AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Temozolomide

Temozolomide, a prodrug that is converted in vivo to a cytotoxic alkylating metabolite, is an alkylating antineoplastic agent.1,2,3

Brain Tumors

Temozolomide is used in adults for the treatment of newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment.1 Temozolomide is also used in adults for the adjuvant treatment of newly diagnosed anaplastic astrocytoma and for the treatment of refractory disease.1

Glioblastoma

Temozolomide is used in adults concomitantly with radiation therapy for the treatment of newly diagnosed glioblastoma multiforme and then as maintenance treatment.1

Clinical Experience

Efficacy of temozolomide in patients with newly diagnosed glioblastoma is based on a randomized, multicenter, open-label trial (EORTC-NCIC 26981-22981; MK-7365-051) involving 573 patients.1,8 Patients were randomized to temozolomide (75 mg/m² once daily) with standard fractionated radiation therapy (total dose of 60 Gy in 30 daily fractions of 2 Gy each) for 42 days (up to a maximum of 49 days) followed by a 4-week rest period and then adjuvant therapy with up to 6 cycles of temozolomide (150 or 200 mg/m²) on days 1-5 of every 28-day cycle or radiation therapy alone.1,8,20 The median age of patients was 56 years and 84% of patients had undergone debulking surgery.8 Salvage therapy with temozolomide was administered upon disease progression in 22% of patients who received initial therapy with temozolomide and radiation therapy and in 57% of patients who received initial therapy with radiation therapy alone.1

Overall survival was prolonged (unadjusted hazard ratio for death: 0.63) and median survival was increased by 2.5 months (14.6 versus 12.1 months) in patients receiving concomitant temozolomide and radiation therapy followed by adjuvant temozolomide compared with those receiving radiation therapy alone as initial therapy for glioblastoma multiforme.1,8 At a median follow-up of 61 months, overall survival benefit in patients receiving temozolomide and radiation therapy followed by adjuvant temozolomide compared with radiation therapy alone remained similar to the initial results.20 A subgroup analysis of tumor specimens in 206 patients for whom adequate tumor specimens were available indicated that methylation status of the MGMT promoter was a strong prognostic biomarker for overall survival benefit.20 Results of the subgroup analysis also suggested that the effect of temozolomide and radiation therapy followed by adjuvant temozolomide on overall survival was consistent regardless of MGMT promoter methylation status; however, progression-free survival benefit was observed only in temozolomide-treated patients with MGMT promoter methylated disease.20 Nausea (36 versus 16%), vomiting (20 versus 6%), anorexia (19 versus 9%), constipation (18 versus 6%), and thrombocytopenia (4 versus 1%) occurred more frequently in patients receiving concomitant temozolomide and radiation therapy than in those receiving radiation therapy alone.1

Among elderly patients with good performance status, the addition of concomitant and adjuvant temozolomide to hypofractionated radiation therapy appears to be safe and efficacious without impairing quality of life.28,30 In a randomized phase 3 study, 562 patients 65 years of age or older with newly diagnosed glioblastoma multiforme received temozolomide 75 mg/m² once daily with hypofractionated radiation therapy (total dose of 40 Gy in 15 daily fractions) over a period of 3 weeks followed by maintenance therapy with up to 12 cycles of temozolomide (150 or 200 mg/m²) on days 1-5 of every 28-day cycle; or hypofractionated radiation therapy alone.29 Overall survival was prolonged (hazard ratio for death: 0.67; 95% confidence interval 0.56-0.80) and median survival was increased by 1.7 months (9.3 versus 7.6 months) in patients receiving concomitant temozolomide and hypofractionated radiation therapy followed by maintenance therapy with temozolomide compared with those receiving hypofractionated radiation therapy alone as initial therapy for glioblastoma multiforme.29 Although the magnitude of overall survival benefit was greatest in patients with methylated MGMT promoter receiving concomitant temozolomide and hypofractionated radiation therapy followed by adjuvant temozolomide compared with patients receiving hypofractionated radiation therapy alone, a numerical, but not statistically significant, overall survival benefit was observed in patients with unmethylated MGMT promoter (10.0 versus 7.9 months; hazard ratio of 0.75 with a 95% confidence interval 0.56-1.01).29

