Temozolomide (Page 4 of 8)
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of temozolomide. 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 the drug exposure.
Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome
Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide capsules and, in some cases, recurred upon rechallenge.
Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes.
Hepatobiliary: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.
Infections: Serious opportunistic infections, including some cases with fatal outcomes with bacterial, viral (primary and reactivated), fungal, and protozoan organisms.
Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.
Endocrine: Diabetes insipidus
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies, temozolomide 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 temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of temozolomide 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/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8 to 12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2) caused embryolethality as indicated by increased resorptions.
8.2 Lactation
There are no data on the presence of temozolomide 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 temozolomide and for at least 1 week after the final dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating temozolomide [see Use in Specific Population (8.1)].
Contraception
Females
Temozolomide can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Population (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with temozolomide 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 temozolomide and for at least 3 months after the final dose [see Use in Specific Population (8.1), Nonclinical Toxicology (13.1)]. Advise male patients not to donate semen during treatment with temozolomide and for at least 3 months after the final dose.
Infertility
Temozolomide may impair male fertility [see Nonclinical Toxicology (13.1)] . Limited data from male patients show changes in sperm parameters during treatment with temozolomide; however, no information is available on the duration or reversibility of these changes.
8.4 Pediatric Use
Safety and effectiveness of temozolomide have not been established in pediatric patients. Safety and effectiveness of temozolomide 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.
8.5 Geriatric Use
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) and Adverse Reactions (6.1)].
8.6 Renal Impairment
No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 [see Clinical Pharmacology (12.3)]. The recommended dose of temozolomide has not been established for patients with severe renal impairment (CLcr < 36 mL/min/m 2) or for patients with end-stage renal disease on dialysis.
8.7 Hepatic Impairment
No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child Pugh class A and B) [see Clinical Pharmacology (12.3)]. The recommended dose of temozolomide has not been established for patients with severe hepatic impairment (Child-Pugh class C).
10 OVERDOSAGE
Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.
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