Temodal Adverse Reactions

Adult Patients with Newly diagnosed glioblastoma multiforme: Table 4 provides treatment emergent adverse events, in (causality not determined during clinical trials) patients with newly diagnosed glioblastoma multiforme during the concomitant and adjuvant phases of treatment. (See Tables 4A and 4B.)

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Laboratory results: Myelosuppression, (neutropenia and thrombocytopenia), which are known dose-limiting toxicities for most cytotoxic agents, including TEMODAL, were observed. When laboratory abnormalities and adverse events were combined across concomitant and adjuvant treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8% of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14% of the patients who received TEMODAL.
Adverse effects in patients with recurrent or progressive glioma, or malignant melanoma: In clinical trials, the most frequently occurring undesirable effects were gastrointestinal disturbances, specifically nausea (43%) and vomiting (36%). These effects were usually Grade 1 or 2 (mild to moderate in severity) and were either self-limiting or readily controlled with standard antiemetic therapy. The incidence of severe nausea and vomiting was 4%.
Other adverse events reported frequently include fatigue (22%), constipation (17%), and headache (14%). Anorexia (11%), diarrhoea (8%), rash, fever, asthenia and somnolence (6% each) were also reported. Less common (2% to 5%) and in descending order of frequency, were abdominal pain, pain, dizziness, weight decrease, malaise, dyspnea, alopecia, rigors, pruritus, dyspepsia, taste perversion, paresthesia and petechiae.
Laboratory results: Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17%, respectively, of patients treated for glioma, and 20% and 22%, respectively, of patients with metastatic melanoma. This led to hospitalization and/or discontinuation of TEMODAL in 8% and 4%, respectively, of patients with glioma, and 3% and 1.3%, respectively, of those with melanoma. Myelosuppression was predictable (usually within the first few cycles, with the nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. Pancytopenia, leukopenia, and anemia have also been reported. Lymphopenia has also been reported very commonly.
In a population pharmacokinetics analysis of clinical trial experience, there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC <500 cells/μL), 12% versus 5%, and thrombocytopenia (<20,000 cells/μL), 9% versus 3%, in women vs. men in the first cycle of therapy. In a 400-subject recurrent glioma data set, Grade 4 neutropenia occurred in 8% of female versus 4% of male subjects and Grade 4 thrombocytopenia in 8% of female vs. 3% of male subjects in the first cycle of therapy. In a study of 288 subjects with newly diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3% of female vs 0% of male subjects and Grade 4 thrombocytopenia in 1% of female vs 0% of male subjects in the first cycle of therapy.
During the marketing of TEMODAL, cases of erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome and allergic reactions, including anaphylaxis, have been reported very rarely. There have been reported cases of hepatotoxicity including elevations of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis. Hepatic injury, including fatal hepatic failure, has been reported uncommonly (Frequencies estimated based on relevant clinical trials.) (see Precautions).
Rare cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP) and both primary and reactivated cytomegalovirus (CMV) infection have been reported. Cases of reactivation of hepatitis B infections, including some cases with fatal outcomes, have also been reported (see Precautions). Cases of herpes simplex encephalitis, including cases with fatal outcomes, have also been reported. Cases of interstitial pneumonitis/pneumonitis and pulmonary fibrosis have been reported very rarely. Very rare cases of myelodysplastic syndrome (MDS) and secondary malignancies, including myeloid leukemia have also been observed. Prolonged pancytopenia, which may result in aplastic anemia has been reported, and in some cases has resulted in a fatal outcome. Diabetes insipidus has also been reported.