Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/68
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Temodar (Capsule)
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Dosage of TEMODAR Capsules must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For TEMODAR dosage calculations based on body surface area (BSA) see Table 9. For suggested capsule combinations on a daily dose see Table 10.<br/>Patients with Newly Diagnosed High Grade Glioma:<br/>Concomitant Phase: TEMODAR is administered orally at 75 mg/mdaily for 42 days concomitant with focal radiotherapy (60Gy administered in 30 fractions) followed by maintenance TEMODAR for 6 cycles. Focal RT includes the tumor bed or resection site with a 2���3 cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The TEMODAR dose should 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��10/L platelet count���100��10/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. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and non-hematological toxicity criteria as noted in Table 5. PCP prophylaxis is required during the concomitant administration of TEMODAR and radiotherapy andshould be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC grade���1).<br/>Maintenance Phase Cycle 1: Four weeks after completing the TEMODAR + RT phase, TEMODAR is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/monce daily for 5 days followed by 23 days without treatment.<br/>Cycles 2���6: At the start of Cycle 2, the dose is escalated to 200 mg/m, 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��10/L, and the platelet count is���100��10/L. The dose remains at 200 mg/mper day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.<br/>Dose reduction or discontinuation during maintenance: Dose reductions during the maintenance phase should be applied according to Tables 6 and 7. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of TEMODAR) or within 48 hours of that day, and weekly until the ANC is above 1.5��10/L (1,500/��L) and the platelet count exceeds 100��10/L (100,000/��L). The next cycle of TEMODAR should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst non-hematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 6 and 7.<br/>Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/morally once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are���1.5��10/L (1,500/��L) and both the nadir and Day 29, Day 1 of next cycle platelet counts are���100��10/L (100,000/��L), the TEMODAR dose may be increased to 200 mg/m/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5��10/L (1,500/��L) and the platelet count exceeds 100��10/L (100,000/��L). The next cycle of TEMODAR should not be started until the ANC and platelet count exceed these levels. If the ANC falls to<1.0��10/L (1,000/��L) or the platelet count is<50��10/L (50,000/��L) during any cycle, the next cycle should be reduced by 50 mg/m, but not below 100 mg/m, the lowest recommended dose (see Table 8). TEMODAR therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years; but the optimum duration of therapy is not known. In clinical trials, TEMODAR was administered under both fasting and non-fasting conditions; however, absorption is affected by food and consistency of administration with respect to food is recommended. There are no dietary restrictions with TEMODAR. To reduce nausea and vomiting, TEMODAR should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administrationof TEMODAR Capsules. TEMODAR (temozolomide) Capsules should not be opened or chewed. They should be swallowed whole with a glass of water.<br/>Handling and Disposal: TEMODAR causes the rapid appearance of malignant tumors in rats. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
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TEMODAR Capsules for oral administration contain temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula is: The material is a white to light tan/light pink powder with a molecular formula of CHNOand a molecular weight of 194.15. The molecule is stable at acidic pH (<5), and labile at pH>7, hence TEMODAR can be administered orally. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH. Each capsule contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients for TEMODAR Capsules are lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and stearic acid. The 5 mg, 20 mg, 100 mg, and 250 mg gelatin capsule shells contain titanium dioxide. The capsules are white and imprinted with pharmaceutical ink. The body of the capsules for the 140 mg and 180 mg strengths is made of gelatin, and is opaque white. The cap is also made of gelatin, and the colors vary based on the dosage strength. TEMODAR 5 mg: green imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, titanium dioxide, yellow iron oxide, and FD&C Blue #2 aluminum lake. TEMODAR 20 mg: brown imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, titanium dioxide, black iron oxide, yellow iron oxide, brown iron oxide, and red iron oxide. TEMODAR 100 mg: blue imprint contains pharmaceutical glaze (modified) in an ethanol/shellac mixture, isopropyl alcohol, n-butyl alcohol, propylene glycol, titanium dioxide, and FD&C Blue #2 aluminum lake. TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, FD&C Blue #2, and titanium dioxide. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. TEMODAR 180 mg: The orange cap contains gelatin, sodium lauryl sulfate, titanium dioxide, iron oxide red and iron oxide yellow. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. TEMODAR 250 mg: black imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, and black iron oxide.
