organogenesis caused numerous external,
internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data). 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
Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m2 (0.38 and 0.75 times the human dose of 200 mg/m2) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal
organs and skeleton in both species.
In rabbits, temozolomide at the 150 mg/m2 dose (0.75 times the human dose of 200 mg/m2) caused embryolethality as indicated by increased resorptions.
Renal Impairment
(Newly
added information)
No dosage
adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m2 [see Clinical Pharmacology (12.3)]. The recommended dose of TEMODAR has not been established for patients with severe renal impairment (CLcr < 36 mL/min/m2) or for patients with end-stage renal disease
on dialysis.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling Information
(Newly
added information)
Advise the patient to read the FDA-approved patient
labeling (Patient Information).
Myelosuppression
Inform patients that TEMODAR
can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact
their healthcare provider
immediately for bleeding, fever, or other signs
of infection [see Warnings
and Precautions (5.1)].
Myelodysplastic Syndrome and Secondary
Malignancies
Advise patients of the increased
risk of myelodysplastic syndrome and secondary malignancies [see Warnings
and Precautions (5.2)].
Pneumocystis Pneumonia
Advise patients of the increased
risk of Pneumocystis pneumonia and to contact their healthcare provided immediately for new or worsening pulmonary
symptoms. Inform patients that prophylaxis for Pneumocystis pneumonia may be needed [see Dosage and Administration (2.1), Warnings
and Precautions (5.3)].
Hepatotoxicity
Advise patients of the increased
risk of hepatotoxicity and
to contact their healthcare provider immediately for signs or symptoms of hepatoxicity [see Warnings and Precautions (5.4)].
Administration Instructions
Advise patient to not open capsules. If capsules are accidentally opened or damaged, advise patients
to take rigorous precautions with capsule contents
to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact,
the hands should be washed.
[see Dosage and Administration (2.3)].
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
[see Warnings and Precautions (5.5), Use in Specific
Populations (8.1)].
Advise females of reproductive potential
to use effective contraception during treatment
with TEMODAR and for at least 6 months after the last dose [see Use in Specific
Populations (8.3)].
Advise male patients
with pregnant partners
or female partners of reproductive potential to use condoms during treatment with TEMODAR and for at least 3 months after the final dose [see Use in Specific
Populations (8.3), Nonclinical Toxicology (13.1)].
Advise male patients not to donate semen during treatment
with TEMODAR and for at least 3 months after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Lactation
Advise women not to breastfeed during treatment with TEMODAR and for at least 1 week after the final dose [see Use in Specific Populations (8.2)].
Infertility
Advise
males of reproductive potential that TEMODAR
may impair fertility
[see Use in Specific
Populations (8.3), Nonclinical Toxicology (13.1)].
Other
Update reflects labeling change from November 2019
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