Introduction

Alkylating antineoplastic agent; prodrug.

Uses for Temozolomide

Brain Tumors

Adjunct to radiation therapy for treatment of newly diagnosed glioblastoma multiforme; also used as adjuvant therapy.

Treatment of refractory anaplastic astrocytoma in adults whose disease has progressed after therapy with a nitrosourea and procarbazine.

Temozolomide Dosage and Administration

General

Pretreatment Screening

• Complete blood cell counts (CBCs) prior to each cycle.

• Liver function tests prior to each cycle.

• Screen for hepatitis.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Closely monitor all patients, particularly those receiving concomitant corticosteroids, for the development of lymphocytopenia or Pneumocystis jiroveci (formerly P. carinii) pneumonia (PCP).

• Concomitant temozolomide and radiation therapy: Complete blood cell counts (CBCs) weekly during treatment.

• Maintenance temozolomide: CBCs on day 22 and then weekly.

• Liver function tests half-way through the first treatment cycle and 2–4 weeks following the last dose of temozolomide.

Premedication and Prophylaxis

• Administer prophylaxis for PCP (e.g., inhaled pentamidine, oral co-trimoxazole) during concomitant temozolomide and radiation therapy\. In patients with lymphocytopenia, continue PCP prophylaxis until lymphocytopenia resolves to grade 1 or less.

Dispensing and Administration Precautions

• Patients may need to take combinations of temozolomide capsules of different strengths to receive the correct daily dose. To minimize the risk of inappropriate dosing, the clinician or pharmacist should provide written instructions for the dosage schedule.

Handling and Disposal

• Procedures for proper handling and disposal of antineoplastic agents should be followed when preparing or administering temozolomide.

Other General Considerations

• Adjust dosage based on nadir platelet and ANC during the previous cycle and ANC and platelet counts on day 1 of the next cycle.

• Consider hepatitis prophylaxis with antiviral agents as clinically indicated.

Administration

Administer orally or by IV infusion.

Oral Administration

Administer orally once daily with a full glass of water and in a consistent manner relative to food intake. Swallow capsule intact.

Administration on an empty stomach may reduce incidence of nausea and vomiting; may give antiemetics prior to and/or following temozolomide administration.

Bedtime administration may be advisable.

Do not open capsules. If accidentally opened or damaged, avoid inhalation or contact with skin or mucous membranes.

Dispensing and Administration Precautions

Based on the dose prescribed, determine the number of each strength capsules needed (e.g., for a dose of 275 mg daily for 5 days, dispense five 250 mg-capsules, five 20-mg capsules, and five 5-mg capsules). Dispense each strength of capsules in a separate container. Label each container with the strength per capsule and with the appropriate number of capsules to be taken each day. Instruct the patient to take the appropriate number of capsules from each container to equal the total daily dose.

IV Infusion

Administer by IV infusion. Use an infusion pump to administer the drug. Flush the IV line before and after each temozolomide infusion.

Vials are for single use only. Store at 2–8°C.

Reconstitution

Must be reconstituted prior to administration.

Allow vials to reach room temperature prior to reconstitution. Reconstitute powder for injection by adding 41 mL of sterile water for injection to a vial containing 100 mg of temozolomide, resulting in a solution containing 2.5 mg/mL of temozolomide; gently swirl (do not shake).

Do not further dilute the reconstituted solution prior to administration. Using aseptic technique, transfer up to 40 mL from each vial of reconstituted solution needed to reach the calculated dosage to an empty 250-mL infusion bag. Do not infuse drugs or solutions other than 0.9% sodium chloride through the same IV line.

Store reconstituted solution at room temperature for up to 14 hours (including infusion time).

Rate of Administration

Administer by IV infusion over 90 minutes using an infusion pump. Infusion over a shorter or longer duration may result in suboptimal dosing.

