Brand name: Temodar
Drug class: Antineoplastic Agents
VA class: AN100
Chemical name: 3,4-Dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide
Molecular formula: C6H6N6O2
CAS number: 85622-93-1
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
Oral or IVInitial 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
Oral or IVInitially, 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
Oral or IVDuring initial phase (concomitant temozolomide and radiotherapy), monitor CBC at baseline, then weekly, and adjust dosing schedule as appropriate. (See Table 1.)
Hematologic and Nonhematologic Measurements |
Comments |
---|---|
If ANC ≥1500/mm3, platelet count ≥100,000/mm3, and nonhematologic toxicity ≤ grade 1 (excluding alopecia, nausea, and vomiting) |
Continue recommended initial dosage (75 mg/m2 daily concomitantly with radiation therapy) for 42 days (up to 49 days) |
If ANC 500–1499/mm3, platelet count 10,000–99,999/mm3, or grade 2 nonhematologic toxicity (excluding alopecia, nausea, and vomiting) |
Postpone therapy until ANC ≥1500/mm3, platelet count ≥100,000/mm3, and nonhematologic toxicity ≤ grade 1; then resume therapy at previous dosage |
If ANC <500/mm3, platelet count <10,000/mm3, or grade 3 or 4 nonhematologic toxicity (excluding alopecia, nausea, and vomiting) |
Discontinue temozolomide |
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.
Hematologic and Nonhematologic Measurements |
Comments |
---|---|
If ANC >1500/mm3, platelet count >100,000/mm3, and nonhematologic toxicity ≤ grade 2 (excluding alopecia, nausea, and vomiting) |
Increase dosage from 150 mg/m2 to 200 mg/m2 daily for 5 consecutive days of cycle 2. For subsequent cycles, administer 200 mg/m2 daily for 5 consecutive days, unless toxicity occurs |
If ANC <1000/mm3, platelet count <50,000/mm3, or nonhematologic toxicity grade 3 during previous cycle (excluding alopecia, nausea, and vomiting) |
Postpone therapy until ANC >1500/mm3 and platelet count >100,000/mm3; then, reduce dosage for next cycle by 50 mg/m2 daily, but not to <100 mg/m2 daily (lowest recommended dosage) |
If nonhematologic toxicity grade 4 occurs (excluding alopecia, nausea, and vomiting); the same nonhematologic toxicity grade 3 recurs after dosage reduction; or dosage reduction to <100 mg/m2 daily is required |
Discontinue temozolomide |
Refractory Anaplastic Astrocytoma
Oral or IVObtain 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.)
Hematologic Measurements |
Comments |
---|---|
If both ANC and platelet count >1500/mm3 and >100,000/mm3, respectively, at nadir and day-of-dosing |
Increase dosage from 150 mg/m2 to 200 mg/m2 daily for 5 consecutive days of next 28-day cycle |
If ANC <1000/mm3 or platelet count <50,000/mm3 during previous cycle |
Postpone therapy until ANC >1500/mm3 and platelet count >100,000/mm3; then reduce dosage for next cycle by 50 mg/m2 daily If dosage reduction to 100 mg/m2 daily not tolerated, discontinue drug |
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
Clcr of 36–130 mL/minute per m2: No dosage adjustment necessary.
Use in patients with severe renal impairment (Clcr <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.
Cautions for Temozolomide
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 Clcr 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.
Interactions for Temozolomide
Temozolomide and MTIC only minimally metabolized by CYP isoenzymes.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Carbamazepine |
Unlikely to affect temozolomide clearance Possible additive hematologic toxicity (i.e., aplastic anemia) |
Concomitant administration may complicate assessment of hematologic toxicity |
Co-trimoxazole |
Possible additive hematologic toxicity (i.e., aplastic anemia) |
Concomitant administration may complicate assessment of hematologic toxicity |
Dexamethasone |
Unlikely to affect temozolomide clearance |
|
Histamine H2-receptor antagonists |
Unlikely to affect temozolomide clearance |
|
Ondansetron |
Unlikely to affect temozolomide clearance |
|
Phenobarbital |
Unlikely to affect temozolomide clearance |
|
Phenytoin |
Unlikely to affect temozolomide clearance Possible additive hematologic toxicity (i.e., aplastic anemia) |
Concomitant administration may complicate assessment of hematologic toxicity |
Prochlorperazine |
Unlikely to affect temozolomide clearance |
|
Valproic acid |
5% decrease in temozolomide clearance |
Clinical importance unknown |
Temozolomide Pharmacokinetics
Absorption
Bioavailability
Rapidly and completely absorbed after oral administration, with nearly 100% bioavailability. Peak plasma concentrations usually are attained within 1 hour.
