Temodal

Temozolomide.

Each TEMODAL Capsule contains 20 mg or 100 mg temozolomide.

TEMODAL is an imidazotetrazine alkylating agent with antitumor activity. It undergoes rapid chemical conversion in the systemic circulation at physiologic pH to the active compound, MTIC (monomethyl triazeno imidazole carboxamide). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O⁶ position of guanine with additional alkylation also occurring at the N⁷ position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

TEMODAL Capsules are indicated for the treatment of patients with: newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as adjuvant treatment; malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.
TEMODAL Capsules are also indicated as first-line treatment for patients with advanced metastatic malignant melanoma.

Adult patients with newly diagnosed glioblastoma multiforme: Concomitant phase: TEMODAL is administered orally at 75 mg/m² daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by adjuvant TEMODAL for 6 cycles. No dose reductions are recommended; however, dose interruptions may occur based on patient tolerance. The TEMODAL dose can be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count ≥1.5 x 10⁹/L; thrombocyte count ≥100 x 10⁹/L; common toxicity criteria (CTC) non-hematological toxicity ≤Grade 1 (except for alopecia, nausea and vomiting). During treatment, a complete blood count should be obtained weekly. TEMODAL dosing should be interrupted or discontinued during concomitant phase according to the hematological and non-hematological toxicity criteria as noted in Table 1. (See Table 1.)

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Adjuvant Phase: Four weeks after completing the TEMODAL + Radiotherapy phase, TEMODAL is administered for an additional 6 cycles of adjuvant treatment. Dosage in Cycle 1 (adjuvant) is 150 mg/m² once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m² if the CTC non-hematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥1.5 x 10⁹/L, and the thrombocyte count is ≥100 x 10⁹/L. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. The dose remains at 200 mg/m² per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions during the adjuvant phase should be applied according to Tables 2 and 3.
During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of TEMODAL). The TEMODAL dose should be reduced or discontinued according to Table 3. (See Tables 2 and 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Adults with recurrent or progressive malignant glioma: In patients previously untreated with chemotherapy, TEMODAL is administered orally at a dose of 200 mg/m² once daily for 5 days per 28-day cycle. In patients previously treated with chemotherapy, the initial dose is 150 mg/m² once daily, to be increased in the second cycle to 200 mg/m² daily providing the absolute neutrophil count (ANC) is ≥1.5 x 10⁹/L and the thrombocyte count is ≥100 x 10⁹/L on Day 1 of the next cycle.
Adults with Metastatic malignant melanoma: For patients with metastatic malignant melanoma, the recommended dose is 200 mg/m² once daily for 5 days per 28-day cycle.
Pediatric patients with recurrent or progressive malignant glioma: In patients 3 years of age or older, TEMODAL is administered orally at a dose of 200 mg/m² once daily for 5 days per 28-day cycle. Pediatric patients previously treated with chemotherapy should receive an initial dose of 150 mg/m² once daily for 5 days, with escalation to 200 mg/m² once daily at the next cycle if there is no hematologic toxicity.
Laboratory parameters for dose modification in recurrent or progressive malignant glioma, or malignant melanoma: Patients treated with TEMODAL may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: absolute neutrophil count (ANC) ≥1.5 x 10⁹/L and platelets ≥100 x 10⁹/L. A complete blood count must be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC is above 1.5 x 10⁹/L and platelet count exceeds 100 x 10⁹/L. If the ANC falls to <1.0 x 10⁹/L or the platelet count is <50 x 10⁹/L during any cycle, the next cycle should be reduced one dose level. Dose levels include 100 mg/m², 150 mg/m², and 200 mg/m². The lowest recommended dose is 100 mg/m².
All Patients: TEMODAL should be administered in the fasting state, at least one hour before a meal.
TEMODAL Capsules must not be opened or chewed, but are to be swallowed whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membrane.

Doses of 500, 750, 1,000, and 1,250 mg/m² (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematological and was reported at any dose but is expected to be more severe at higher doses. An overdose of 2,000 mg per day for 5 days was taken by one patient and the adverse events 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 events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.

TEMODAL is contraindicated in patients who have a history of hypersensitivity reaction to its components or to dacarbazine (DTIC).
TEMODAL is contraindicated for use during pregnancy or lactation (see Use in Pregnancy & Lactation).
TEMODAL is contraindicated in patients with severe myelosuppression.

Patients who received concomitant TEMODAL and radiotherapy in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis carinii pneumonia. Thus, prophylaxis against Pneumocystis carinii pneumonia is required for all patients receiving concomitant TEMODAL and radiotherapy for the 42-day regimen (with a maximum of 49 days). There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids should be observed closely for the development of PCP regardless of the regimen.
Antiemetic therapy: Nausea and vomiting are very commonly associated with TEMODAL, and guidelines are provided.
Patients with newly diagnosed glioblastoma multiforme: Antiemetic prophylaxis is recommended prior to the initial dose of concomitant temozolomide. Antiemetic prophylaxis is strongly recommended during the adjuvant phase.
Patients with recurrent or progressive glioma: Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require antiemetic therapy.
All Patients: Use in patients with hepatic or renal impairment: The pharmacokinetics of TEMODAL were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TEMODAL in patients with severe hepatic impairment (Child-Pugh grade C) or with renal impairment. Based on the pharmacokinetic properties of TEMODAL, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TEMODAL is administered in these patients.
Hepatotoxicity: Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TEMODAL. Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42-day treatment cycle, liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.
Additionally, hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Patients should be screened for HBV infection before treatment initiation. Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with TEMODAL. Therapy should be discontinued for patients with evidence of active hepatitis B infection.
Use in Children: There is no clinical experience with use of TEMODAL in children under the age of 3 years. Experience in older children and adolescents is very limited.
Use in the Elderly: Elderly patients (>70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients.

Effects on fertility: TEMODAL is contraindicated in women who intend to become pregnant, and effective contraception should be used by female patients during and for at least 6 months after treatment with temozolomide (see Contraindications).
Use in men: Effective contraception should be used by male patients treated with TEMODAL. Temozolomide can have genotoxic effects. Therefore, men being treated with temozolomide are advised not to father a child for at least 3 months after receiving the final dose and to seek advice on cryoconservation of spermatozoa prior to treatment because of the possibility of irreversible impairment in fertility due to therapy with temozolomide. Semen donation is also not advised during treatment and for at least 3 months after the final dose.
Use in pregnancy: Cytotoxic agents can produce spontaneous abortion, foetal loss and birth defects. There are no studies in pregnant women. In preclinical studies in rats and rabbits administered 150 mg/m², (associated with systemic exposure below that anticipated in humans) teratogenicity and/or foetal toxicity were demonstrated. TEMODAL, therefore, should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus. Women of childbearing potential should be advised to avoid pregnancy if they are going to receive TEMODAL treatment and for 6 months after discontinuation of TEMODAL therapy.
Use in lactation: It is not known whether TEMODAL is excreted in human milk. A peri/postnatal study in rats found that treatment with temozolomide at doses of greater than 25 mg/m²/day decreased pup growth and retarded development. Given its potential adverse effects in the newborn, TEMODAL must not be used by breastfeeding women.

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.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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.

Administration of TEMODAL with ranitidine or with food did not result in clinically significant alterations in the extent of absorption of TEMODAL. Co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H₂ receptor antagonists, or phenobarbital did not alter the clearance of TEMODAL. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of temozolomide.
Use of TEMODAL in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Cytotoxic Chemotherapy

L01AX03 - temozolomide ; Belongs to the class of other alkylating agents. Used in the treatment of cancer.

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