Dosage

Recommended IV dosage is the same as the oral dose. Bioequivalence of oral and IV doses of temozolomide established only when temozolomide for injection is administered by IV infusion over 90 minutes.

Adults

Brain Tumors

Glioblastoma Multiforme

Initial Phase: 75 mg/m² daily for 42 days (up to 49 days) concomitantly with focal radiotherapy (60 Gy administered in 30 fractions). Monitor CBC weekly; interrupt or discontinue temozolomide if severe hematologic or nonhematologic toxicities occur. (See Table 1.)

Four weeks after completing initial phase (temozolomide and radiation therapy), initiate maintenance therapy (six 28-day cycles of temozolomide).

Maintenance Phase: 150 mg/m² once daily for 5 consecutive days followed by a 23-day rest period for a 28-day cycle (six cycles). Periodically monitor CBC; do not resume dosing until criteria for continuance of therapy are met. (See Table 2.) For cycle 2, may increase dosage to 200 mg/m² once daily for 5 days only if nonhematologic toxicity (excluding alopecia, nausea, and vomiting) from cycle 1 is ≤ grade 2, ANC ≥1500/mm³, and platelet count ≥100,000/mm³. For cycles 3–6, continue dosage of 200 mg/m² once daily for 5 consecutive days of each 28-day cycle, unless toxicity occurs. If dosage was not increased for cycle 2, do not increase dosage for subsequent cycles.

Refractory Anaplastic Astrocytoma

Initially, 150 mg/m² once daily for 5 consecutive days of a 28-day treatment cycle. Monitor CBC periodically; adjust subsequent dosages and dosing schedule as appropriate. (See Table 3.) For next cycle, increase dosage to 200 mg/m² once daily for 5 days only if nadir and day-of-dosing (day 29, day 1 of next cycle) ANC and platelet count ≥1500/mm³ and ≥100,000/mm³, respectively.

Continue therapy until disease progression occurs. In the pivotal clinical study, treatment could be continued for a maximum of 2 years; however, optimum duration of therapy is not known.

Dosage Modification for Toxicity

Glioblastoma Multiforme

During initial phase (concomitant temozolomide and radiotherapy), monitor CBC at baseline, then weekly, and adjust dosing schedule as appropriate. (See Table 1.)

During maintenance therapy, obtain CBC at baseline, then on day 22 of cycle, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³. Withhold next cycle until these counts are exceeded. Adjust dosage and schedule for next cycle based on nadir hematologic measurements (i.e., ANC and platelet counts) and most severe nonhematologic toxicity during previous cycle. (See Table 2.)

For patients who experience toxicity (ANC >1500/mm³, platelet count >100,000/mm³, and nonhematologic toxicities that are grade 2 or less in severity) during cycle 1, the temozolomide dose should not be increased for cycle 2 or any subsequent cycle of therapy.

Refractory Anaplastic Astrocytoma

Obtain CBC at baseline and then on day 22, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³. Withhold next cycle until these counts are exceeded; adjust subsequent dosages based on nadir hematologic measurements (i.e., ANC and platelet counts) during previous cycle and on day 29 (i.e., day 1 of next cycle). (See Table 3.)

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustment necessary.

Use in patients with severe hepatic impairment (Child-Pugh class C) not established.

Renal Impairment

Cl_cr of 36–130 mL/minute per m²: No dosage adjustment necessary.

Use in patients with severe renal impairment (Cl_cr <36 mL/minute per m²) or end-stage renal disease requiring dialysis not established.

Geriatric Patients

Increased risk of developing myelosuppression, but no specific dosage recommendations other than usual adjustment for hematologic toxicity.

Select dosage with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Gender

Increased risk of myelosuppression but no specific dosage recommendations other than usual adjustment for hematologic toxicity.

Contraindications

• Known hypersensitivity (e.g., anaphylaxis) to temozolomide or any ingredient in the formulation.

• Known hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).

