Antineoplastic Agent, Alkylating Agent

Treatment of adult patients with refractory (first relapse) anaplastic astrocytoma who have experienced disease progression on nitrosourea and procarbazine

D

May cause fetal harm when administered to pregnant women. Animal studies, at doses less than used in humans, resulted in numerous birth defects. Testicular toxicity was demonstrated in animal studies using smaller doses than recommended for cancer treatment. Male and female patients should avoid pregnancy while receiving drug. It is not known whether temozolomide is excreted in breast milk, but breast-feeding is not recommended.

History of hypersensitivity reaction to any of its components or in patients who have a hypersensitivity to DTIC (since both drugs are metabolized to MTIC)

Prior to dosing, patients must have an absolute neutrophil count (ANC) of greater than or equal to 1.5 x 10 9/L and a platelet count of greater than or equal to 100 x 10 9/L. Must have ANC >1,500/mL, platelet count >100,000/mL before starting each cycle. Geriatric patients and women have a higher incidence of myelosuppression. Safety/efficacy in pediatrics not established. Use caution in patients with severe hepatic or renal impairment. The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered.

Women and elderly ( greater than or equal to 70 years of age) have a higher incidence of grade 4 neutropenia and thrombocytopenia. Nausea, vomiting, fatigue, and hematologic effects are drug-related; it is unclear about the others. Nausea and vomiting easily controlled with antiemetics. Myelosuppression was the dose-limiting event (occurred within first few cycles, not cumulative). Hematologic effects are as follows (all percentages appear as grade 3/4): Anemia (4%), neutropenia (11%), granulocytopenia (14%), and thrombocytopenia (19%). Other grade 3/4 reactions included nausea (10%), vomiting (6%), hemiparesis (6%), headache (6%), weakness (6%), fatigue (4%), and fever (2%).

Cardiovascular: Peripheral edema (11%)

Central nervous system: Headache (41%), fatigue (34%), convulsions (23%), hemiparesis (29%), dizziness (19%), fever (11%), coordination abnormality (11%), amnesia (10%), insomnia (10%)

Gastrointestinal: Nausea (53%), vomiting (42%), constipation (33%), diarrhea (16%)

Hematologic: See above in text

Neuromuscular & skeletal: Weakness (13%)

Miscellaneous: Viral infection (11%)

1% to 10%:

Central nervous system: Somnolence (9%), ataxia (8%), confusion (5%), anxiety (7%), depression (6%)

Dermatologic: Rash (8%), pruritus (8%)

Gastrointestinal: Dysphagia (7%), abdominal pain (9%), anorexia (9%), weight gain (5%)

Endocrine and Metabolic: Adrenal hypercorticism (8%), breast pain in females (6%)

Genitourinary: Urinary incontinence (8%), urinary tract infection (8%), micturition increased (6%)

Neuromuscular and Skeletal: Paresthesia (9%), back pain (8%), myalgia (5%)

Ocular: Diplopia (5%), vision abnormality (5%)

Respiratory: Upper respiratory tract infection (8%), pharyngitis (8%), sinusitis (6%), cough (5%)

Dose-limiting toxicity is hematological. In the event of an overdose, hematological evaluation is necessary. Treatment is supportive.

Although valproic acid reduces the clearance of temozolomide by 5%, the clinical significance of this is unknown

Store at controlled room temperature (15°C to 10°C/59°F to 86°F)

Temozolomide (prodrug) is hydrolyzed to MTIC (active form). The cytotoxic effects of MTIC is through alkylation of DNA (O⁶, N⁷ of guanine).

Absorption: T_max: 1 hour when taken on empty stomach

Distribution: V_d (parent compound): 0.4 L/kg; poorly protein bound (15%)

Metabolism: Temozolomide (prodrug) is hydrolyzed to the active form, MTIC. MTIC is hydrolyzed to AIC (intermediate in purine and nucleic acid biosynthesis). Cytochrome P-450 plays a minor role in metabolism.

Half-life: Mean elimination half-life: 1.8 hours (parent compound)

Elimination: 38% recovered in urine in 7 days; 0.8% recovered in feces in 7 days

Dosage is adjusted according to nadir neutrophil and platelet counts of previous cycle and counts at the time of the next cycle

Measure day 22 ANC and platelets. Measure day 29 ANC and platelets. Based on lowest counts at either day 22 or day 29:

On day 22 or day 29, if ANC <1,000/mL or the platelet count is <50,000/mL, postpone therapy until ANC >1,500/mL and platelet count >100,000/mL. Reduce dose by 50 mg/m² for subsequent cycle.

If ANC 1,000-1,500/mL or platelets 50,000-100,000/mL, postpone therapy until ANC >1,500/mL and platelet count >100,000/mL; maintain initial dose.

If ANC >1,500/mL (on day 22 and day 29) and platelet count >100,000/mL, increase dose to, or maintain dose at 200 mg/m²/day for 5 for subsequent cycle.

Temazolamide therapy can be continued until disease progression. Treatment could be continued for a maximum of 2 years in the clinical trial, but the optimum duration of therapy is not known.

Dosage adjustment in renal impairment: Caution should be used when administered to patients with severe renal impairment (Cl_cr <39 mL/minute)

Dosage adjustment in hepatic impairment: Caution should be used when administering to patients with severe hepatic impairment

Dosage adjustment in the elderly: Patients greater than or equal to 70 years of age had a higher incidence of grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than patients <70 years of age

Food reduces rate and extent of absorption. In addition, the incidence of nausea/vomiting is decreased when the drug is taken on an empty stomach.

Capsules should not be opened or chewed but swallowed whole with a glass of water. May be administered on an empty stomach to reduce nausea and vomiting. Bedtime administration may be advised.

A complete blood count on day 22 of cycle or within 48 hours of that day and weekly until the ANC >1500 mL, platelet count >100,000/mL

No information available to require special precautions

No effects or complications reported

Swallow capsules whole with a glass of water. Take on an empty stomach at similar time each day. If you have nausea and vomiting, contact healthcare provider for medicine to decrease this. Male and female patients who take temozolomide should protect against pregnancy (use effective contraception). Do not breast-feed while on medicine. Blood work necessary on day 22 and day 29 of each cycle to determine when to start next cycle and how much medicine to give.

Capsules should not be opened. Educate patients about most frequent side effects and blood work required.

Capsule: 5 mg, 20 mg, 100 mg, 250 mg

American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs, Am J Hosp Pharm, 1990, 47:1033-49.

Clinical Oncological Society of Australia, "Guidelines and Recommendations for Safe Handling of Antineoplastic Agents," Med J Australia, 1983;1:426-8.

"Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines)," Am J Health-Syst Pharm, 1996, 53:1669-85.

"Guidelines for Handling Parenteral Antineoplastics," JAMA, 1985, 253(11):1590-2.

Jones RB, et al, "Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center," CA-A Cancer Journal for Clinicians, 1983, (Sept/Oct) 258-63.

National Study Commission on Cytotoxic Exposure: Recommendations for Handling Cytotoxic Agents. Massachusetts College of Pharmacy and Allied Health Sciences, Boston, MA.

"Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs," NIH Publication No. 83-2621. U.S. Government Printing office, Washington, DC.