Clinical Perspective

Malignant gliomas often have inactivated MGMT (also referred to as O6-methylguanine DNA methyltransferase) due to aberrant methylation of its promoter region.17,19,20,21,22,28 The presence of MGMT promoter methylation has been used as a prognostic and predictive marker for response to therapy with alkylating agents.17,18,20,21,22,27 High expression of MGMT in cancer cells, such as glioma cells, account for the predominant mechanism of resistance to alkylating agents.17,18,20,21,22,27 Epigenetic silencing of MGMT by promoter methylation has been associated with improved survival in patients with glioblastoma multiforme receiving temozolomide, with or without radiation therapy.17,19,20,21,22,28 In the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) 26981-22981 study, overall survival benefit was observed regardless of MGMT promoter methylation status in patients with glioblastoma receiving concomitant temozolomide and radiation therapy; however, the magnitude of benefit was more pronounced in patients with methylated MGMT promoter.28

Lack of standardization in MGMT promoter methylation assays complicates interpretation of the prognostic and predictive impact of MGMT methylation status.17,21,23 Common methods for quantitating methylation status include methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ), both of which evaluate the MGMT promoter region, and immunohistochemistry (IHC), which evaluates MGMT protein expression.17,21,23 In a meta-analysis, MSP and PSQ appeared to be more prognostic for overall survival than IHC in patients with glioblastoma treated with temozolomide.23 The exact promoter regions (5'-cytosine-phosphate-guanine-3' [CpG]) and thresholds for interpretation are not well-defined; however, targeting multiple CpG promoter sites is likely to be more prognostic than targeting a single site.23

The current standard of treatment for newly diagnosed patients with glioblastoma includes maximum safe surgical resection followed by radiotherapy with concurrent and adjuvant chemotherapy with or without Tumor Treating Fields.31 Radiation therapy remains a key adjuvant therapy for most patients with glioblastoma given the locally recurrent pattern of disease spread after surgical resection.31 Temozolomide is the recommended systemic therapy in newly diagnosed glioblastoma due to its demonstrated survival benefit, with the greatest benefit seen in patients who harbor MGMT promoter methylation.31 Experts recommend conventional radiation therapy with concurrent and adjuvant temozolomide in glioblastoma patients up to 70 years of age with reasonable performance status.28,31 In elderly glioblastoma patients ≥70 years of age with reasonable performance status, hypofractionated radiation therapy with concurrent and adjuvant temozolomide may be considered.28

Anaplastic Astrocytoma

Temozolomide is used for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma and in the treatment of refractory disease.1

Clinical Experience

The use of temozolomide as an adjuvant treatment in adults with newly diagnosed anaplastic astrocytoma is based on studies in the published literature in addition to interim results from the ongoing open-label, randomized, multicenter, phase 3 CATNON trial.1,32,33 Enrolled patients in CATNON had newly diagnosed anaplastic glioma without 1p/19q co-deletion, a World Health Organization (WHO) performance status score of 0-2, and adequate hematological, renal, and liver function, and were taking stable or decreasing corticosteroid doses.32,33 Patients were randomly assigned to radiotherapy alone, radiotherapy with adjuvant temozolomide (12 four-week cycles of 150-200 mg/m² given on days 1-5), radiotherapy with concurrent temozolomide (75 mg/m² per day), or radiotherapy and concurrent temozolomide plus adjuvant temozolomide.32,33 The primary endpoint was overall survival.32,33

At the initial interim analysis, the hazard ratio for overall survival for patients administered adjuvant temozolomide was 0.65 (99.145% confidence interval: 0.45-0.93); the median follow-up was 27 months.32 Median overall survival was not reached among patients who received adjuvant temozolomide and was 41.1 months in patients who did not receive adjuvant temozolomide.32 At 5 years, overall survival was 55.9% versus 44.1% in the respective groups.32 Similar beneficial results with the use of adjuvant temozolomide were observed at a second interim analysis conducted at a median follow-up of 55.7 months.33 Adjuvant temozolomide significantly improved median overall survival compared with no adjuvant temozolomide therapy (82.3 versus 46.9 months).33 However, administration of concurrent temozolomide did not result in a significant improvement in median overall survival when compared to no concurrent temozolomide therapy (66.9 months versus 60.4 months).33