Warnings/Precautions

Hematologic Effects

Prolonged pancytopenia reported; may result in potentially fatal aplastic anemia. Assessment of patients for such effects may be complicated by concomitant administration of drugs associated with aplastic anemia (i.e., carbamazepine, phenytoin, co-trimoxazole). (See Specific Drugs under Interactions.)

Myelosuppression (dose-limiting thrombocytopenia and neutropenia). Higher incidence of myelosuppression in geriatric patients and women.

In patients with refractory anaplastic astrocytoma, myelosuppression generally occurs late in treatment cycle (e.g., 26–28 days), usually develops during first few cycles of therapy, resolves within 14 days, and was not cumulative.

Hospitalization, blood transfusion, or drug discontinuance may be required.

Monitor CBC periodically and adjust dosage and schedule as appropriate. (See Dosage and Administration.)

Development of Myelodysplastic Syndrome and Secondary Malignancies

Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, reported.

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Risk of Pneumocystis jiroveci pneumonia (PCP), particularly with longer dosage regimen.

Closely monitor all patients (particularly those receiving corticosteroids) for development of PCP (regardless of regimen).

PCP prophylaxis required for all patients receiving temozolomide in conjunction with radiation therapy for glioblastoma multiforme; continue prophylaxis in patients who develop lymphocytopenia until lymphocytopenia resolves (≤ grade 1).

Hepatic Effects

Severe, sometimes fatal, hepatotoxicity (i.e., increased serum aminotransferase concentrations, hyperbilirubinemia, cholestasis, hepatitis) and fatal, reactivation of hepatitis B reported. Evaluate liver function at baseline, halfway through the first treatment cycle, prior to each subsequent cycle, and 2–4 weeks following the last dose of the drug. Consider hepatitis screening and prophylactic antiviral therapy when clinically appropriate.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Teratogenicity and embryolethality demonstrated in animals. Spontaneous abortion and congenital malformations reported during pregnancy in postmarketing surveillance.

Avoid pregnancy during therapy. Perform a pregnancy test prior to initiation of therapy. Advise females of reproductive potential to use effective contraceptive methods during and for ≥6 months after the last dose. Men with such female partners require contraceptive methods during therapy and for ≥3 months after the last dose. Male patients should not donate semen during treatment or for ≥3 months after the last dose.

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Impairment of Fertility

May impair male fertility. Duration or reversibility not known.

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome reported.

Specific Populations

Pregnancy

May cause fetal harm.

Avoid pregnancy during therapy. Perform a pregnancy test prior to initiation of therapy. Advise females of reproductive potential to use effective contraceptive methods during and for ≥6 months after the last dose. Men with such female partners require contraceptive methods during therapy and for ≥3 months after the last dose. Male patients should not donate semen during treatment or for ≥3 months after the last dose.

Lactation

Not known whether temozolomide or its metabolites are distributed into milk. Discontinue breast-feeding during treatment and for ≥1 week after the last dose because of potential risk to breast-fed infants. Effects of the drug on breast-fed infants or on the production of milk are unknown.

Pediatric Use

Safety and efficacy not established in children. Adverse effects reported in children 3–18 years of age were similar to those in adults in a clinical study.

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether geriatric patients respond differently than younger adults. Caution advised. Select dosage with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

In patients with refractory anaplastic astrocytoma, higher incidence of grade 4 thrombocytopenia and/or neutropenia reported in those ≥70 years of age compared with younger adults.

In patients with glioblastoma multiforme, adverse effect profile in those ≥65 years of age similar to that in younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). No dosage adjustment necessary.

Renal Impairment

Pharmacokinetics not substantially altered in patients with Cl_cr of 36–130 mL/minute per m². No dosage adjustment necessary.

Common Adverse Effects

In patients with glioblastoma multiforme (concomitant temozolomide and radiation therapy): Alopecia (69%), nausea (36%), vomiting (20%), anorexia (19%), headache (19%), constipation (18%).

