Temozolomide

Trade Names:
Temodar
- Capsules 5 mg
- Capsules 20 mg
- Capsules 100 mg
- Capsules 140 mg
- Capsules 180 mg
- Capsules 250 mg
- Injection, lyophilized powder for solution 2.5 mg/mL

Pharmacology

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Temozolomide is a prodrug that undergoes rapid nonenzymatic conversion to the reactive compound MTIC. Cytotoxicity and antiproliferative activity against tumor cells are thought to be primarily caused by alkylation (methylation) of specific guanine-rich areas of DNA.

Pharmacokinetics

Absorption

Temozolomide is rapidly and completely absorbed after oral administration; T _max is 1 h. Food reduces the rate and extent of absorption.

Distribution

Weakly bound to plasma proteins (15%); Vd is 0.4 L/kg.

Metabolism

CYP-450 plays only a minor role in the metabolism of temozolomide's active metabolites.

Elimination

The half-life is 1.8 h. Overall Cl is approximately 5.5 L/h/m ² . About 38% of the administered drug is recovered in the urine and 1% in the feces.

Special Populations

Over the range of CrCl 36 to 130 mL/min/m ² , there was no effect on renal Cl.

Pharmacokinetics in patients with mild to moderate hepatic function impairment are similar to those in patients with healthy renal function.

In patients 19 to 78 yr of age, there was no difference in pharmacokinetics.

Women have approximately 5% lower Cl than men.

Effects of race on pharmacokinetics have not been studied.

Indications and Usage

Refractory anaplastic astrocytoma; treatment of newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

Unlabeled Uses

Metastatic melanoma.

Contraindications

Hypersensitivity to any component of the product; hypersensitivity to dacarbazine.

Dosage and Administration

The recommended dose for temozolomide as an IV infusion over 90 min is the same as the dose for the oral capsule formulation. Dosage calculations are based on body surface area (BSA).

PO/IV 150 mg/m ² /day for 5 days; may repeat at 28-day intervals. Based on hematologic response, titrate up to target maintenance dosage of 200 mg/m ² /day for 5 days of each cycle.

If absolute neutrophil count (ANC) is more than 1,500/mcL and platelets are more than 100,000/mcL on either day 22 or day 1 of the next cycle, then increase dosage 50 mg/m ² /day for that cycle; do not increase above max dosage of 200 mg/m ² /day. If ANC is 1,000 to 1,500/mcL and platelets are 50,000 to 100,000/mcL on either day 22 or day 1 of next cycle, postpone therapy until ANC is more than 1,500/mcL and platelets are more than 100,000/mcL, then resume previous dose. If ANC is less than 1,000/mcL and platelets are less than 50,000/mcL on either day 22 or day 1 of next cycle, postpone therapy until ANC is more than 1,500/mcL and platelets are more than 100,000/mcL, then reduce dosage 50 mg/m ² /day for subsequent cycles. Do not reduce below minimum dosage of 100 mg/m ² /day. Discontinue therapy if patient cannot tolerate 100 mg/m ² /day.

PO/IV 75 mg/m ² /day for 42 days concomitant with focal radiotherapy. The concomitant phase is usually followed by 6 cycles of maintenance therapy. Continue therapy until disease progression occurs. Continue therapy if ANC is at least 1,500/mcL, platelets are at least 100,000/mcL, and common toxicity criteria (CTC) nonhematological toxicity (except for alopecia, nausea, vomiting) is grade 1 or less. Interrupt therapy if ANC is 500 to less than 1,500/mcL, platelets are 10,000 to less than 100,000/mcL, and CTC nonhematological toxicity (except for alopecia, nausea, vomiting) is grade 2. Discontinue therapy if ANC is less than 500/mcL, platelets are less than 10,000/mcL, and CTC nonhematological toxicity (except for alopecia, nausea, vomiting) is grade 3 or 4.

Beginning 4 wk after completing concomitant phase, 150 mg/m ² /day for 5 days followed by 23 days without treatment.

Escalate dosage to 200 mg/m ² /day if CTC nonhematological toxicity for cycle 1 is grade 2 or less (except for alopecia, nausea, vomiting), ANC is at least 1,500/mcL, and platelets are at least 100,000/mcL. Dosage remains at 200 mg/m ² /day for first 5 days of each subsequent cycle, except if toxicity occurs. If dose is not escalated at cycle 2, escalation should not be done in subsequent cycles.

If ANC is less than 1,500/mcL and platelets are less than 100,000/mcL, do not start next cycle until ANC is more than 1,500/mcL and platelets are more than 100,000/mcL; reduce dosage for next cycle to 50 mg/m ² /day if ANC is less than 1,000/mcL, platelets were less than 50,000/mcL, and CTC nonhematological toxicity (except for alopecia, nausea, vomiting) was grade 3. Discontinue therapy if CTC nonhematological toxicity (except for alopecia, nausea, vomiting) is grade 4, temozolomide dose is to be reduced to less than 100 mg/m ² /day, or if grade 3 CTC nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. Pneumocystis carinii pneumonia (PCP) prophylaxis is required and should be continued in patients who develop lymphadenopathy until recovery from lymphocytopenia (CTC grade of 1 or less).