The use of temozolomide in refractory anaplastic astrocytoma is based on tumor response rates in this population from an uncontrolled phase 2 study.1,4 In a single-arm, multicenter study in 162 patients with relapsed anaplastic astrocytoma who had a baseline Karnofsky performance status of 70 or greater, efficacy in a subgroup of 54 patients with refractory disease (i.e., progression following treatment with a nitrosourea and procarbazine) was demonstrated by an overall (complete plus partial) tumor response rate of 22% and a complete response rate of 9%.1,4 Median durations of all responses and complete responses were 50 and 64 weeks, respectively.1 Progression-free survival at 6 and 12 months was 45 and 29%, respectively; median progression-free survival was 4.4 months; 12-month overall survival was 65%; and median overall survival was 15.9 months.1

General

Pretreatment Screening

• Obtain a complete blood count (CBC) and monitor absolute neutrophil count (ANC) and platelet count before initiation of treatment.1 Withhold dosing until patients have an ANC ≥1500/mm³ and a platelet count ≥100,000/mm³.1
• Monitor liver function tests at baseline and prior to each cycle.1
• Screen for hepatitis.9
• Verify pregnancy status in females of reproductive potential.1

Patient Monitoring

• When used in combination with radiotherapy, obtain a CBC weekly during treatment and as clinically indicated.1
• Monitor ANC and platelet counts as clinically indicated during treatment.1
• For 28-day treatment cycles, obtain a CBC prior to treatment on Day 1 and Day 22 of each cycle.1 Perform CBCs weekly until recovery if the ANC is <1500/mm³ and the platelet count is <100,000/mm³.1
• Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia or Pneumocystis jiroveci (formerly P. carinii ) pneumonia (PCP).1
• Obtain liver function tests half-way through the first treatment cycle and 2-4 weeks following the last dose of temozolomide.1

Premedication and Prophylaxis

• Administer prophylaxis for Pneumocystis jiroveci (e.g., inhaled pentamidine, oral co-trimoxazole) during concomitant temozolomide and radiation therapy.1,8 In patients with lymphopenia, continue Pneumocystis jiroveci prophylaxis until lymphocytopenia resolves to grade 1 or less.1
• Clinicians should consider antiemetic therapy prior to and following temozolomide administration.1

Dispensing and Administration Precautions

Handling and Disposal

• Temozolomide is a hazardous medication.1 Clinicians and patients should follow applicable special handling and disposal procedures.1
• Patients may need to take combinations of temozolomide capsules of different strengths to receive the correct daily dose.13 To minimize the risk of inappropriate dosing, the clinician or pharmacist should provide written instructions for the dosage schedule.

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.1
• Consider hepatitis prophylaxis with antiviral agents as clinically indicated.9

Reconstitution and Administration

Temozolomide is administered orally or by IV infusion.1

Oral Administration

When given orally, temozolomide capsule is administered once daily at the same time each day and should be swallowed intact with water.1 Patients should be advised not to open, chew, or dissolve capsule contents.1 If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation of capsule contents or contact with the skin or mucous membranes.1 If contact with skin occurs, the affected area should be washed thoroughly immediately.1 Because food may decrease the rate and extent of absorption of temozolomide, the drug should be administered in a consistent manner relative to food intake.1 To reduce nausea and vomiting, administration of temozolomide on an empty stomach or at bedtime may be advisable.1 Store capsules at 25ºC (excursions permitted between 15-30ºC).1

Based on the dose prescribed, 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) should be determined.12 Each strength of capsules should be dispensed in a separate container.12 Each container should be labeled with the strength per capsule and with the appropriate number of capsules to be taken each day.12 The patient should be instructed to take the appropriate number of capsules from each container to equal the total daily dose.12

IV Administration

Temozolomide for injection should be stored at 2-8°C and must be reconstituted prior to administration.1 Prior to reconstitution, temozolomide for injection should be brought to room temperature.1 Temozolomide for injection should be reconstituted by adding 41 mL of sterile water for injection to a vial labeled as containing 100 mg of temozolomide to provide a solution containing 2.5 mg/mL of the drug; reconstituted vials should be gently swirled but not shaken.1 The reconstituted solution may be stored at room temperature (25°C) for up to 14 hours (including infusion time).1 Reconstituted temozolomide for injection should be a clear solution free of visible particles; the drug should be discarded if the solution contains visible particulate matter.1 The reconstituted solution should not be further diluted prior to administration.1 Using aseptic technique, withdraw up to 40 mL from each reconstituted vial to reach the total dose and discard any unused portion.1 The reconstituted solution should then be transferred from each vial into an empty 250 mL infusion bag.1 IV lines should be flushed before and after each temozolomide infusion.1 The manufacturer states that drugs or solutions other than 0.9% sodium chloride injection should not be infused through the same IV line.1