In patients with glioblastoma multiforme (maintenance temozolomide therapy): Alopecia (55%), nausea (49%), vomiting (29%), anorexia (27%), headache (23%), constipation (22%).

In patients with refractory anaplastic astrocytoma: Nausea (53%), vomiting (42%), headache (41%), fatigue (34%), constipation (33%), convulsions (23%).

IV temozolomide: Pain, irritation, pruritus, warmth, swelling, erythema at the injection site, petechiae, hematoma.

General

Pretreatment Screening

• Complete blood cell counts (CBCs) prior to each cycle.

• Liver function tests prior to each cycle.

• Screen for hepatitis.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Closely monitor all patients, particularly those receiving concomitant corticosteroids, for the development of lymphocytopenia or Pneumocystis jiroveci (formerly P. carinii) pneumonia (PCP).

• Concomitant temozolomide and radiation therapy: Complete blood cell counts (CBCs) weekly during treatment.

• Maintenance temozolomide: CBCs on day 22 and then weekly.

• Liver function tests half-way through the first treatment cycle and 2–4 weeks following the last dose of temozolomide.

Premedication and Prophylaxis

• Administer prophylaxis for PCP (e.g., inhaled pentamidine, oral co-trimoxazole) during concomitant temozolomide and radiation therapy\. In patients with lymphocytopenia, continue PCP prophylaxis until lymphocytopenia resolves to grade 1 or less.

Dispensing and Administration Precautions

• Patients may need to take combinations of temozolomide capsules of different strengths to receive the correct daily dose. To minimize the risk of inappropriate dosing, the clinician or pharmacist should provide written instructions for the dosage schedule.

Handling and Disposal

• Procedures for proper handling and disposal of antineoplastic agents should be followed when preparing or administering temozolomide.

Other General Considerations

• Adjust dosage based on nadir platelet and ANC during the previous cycle and ANC and platelet counts on day 1 of the next cycle.

• Consider hepatitis prophylaxis with antiviral agents as clinically indicated.

Administration

Administer orally or by IV infusion.

Oral Administration

Administer orally once daily with a full glass of water and in a consistent manner relative to food intake. Swallow capsule intact.

Administration on an empty stomach may reduce incidence of nausea and vomiting; may give antiemetics prior to and/or following temozolomide administration.

Bedtime administration may be advisable.

Do not open capsules. If accidentally opened or damaged, avoid inhalation or contact with skin or mucous membranes.

Dispensing and Administration Precautions

Based on the dose prescribed, determine the number of each strength capsules needed (e.g., for a dose of 275 mg daily for 5 days, dispense five 250 mg-capsules, five 20-mg capsules, and five 5-mg capsules). Dispense each strength of capsules in a separate container. Label each container with the strength per capsule and with the appropriate number of capsules to be taken each day. Instruct the patient to take the appropriate number of capsules from each container to equal the total daily dose.

IV Infusion

Administer by IV infusion. Use an infusion pump to administer the drug. Flush the IV line before and after each temozolomide infusion.

Vials are for single use only. Store at 2–8°C.

Reconstitution

Must be reconstituted prior to administration.

Allow vials to reach room temperature prior to reconstitution. Reconstitute powder for injection by adding 41 mL of sterile water for injection to a vial containing 100 mg of temozolomide, resulting in a solution containing 2.5 mg/mL of temozolomide; gently swirl (do not shake).

Do not further dilute the reconstituted solution prior to administration. Using aseptic technique, transfer up to 40 mL from each vial of reconstituted solution needed to reach the calculated dosage to an empty 250-mL infusion bag. Do not infuse drugs or solutions other than 0.9% sodium chloride through the same IV line.

Store reconstituted solution at room temperature for up to 14 hours (including infusion time).

Rate of Administration

Administer by IV infusion over 90 minutes using an infusion pump. Infusion over a shorter or longer duration may result in suboptimal dosing.