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.
Food
Food decreases rate and extent of absorption after oral administration. Modified high fat breakfast decreased mean peak plasma temozolomide concentrations (32%) and AUC (9%).
Distribution
Extent
Efficiently crosses the blood brain barrier.
Not known whether temozolomide is distributed into milk.
Plasma Protein Binding
Approximately 15%.
Elimination
Metabolism
Temozolomide is a prodrug; undergoes rapid, nonenzymatic hydrolysis at physiologic pH to MTIC. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and to methylhydrazine.
CYP isoenzymes play only a minor role in metabolism of temozolomide and MTIC.
Elimination Route
About 38% of administered dose is recovered over 7 days, principally in urine with <1% in feces.
Half-life
Approximately 1.8 hours. Apparent half-lives for metabolites MTIC and AIC are 2.1 and 2.6 hours, respectively.
Special Populations
In patients with mild to moderate hepatic impairment, pharmacokinetic profile resembles that in patients with normal hepatic function. Not studied in patients with severe hepatic impairment.
Clearance is not affected by renal function in patients with Clcr 36–130 mL/minute per m2. Not studied in patients with severe renal impairment (Clcr<36 mL/minute per m2) or patients with end-stage renal disease receiving dialysis.
Stability
Storage
Oral
Capsules
25°C (excursions permitted between 15–30°C).
Parenteral
Powder for Injection
2–8°C. Store reconstituted solution at 25°C and use within 14 hours (including infusion time).
Actions
-
Temozolomide is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to MTIC.
-
MTIC is further hydrolyzed to active metabolites that may alkylate DNA at the O6 and N7 positions of guanine.
Advice to Patients
-
Importance of adherence to dosage and laboratory appointment schedules.
-
Risk of developing myelodysplastic syndrome and secondary malignancies.
-
Importance of Pneumocystis jiroveci pneumonia (PCP) prophylaxis for patients with glioblastoma multiforme (see Pneumocystis jiroveci Pneumonia under Cautions). Importance of patients informing clinicians of signs and symptoms of PCP infection (e.g., shortness of breath, fever, chills, dry cough).
-
Risk of hepatotoxicity. Importance of patients informing clinicians of signs and symptoms of hepatotoxicity.
-
Risk of fetal harm. Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breastfeed. Necessity of advising 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. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
-
Advise females not to breastfeed while receiving temozolomide and for ≥1 week after the last dose.
-
Risk of impaired fertility in males.
-
Necessity of advising male patients not to donate semen while receiving temozolomide and for ≥3 months after the last dose.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.
-
Importance of taking temozolomide in a consistent manner relative to food intake to ensure consistent bioavailability and clinical effect.
-
Importance of swallowing capsules whole, without chewing.
-
Importance of avoiding exposure to capsule contents (carcinogen potential) and for correct, safe storage and disposal away from children and pets.
-
Advise of risk of nausea and vomiting. Premedication with antiemetics and bedtime administration recommended.
-
Advise of risk of low platelet counts and possible risk of bleeding. Importance of patients informing clinicians of any unusual bruising or bleeding.
-
Importance of providing a copy of manufacturer's patient information, including written, patient-specific instructions for how to take the medication. (See General Precautions under Cautions.)
-
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
5 mg* |
Temozolomide Capsules |
Merck |
20 mg* |
Temozolomide Capsules |
Merck |
||
100 mg* |
Temodar |
Merck |
||
Temozolomide Capsules |
||||
140 mg* |
Temodar |
Merck |
||
Temozolomide Capsules |
||||
180 mg* |
Temodar |
Merck |
||
Temozolomide Capsules |
||||
250 mg* |
Temodar |
Merck |
||
Temozolomide Capsules |
||||
Parenteral |
For injection, for IV infusion |
100 mg |
Temodar for Injection |
Merck |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions February 28, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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