Rate of Administration

Temozolomide for injection should be administered by IV infusion over 90 minutes using an infusion pump.1

Infusion of temozolomide over a shorter or longer duration may result in suboptimal dosing.1

Dosage

Glioblastoma

Concomitant Use Phase

During the concomitant use phase of therapy, the initial oral or IV dosage of temozolomide for the treatment of newly diagnosed glioblastoma is 75 mg/m² once daily for 42 to 49 consecutive days.1 Temozolomide is to be administered concomitantly with focal radiotherapy.1 Focal radiotherapy includes the tumor bed or resection site with a 2-3 cm margin.1 Other administration schedules have been used.1

Temozolomide dosing should be interrupted for any of the following criteria: ANC of ≥500 and <1500/mm³, platelet count of ≥10,000 and <100,000/mm³, or any grade 2 nonhematologic toxicity (except alopecia, nausea, and vomiting).1 Temozolomide therapy may be resumed at the same dose when ANC ≥1500/mm³, platelet count ≥100,000/mm³, and non-hematological adverse reactions resolve to grade 1 or less.1

Temozolomide dosing should be discontinued for any of the following criteria: ANC <500/mm³, platelet count <10,000/mm³, or any grade 3 or 4 nonhematologic toxicity (except alopecia, nausea, and vomiting).1

Single Agent Maintenance Use Phase

The maintenance phase of therapy is initiated after a 4-week rest period following completion of temozolomide and radiation therapy.1 The maintenance phase consists of six 28-day cycles of treatment.1

During the maintenance phase of therapy, the initial oral or IV dosage of temozolomide is 150 mg/m² once daily on days 1 to 5 of cycle 1.1 The dosage may be increased to 200 mg/m² once daily on days 1 to 5 before starting cycle 2 if no dosage interruptions or discontinuations are required.1 If the temozolomide dosage is not increased at cycle 2 onset, do not increase the dosage for cycles 3 to 6.1

A CBC should be obtained prior to treatment on day 1 and day 22 of each treatment cycle, and then weekly until recovery if ANC <1500/mm³ and platelet count <100,000/mm³. The next cycle should not be initiated until ANC and platelet counts exceed these levels.1

Temozolomide dosing should be interrupted for any of the following criteria: ANC <1000/mm³, platelet count <50,000/mm³, or any grade 3 nonhematologic toxicity (except alopecia, nausea, and vomiting).1 Temozolomide therapy may be resumed at a reduced dose (i.e., decreased by 50 mg/m² per day) for the next cycle when ANC is ≥1500/mm³, platelet count is ≥100,000/mm³, and nonhematological adverse reactions resolve to grade 1 or less.1

Temozolomide dosing should be discontinued for any of the following criteria: inability to tolerate a dose of 100 mg/m² per day, recurrence of the same grade 3 nonhematologic toxicity following dose reduction, or any grade 4 nonhematologic toxicity (except alopecia, nausea, and vomiting).1

Anaplastic Astrocytoma

Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma

Temozolomide should be administered orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles beginning 4 weeks after the end of radiotherapy.1 The recommended dosage of temozolomide for cycle 1 is 150 mg/m² once daily on days 1 to 5.1 The dosage may be increased to 200 mg/m² once daily on days 1 to 5 for cycles 2 to 12 if the patient experienced no or minimal toxicity in cycle 1.1 If the temozolomide dosage is not increased at cycle 2 onset, do not increase the dosage during subsequent cycles.1

A CBC should be obtained prior to treatment on day 1 and day 22 of each treatment cycle, and then weekly until recovery if ANC <1500/mm³ and platelet count <100,000/mm³.1 The next cycle should not be initiated until ANC and platelet counts exceed these levels.1