Dosage

Recommended IV dosage is the same as the oral dose. Bioequivalence of oral and IV doses of temozolomide established only when temozolomide for injection is administered by IV infusion over 90 minutes.

Adults

Brain Tumors

Glioblastoma Multiforme

Initial Phase: 75 mg/m² daily for 42 days (up to 49 days) concomitantly with focal radiotherapy (60 Gy administered in 30 fractions). Monitor CBC weekly; interrupt or discontinue temozolomide if severe hematologic or nonhematologic toxicities occur. (See Table 1.)

Four weeks after completing initial phase (temozolomide and radiation therapy), initiate maintenance therapy (six 28-day cycles of temozolomide).

Maintenance Phase: 150 mg/m² once daily for 5 consecutive days followed by a 23-day rest period for a 28-day cycle (six cycles). Periodically monitor CBC; do not resume dosing until criteria for continuance of therapy are met. (See Table 2.) For cycle 2, may increase dosage to 200 mg/m² once daily for 5 days only if nonhematologic toxicity (excluding alopecia, nausea, and vomiting) from cycle 1 is ≤ grade 2, ANC ≥1500/mm³, and platelet count ≥100,000/mm³. For cycles 3–6, continue dosage of 200 mg/m² once daily for 5 consecutive days of each 28-day cycle, unless toxicity occurs. If dosage was not increased for cycle 2, do not increase dosage for subsequent cycles.

Refractory Anaplastic Astrocytoma

Initially, 150 mg/m² once daily for 5 consecutive days of a 28-day treatment cycle. Monitor CBC periodically; adjust subsequent dosages and dosing schedule as appropriate. (See Table 3.) For next cycle, increase dosage to 200 mg/m² once daily for 5 days only if nadir and day-of-dosing (day 29, day 1 of next cycle) ANC and platelet count ≥1500/mm³ and ≥100,000/mm³, respectively.

Continue therapy until disease progression occurs. In the pivotal clinical study, treatment could be continued for a maximum of 2 years; however, optimum duration of therapy is not known.

Dosage Modification for Toxicity

Glioblastoma Multiforme

During initial phase (concomitant temozolomide and radiotherapy), monitor CBC at baseline, then weekly, and adjust dosing schedule as appropriate. (See Table 1.)

During maintenance therapy, obtain CBC at baseline, then on day 22 of cycle, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³. Withhold next cycle until these counts are exceeded. Adjust dosage and schedule for next cycle based on nadir hematologic measurements (i.e., ANC and platelet counts) and most severe nonhematologic toxicity during previous cycle. (See Table 2.)

For patients who experience toxicity (ANC >1500/mm³, platelet count >100,000/mm³, and nonhematologic toxicities that are grade 2 or less in severity) during cycle 1, the temozolomide dose should not be increased for cycle 2 or any subsequent cycle of therapy.

Refractory Anaplastic Astrocytoma

Obtain CBC at baseline and then on day 22, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³. Withhold next cycle until these counts are exceeded; adjust subsequent dosages based on nadir hematologic measurements (i.e., ANC and platelet counts) during previous cycle and on day 29 (i.e., day 1 of next cycle). (See Table 3.)

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustment necessary.

Use in patients with severe hepatic impairment (Child-Pugh class C) not established.

Renal Impairment

Cl_cr of 36–130 mL/minute per m²: No dosage adjustment necessary.

Use in patients with severe renal impairment (Cl_cr <36 mL/minute per m²) or end-stage renal disease requiring dialysis not established.

Geriatric Patients

Increased risk of developing myelosuppression, but no specific dosage recommendations other than usual adjustment for hematologic toxicity.

Select dosage with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Gender

Increased risk of myelosuppression but no specific dosage recommendations other than usual adjustment for hematologic toxicity.

Temozolomide and MTIC only minimally metabolized by CYP isoenzymes.

Specific Drugs