opylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide.
TEMODAR 5 mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow, sodium lauryl sulfate, and FD&C Blue #2.
TEMODAR 20 mg: The yellow cap contains gelatin, sodium lauryl sulfate, and iron oxide yellow.
TEMODAR 100 mg: The pink cap contains gelatin, titanium dioxide, sodium lauryl sulfate, and iron oxide red.
TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, and FD&C Blue #2.
TEMODAR 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, titanium dioxide, and sodium lauryl sulfate.
TEMODAR 250 mg: The white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate.
TEMODAR for Injection:
Each vial contains 100 mg of sterile and pyrogen-free temozolomide lyophilized powder for intravenous injection. The inactive ingredients are: mannitol (600 mg), L-threonine (160 mg), polysorbate 80 (120 mg), sodium citrate dihydrate (235 mg), and hydrochloric acid (160 mg).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.
12.3 Pharmacokinetics
Absorption:
Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1–2.25 hours) when temozolomide was administered after a modified high-fat breakfast.
A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 TEMODAR for injection administered over 90 minutes is bioequivalent to 150 mg/m2 TEMODAR oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg∙hr/mL and 891 ng∙hr/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg∙hr/mL and 864 ng∙hr/mL, respectively.
Distribution:
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%.
Metabolism and Elimination:
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 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 enzym |