Temozolomide dosing should be interrupted for any of the following criteria: ANC <1000/mm³, platelet count <50,000/mm³, or any grade 3 nonhematologic toxicity (except alopecia, nausea, and vomiting).1 Temozolomide therapy may be resumed at a reduced dose (i.e., decreased by 50 mg/m² per day) for the next cycle when ANC is ≥1500/mm³, platelet count is ≥100,000/mm³, and non-hematological adverse reactions resolve to grade 1 or less.1

Temozolomide dosing should be discontinued for any of the following criteria: inability to tolerate a dose of 100 mg/m² per day, recurrence of the same grade 3 nonhematologic toxicity (except alopecia, nausea, and vomiting) following dose reduction, or any grade 4 nonhematologic toxicity (except alopecia, nausea, and vomiting).1

Refractory Anaplastic Astrocytoma

The initial oral or IV dosage of temozolomide for the treatment of refractory anaplastic astrocytoma in adults is 150 mg/m² daily on days 1 to 5 of each 28-day treatment cycle.1

Subsequent dosage is adjusted based on nadir platelet and ANC during the previous cycle and on ANC and platelet counts on day 1 of the next cycle.1 A CBC should be obtained prior to treatment on day 1 and day 22 of each treatment cycle, and then weekly until recovery if the ANC and platelet counts are <1500 and <100,000/mm³, respectively.1 The next cycle should be withheld until these counts are exceeded.1 If both nadir and day-of-dosing ANC and platelet counts exceed 1500 and 100,000/mm³, respectively, then temozolomide dosage may be increased to 200 mg/m² daily for days 1 to 5 of the next 28-day cycle.1 If either the ANC or platelet count declines to <1000 or 50,000/mm³, respectively, during any cycle, the dosage for the next cycle should be reduced by 50 mg/m² daily.1 Permanently discontinue therapy if patients are unable to tolerate a dosage of 100 mg/m² daily.1

Temozolomide therapy can be continued until disease progression or unacceptable toxicity occurs.1

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).1

Temozolomide has not been studied in patients with severe hepatic impairment (Child-Pugh class C), and the manufacturer provides no specific dosage recommendations for such patients.1

Renal Impairment

No dosage adjustment is necessary in patients with creatinine clearance of 36-130 mL/minute per m².1

Temozolomide has not been studied in patients with creatinine clearance <36 mL/minute per m² and in those with end-stage renal disease requiring dialysis, and the manufacturer provides no specific dosage recommendations for such patients.1

Geriatric Patients

The manufacturer makes no specific recommendations regarding dosage adjustment in geriatric patients other than usual adjustment for ANC and platelet counts.1

Contraindications

• History of serious hypersensitivity reactions to temozolomide, any other ingredients in temozolomide, and dacarbazine, which is metabolized to the same active metabolite as temozolomide.1

Warnings/Precautions

Myelosuppression

Myelosuppression (e.g., pancytopenia, leukopenia, anemia) has been reported with temozolomide, with fatal outcomes observed in some patients.1 In certain cases, assessment has been complicated by exposure to concomitant medications (e.g., carbamazepine, phenytoin, co-trimoxazole) which may be associated with aplastic anemia.14,15,16

In a clinical study (MK-7365-006), myelosuppression with temozolomide usually occurred during the initial cycles of therapy and was not observed to be cumulative in nature.1 The median nadirs occurred for platelets at 26 days (range: 21 to 40 days) and for neutrophils at 28 days (range: 1 to 44 days).1 Myelosuppression resulted in hospitalization, blood transfusion, or discontinuation of temozolomide therapy in approximately 10% of patients.1 In clinical trials, women and geriatric patients have been shown to have an increased risk of developing myelosuppression.1

A complete blood count (CBC) should be obtained and absolute neutrophil count (ANC) and platelet count monitored before therapy initiation and as clinically indicated during treatment.1 When temozolomide is used concurrently with radiotherapy, a CBC should be obtained prior to initiation, weekly during treatment, and as clinically indicated.1

Temozolomide should be withheld if severe myelosuppression occurs.1 Temozolomide may be resumed at the same or reduced dose, or permanently discontinued, based on myelosuppression occurrence.1

Hepatotoxicity

Severe hepatotoxicity sometimes fatal, has occurred in patients receiving temozolomide.1 Reactivation of hepatitis B resulting in death has been reported in a patient receiving temozolomide for glioblastoma.9 Increased serum aminotransferase concentrations, hyperbilirubinemia, cholestasis, and hepatitis have been reported in postmarketing surveillance.1 Liver function tests should be evaluated at baseline, half-way through the first treatment cycle, prior to each subsequent cycle, and approximately 2-4 weeks following the last dose of temozolomide.1 Hepatitis screening and prophylactic therapy with antiviral agents as clinically indicated should be considered in patients receiving temozolomide.9