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Mechanism of Action: Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the Oand Npositions of guanine.<br/>Pharmacokinetics: Temozolomide is rapidly and completely absorbed after oral administration; peak plasma concentrations occur in 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and Tincreased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a modified high-fat breakfast. Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hours and exhibits linear kinetics over the therapeutic dosing range. Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.<br/>Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-car-boxamide (MTIC) and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. About 38% of the administered temozolomide total radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is as unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m.<br/>Special Populations:<br/>Age: Population pharmacokinetic analysis indicates that age (range 19 to 78 years) has no influence on the pharmacokinetics of temozolomide. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy than patients under 70 years of age .<br/>Gender: Population pharmacokinetic analysis indicates that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men. Women have higher incidences of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than men .<br/>Race: The effect of race on the pharmacokinetics of temozolomide has not been studied.<br/>Tobacco Use: Population pharmacokinetic analysis indicates that the oral clearance of temozolomide is similar in smokers and nonsmokers.<br/>Creatinine Clearance: Population pharmacokinetic analysis indicates that creatinine clearance over the range of 36���130 mL/min/mhas no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr<36 mL/min/m). Caution should be exercised when TEMODAR Capsules are administered to patients with severe renal impairment. TEMODAR has not been studied in patients on dialysis.<br/>Hepatically Impaired Patients: In a pharmacokinetic study, the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child's-Pugh Class I���II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.<br/>Drug-Drug Interactions: In a multiple-dose study, administration of TEMODAR Capsules with ranitidine did not change the Cor AUC values for temozolomide or MTIC. Population analysis indicates that administration of valproic acid decreases the clearance of temozolomide by about 5% . Population analysis failed to demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.
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TEMODAR (temozolomide) Capsules are contraindicated in patients who have a history of hypersensitivity reaction to any of its components. TEMODAR is also contraindicated in patients who have a history of hypersensitivity to DTIC, since both drugs are metabolized to MTIC.
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TEMODAR (temozolomide) Capsules are supplied in amber glass bottles with child resistant polypropylene caps containing the following capsule strengths: TEMODAR (temozolomide) Capsules 5 mg:5 count - NDC 0085-1248-01 20 count - NDC 0085-1248-02 TEMODAR (temozolomide) Capsules 20 mg:5 count - NDC 0085-1244-01 20 count - NDC 0085-1244-02 TEMODAR (temozolomide) Capsules 100 mg:5 count - NDC 0085-1259-01 20 count - NDC 0085-1259-02 TEMODAR (temozolomide) Capsules 140 mg:5 count - NDC 0085-1425-01 14 count���NDC 0085-1425-02 TEMODAR (temozolomide) Capsules 180 mg:5 count - NDC 0085-1430-01 14 count���NDC 0085-1430-02 TEMODAR (temozolomide) Capsules 250 mg:5 count - NDC 0085-1252-01 20 count - NDC 0085-1252-02 Store at 25��C (77��F); excursions permitted to 15�����30��C (59�����86��F). [See USP Controlled Room Temperature]
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IMPORTANT DISPENSING INFORMATION For every patient, TEMODAR must be dispensed in a separate vial or in its original glass bottle making sure each container lists the strength per capsule and that patients take the appropriate number of capsules from each bottle or vial. Please see the dispensing instructions below for more information.
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Doses of 500, 750, 1,000, and 1,250 mg/m(total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with 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, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
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Temozolomide
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Temodar (Capsule)
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TEMODAR (temozolomide) Capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. TEMODAR Capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, ie, patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.
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Temodar
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