General Advice

• Capsules should not be opened. If capsules are accidentally opened or damaged, take rigorous precautions to avoid inhalation or contact of capsule contents with skin or mucous membranes.
• Administer prescribed dose once daily. Administer on an empty stomach at bedtime to reduce nausea and vomiting.
• Have patient swallow capsules whole with a glass of water. Caution patient not to crush or chew capsules.
• Administer antiemetic therapy as prescribed.
• Follow institutional procedures for proper handling and disposal of anticancer drugs.
• Temozolomide for injection should be administered only by IV infusion.
• Temozolomide injection should be infused using a pump over a 90-min period.
• Do not infuse other medications simultaneously through the same IV line.

Storage/Stability

Store capsules at controlled room temperature (59° to 86°F).

Store injection refrigerated at 36° to 46°F. After reconstitution, store at 77°F. Use reconstituted product within 14 hours, including infusion time.

Drug Interactions

Food reduces the extent of absorption; mean C _max and AUC are decreased 32% and 9%, respectively, and median T _max is increased 2-fold when administered after a modified high-fat breakfast.

Valproic acid decreases temozolomide Cl by about 5%.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Fatigue (61%); headache (41%); convulsions (23%); hemiparesis (18%); asthenia (13%); dizziness (12%); abnormal coordination (11%); amnesia, insomnia (10%); paresthesia, somnolence (9%); ataxia, paresis (8%); anxiety, dysphasia, impaired memory, weakness (7%); abnormal gait, depression, local convulsions (6%); confusion (5%).

Dermatologic

Alopecia (55%); rash (13%); pruritus (8%); dry skin (5%); erythema (1%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).

EENT

Blurred vision, pharyngitis (8%); abnormal vision, diplopia (5%).

GI

Nausea (53%); vomiting (42%); constipation (33%); anorexia (27%); diarrhea (16%); abdominal pain, stomatitis (9%); taste perversion (5%).

Genitourinary

Urinary incontinence, UTI (8%); female breast pain, increased frequency of micturition (6%).

Hematologic-Lymphatic

Lymphopenia (55%); abnormal platelets (19%). abnormal neutrophils (14%); abnormal WBC (11%); thrombocytopenia (8%); abnormal hemoglobin (4%); prolonged pancytopenia that may result in aplastic anemia (postmarketing).

Hypersensitivity

Allergic reaction (3%).

Metabolic-Nutritional

Weight increase (5%).

Musculoskeletal

Back pain (8%); arthralgia (6%); myalgia (5%).

Respiratory

Coughing, upper respiratory tract infection (8%); sinusitis (6%); dyspnea (5%).

Miscellaneous

Fever (13%); peripheral edema, viral infection (11%); radiation injury (2%); opportunistic infections including PCP (postmarketing).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Elderly

Elderly patients at least 70 yr of age had a higher incidence of grade 4 neutropenia and grade 4 thrombocytopenia in the first cycle of therapy; exercise caution when treating.

Renal Function

Exercise caution when administering to patients with severe renal function impairment.

Hepatic Function

Exercise caution when administering to patients with severe hepatic function impairment.

Special Risk Patients

Women have higher incidences than men of grade 4 neutropenia and thrombocytopenia in the first cycle of therapy.

Myelodysplastic syndrome/secondary malignancies

Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed very rarely.

Myelosuppression

Causes myelosuppression; prior to dosing, patients must have an ANC of at least 1,500/mcL and a platelet count at least 100,000/mcL.

PCP prophylaxis

Prophylaxis against PCP is required for all patients with newly diagnosed glioblastoma multiforme receiving temozolomide and radiotherapy for the 42day regimen.

Overdosage

Symptoms

Bone marrow suppression, death, infection, multi-organ failure, pancytopenia, pyrexia.

Patient Information

• Review the treatment regimen, including dosing schedule, duration of treatment, and monitoring that will be required.
• Advise patient or caregiver to read the patient information leaflet before starting therapy and with each refill.
• Advise patient to take each dose on an empty stomach with a glass of water. Caution patient to swallow capsules whole and not to chew, crush, or open capsules.
• Advise patient that taking dose at bedtime may reduce side effects.
• Caution patient that if capsules are accidentally opened or damaged to take rigorous precautions with the capsule contents to avoid inhalation or contact with skin or mucous membranes. If accidental contact with skin occurs, advise patient to wash thoroughly with soap and water; if contact with mucus membranes occurs, advise patient to flush thoroughly with plain water.
• Instruct patient to keep temozolomide away from children and pets.
• Advise patient or caregiver that additional medications may be given before and/or after temozolomide administration to reduce adverse reactions (eg, vomiting).
• Advise patient or caregiver to immediately report any of the following to health care provider: bleeding or unusual bruising; difficulty breathing; fever, chills, or other signs of infection; hives; mouth or lip sores; paleness; rash; unexplained shortness of breath.
• Advise patient or caregiver to report any of the following to health care provider: persistent nausea, vomiting, constipation, or appetite loss; any unusual or unexplained symptom or feeling.
• Advise patient or caregiver that medication may cause hair loss, but that this is reversible when therapy is stopped.
• Caution women of childbearing potential to avoid becoming pregnant while being treated with temozolomide.
• Caution men to avoid fathering a child during treatment with temozolomide.

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