Pneumocystis Pneumonia

Pneumocystis pneumonia has been observed in patients administered temozolomide, with an increased risk seen in patients administered steroids or receiving longer treatment regimens of temozolomide.1

Prophylaxis against Pneumocystis pneumonia should be provided to all patients with newly diagnosed glioblastoma during the concomitant phase.1 Prophylaxis should be continued in patients with lymphopenia until resolution to grade 1 or less.1 All patients should be monitored for lymphopenia and Pneumocystis pneumonia development.1

Secondary Malignancies

Temozolomide-containing regimens are associated with an increased incidence of secondary malignancies.1 Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on its mechanism of action and animal findings; teratogenicity and embryolethality were demonstrated in animals at doses less than the maximum human dose based on body surface area (200 mg/m²).1 Spontaneous abortion and congenital malformations, including polymalformations with CNS, facial, cardiac, skeletal, and genitourinary system anomalies have been reported with exposure to temozolomide during pregnancy in postmarketing surveillance.1

Pregnancy should be avoided during therapy.1 The manufacturer states that a pregnancy test should be performed prior to starting temozolomide and females of reproductive potential should be advised to use effective contraceptive methods during and for ≥6 months after the last dose.1 In addition, male patients with such female partners should be advised to use effective methods of contraception during and for ≥3 months after the last dose.1 Male patients should not donate semen during therapy and for ≥3 months after the last dose.1 Patients should be apprised of the potential hazard to the fetus if temozolomide is used during pregnancy.1

Exposure to Opened Capsules

Recommended precautions should be observed to avoid exposure to opened capsules of temozolomide.1 (See Dosage and Administration.)

Specific Populations

Pregnancy

Temozolomide can cause fetal harm.1

Lactation

It is not known whether temozolomide or its metabolites are distributed in human milk.1 The effects of the drug on breast-fed infants or on the production of milk are also unknown.1 Patients should discontinue breast-feeding during therapy and for at least 1 week after the last dose because of potential risk, including myelosuppression, in breast-fed infants.1

Females and Males of Reproductive Potential

Temozolomide can cause fetal harm if administered during pregnancy.1 Females of reproductive potential should be advised to use effective contraceptive methods during and for ≥6 months after the last temozolomide dose.1 Male patients with such female partners should also be advised to use effective methods of contraception during and for ≥3 months after the last dose.1

Based on limited data, temozolomide may impair fertility in males.1 Changes in sperm parameters and genotoxic effects on sperm cells have occurred in men receiving temozolomide; however, the duration or reversibility of these effects has not been established.1 Male patients should not donate semen during therapy and for ≥3 months after the last dose.1

Pediatric Use

Safety and efficacy in pediatric patients have not been established.1 Efficacy was not demonstrated in open-label studies of children 3-18 years of age receiving temozolomide mostly for CNS tumors.1 Similar toxicity was observed in pediatric patients and adults.1

Geriatric Use

Experience in those 65 years of age and older with newly diagnosed glioblastoma is insufficient to determine whether they respond differently than younger adults.1

An increased incidence of grade 4 thrombocytopenia and/or neutropenia has been reported in patients 70 years of age or older compared with younger patients receiving temozolomide for refractory anaplastic astrocytoma.1

Similar toxicity was observed in patients 65 years of age or older and younger patients receiving temozolomide for newly diagnosed glioblastoma multiforme.1

Hepatic Impairment

Pharmacokinetics of temozolomide are not substantially altered in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).1

Renal Impairment

Pharmacokinetics of temozolomide are not substantially altered in patients with creatinine clearance of 36-130 mL/minute per m².1

Common Adverse Effects

The most common adverse reactions (≥20%) include: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions.1

Drugs Affecting Hepatic Microsomal Enzymes

Temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) are only minimally metabolized by CYP isoenzymes.1

Carbamazepine

Unlikely to affect temozolomide clearance.1 Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.14,15

Co-trimoxazole

Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.16

Dexamethasone

Unlikely to affect temozolomide clearance.1

Histamine H2-receptor Antagonists

Unlikely to affect temozolomide clearance.1

Ondansetron

Unlikely to affect temozolomide clearance.1

Phenobarbital

Unlikely to affect temozolomide clearance.1

Phenytoin

Unlikely to affect temozolomide clearance.1 Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.14,15,16

Prochlorperazine

Unlikely to affect temozolomide clearance.1

Valproic Acid

Pharmacokinetic interaction (decreased temozolomide clearance by about 5%).1 Clinical importance unknown.1

Description

Temozolomide, an imidazotetrazine derivative, is an antineoplastic agent.1,2,3 Temozolomide is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC).1,2,3 Following administration of temozolomide, the drug undergoes rapid, nonenzymatic hydrolysis at physiologic pH to MTIC.1,3,4 MTIC is thought to exert its cytotoxic effects by acting as an alkylating agent at the O ⁶ and N ⁷ positions of guanine in DNA.1,2,3,4,10

Temozolomide is rapidly and completely absorbed after oral administration, with nearly 100% bioavailability.1,3,6,10 Peak plasma concentrations usually are attained within 1 hour.1,6,10 The bioequivalence of temozolomide (with respect to both peak plasma concentration and AUC) administered orally or as an IV infusion over 90 minutes at a dosage of 150 mg/m² has been demonstrated.1 Food decreases the rate and extent of absorption after oral administration.1 A modified high fat breakfast decreased mean peak plasma temozolomide concentrations (32%) and AUC (9%).1

Temozolomide efficiently crosses the blood brain barrier.6,10 It is not known if temozolomide is distributed into human milk.1 Plasma protein binding is approximately 15%.1 MTIC, the main active metabolite, is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and to methylhydrazine.1 CYP isoenzymes play only a minor role in metabolism of temozolomide and MTIC.1 About 38% of an administered dose is recovered over 7 days, principally in urine with <1% in feces.1 The mean elimination half-life of temozolomide is 1.8 hours.1,3,6,10 Apparent half-lives for metabolites MTIC and AIC are 2.1 and 2.6 hours, respectively.3

In patients with mild to moderate hepatic impairment, the pharmacokinetic profile resembles that in patients with normal hepatic function.1 Temozolomide has not been studied in patients with severe hepatic impairment.1 The pharmacokinetic profile of temozolomide is not affected by renal function in patients with creatinine clearance 36-130 mL/minute per m².1 The drug has not been studied in patients with severe renal impairment (creatinine clearance <36 mL/minute per m²) or in patients with end-stage renal disease receiving dialysis.1

Advice to Patients

• Stress importance of adherence to dosage and laboratory appointment schedules.1
• Advise patients that there is a risk of developing myelodysplastic syndrome and secondary malignancies.1
• Stress importance of Pneumocystis jiroveci pneumonia prophylaxis for certain patients with newly diagnosed glioblastoma.1 Advise patients to inform clinicians of signs and symptoms of PCP infection (e.g., shortness of breath, fever, chills, dry cough).13
• Risk of hepatotoxicity.1 Advise patients to inform clinicians of signs and symptoms of hepatotoxicity.1
• Risk of fetal harm.1 Stress importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breastfeed.1 Advise females of reproductive potential and men with such female partners to use effective contraceptive methods during and for ≥6 and 3 months after the last dose, respectively.1
• Advise females not to breastfeed while receiving temozolomide and for ≥1 week after the last dose.1
• Advise patients of the risk of impaired fertility in males.1
• Advise male patients not to donate semen while receiving temozolomide and for ≥3 months after the last dose.1
• Stress importance of taking temozolomide in a consistent manner relative to food intake to ensure consistent bioavailability and clinical effect.1 Advise patients to swallow capsules whole, without chewing.1
• Inform patients to avoid exposure to capsule contents (carcinogen potential) and to safely store and dispose.1
• Advise patients of risk of nausea and vomiting.1 Premedication with antiemetics and bedtime administration recommended.1
• Advise patients of risk of low platelet counts and possible risk of bleeding.1,13 Stress importance of patients informing clinicians of any unusual bruising or bleeding.1
• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Merck & Co, Inc. Temodar^® (temozolomide) capsules, Temodar (temozolomide) for injection^® prescribing information. Whitehouse Station, NJ; 2023 Sept.

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