Temozolomide

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
Brands: Temodar

Introduction

Alkylating antineoplastic agent; prodrug.^{1 2 3}

Uses for Temozolomide

Brain Tumors

Adjunct to radiation therapy for treatment of newly diagnosed glioblastoma multiforme; also used as maintenance therapy.¹

Treatment of refractory anaplastic astrocytoma in adults whose disease has progressed after therapy with a nitrosourea and procarbazine.¹

Temozolomide Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

  
  


• 
  

  Monitor CBC periodically and adjust dosage and dosing schedule as appropriate.¹ Adjust dosage based on nadir platelet and ANC during the previous cycle and on ANC and platelet counts on day 1 of the next cycle.¹ (See Dosage and also see Dosage Modification under Dosage and Administration.)

  
  

Pneumocystis jiroveci (formerly P. carinii) Pneumonia (PCP)

• 
  

  Prophylaxis for PCP (e.g., inhaled pentamidine, oral co-trimoxazole) required for all patients receiving concomitant temozolomide and radiation therapy for the 42-day regimen for treatment of glioblastoma multiforme.^{1 8} In patients with lymphocytopenia, continue PCP prophylaxis until recovery from lymphocytopenia occurs.¹

  
  


• 
  

  Closely monitor all patients, particularly those receiving concomitant corticosteroids, for the development of PCP.¹ (See Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia under Cautions.)

  
  

Administration

Administer orally or by IV infusion.¹

Oral Administration

Administer orally once daily with a full glass of water and in a consistent manner relative to food intake.¹ Swallow capsule intact.¹

Administration on an empty stomach may reduce incidence of nausea and vomiting; may give antiemetics prior to and/or following temozolomide administration.¹

Bedtime administration may be advisable.¹

Do not open capsules.¹ If accidentally opened or damaged, avoid inhalation or contact with skin or mucous membranes.¹

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).¹² Dispense each strength of capsules in a separate container.¹² Label each container with the strength per capsule and with the appropriate number of capsules to be taken each day.¹² Instruct the patient to take the appropriate number of capsules from each container to equal the total daily dose.¹²

IV Infusion

Administer by IV infusion.¹

Handle cautiously (e.g., use gloves); avoid exposure during handling of powder and preparation of IV solution.¹

Vials are for single use only.¹

Use an infusion pump to administer the drug.¹ Flush the IV line before and after each temozolomide infusion.¹

Reconstitution

Must be reconstituted prior to administration.¹

Allow vials to reach room temperature prior to reconstitution.¹ 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).¹

Do not further dilute the reconstituted solution prior to administration.¹ 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 polyvinylchloride (PVC) infusion bag; compatibility studies with non-PVC bags have not been conducted.¹ Do not infuse other drugs through the same IV line.¹

Store reconstituted solution at room temperature for up to 14 hours (including infusion time).¹

Rate of Administration

Administer by IV infusion over 90 minutes using an infusion pump.¹ Infusion over a shorter or longer duration may result in suboptimal dosing or an increase in infusion-related adverse reactions.¹

Dosage

Calculate dosage according to body surface area.¹

Recommended IV dosage is the same as the oral dose.¹ Bioequivalence of oral and IV doses of temozolomide established only when temozolomide for injection is administered by IV infusion over 90 minutes.¹

Adults

Brain Tumors

Glioblastoma Multiforme

Oral or IV

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

Four weeks after completing initial phase (temozolomide and radiation therapy), initiate maintenance therapy (six 28-day cycles of temozolomide).^{1 8}

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).¹ Periodically monitor CBC; do not resume dosing until criteria for continuance of therapy are met.¹ (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/mm³.¹ For cycles 3–6, continue dosage of 200 mg/m² once daily for 5 consecutive days of each 28-day cycle, unless toxicity occurs.¹ If dosage was not increased for cycle 2, do not increase dosage for subsequent cycles.¹

Refractory Anaplastic Astrocytoma

Oral or IV

Initially, 150 mg/m² once daily for 5 consecutive days of a 28-day treatment cycle.¹ Monitor CBC periodically; adjust subsequent dosages and dosing schedule as appropriate.¹ (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.¹

Continue therapy until disease progression occurs.¹ In the pivotal clinical study, treatment could be continued for a maximum of 2 years; however, optimum duration of therapy is not known.¹

Dosage Modification for Toxicity

Glioblastoma Multiforme

Oral or IV

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

Table 1. Dosage Adjustments during Initial Phase1

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)1
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 dosage1
If ANC <500/mm3, platelet count <10,000/mm3, or grade 3 or 4 nonhematologic toxicity (excluding alopecia, nausea, and vomiting)	Discontinue temozolomide1

During maintenance therapy, obtain CBC at baseline, then on day 22 (i.e., 21 days after first dose) of cycle or within 48 hours of that day, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³.¹ Withhold next cycle until these counts are exceeded.¹ 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.¹ (See Table 2.)

Table 2. Dosage Adjustments during Maintenance Therapy1

Hematologic and Nonhematologic Measurements	Comments
If ANC >1500/mm3, platelet count >100,000/mm3, and nonhematologic toxicity ≤ grade 2 (excluding alopecia, nausea, and vomiting)	Administer 200 mg/m2 daily for 5 consecutive days of cycle 2.1 For subsequent cycles, administer 200 mg/m2 daily for 5 consecutive days, unless toxicity occurs1
If ANC 1000–1500/mm3or platelet count 50,000–100,000/mm3 during previous cycle	Postpone therapy until ANC >1500/mm3and platelet count >100,000/mm3; then, resume therapy at previous dosage1
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/mm3and 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)1
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 temozolomide1

Refractory Anaplastic Astrocytoma

Oral or IV

Obtain CBC at baseline and then on day 22 (i.e., 21 days after first dose) of cycle or within 48 hours of that day, and weekly until ANC is >1500/mm³ and platelet count is >100,000/mm³.¹ 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).¹ (See Table 3.)

Table 3. Dosage Adjustments for Hematologic Toxicity

Hematologic Measurements	Comments
If both ANC and platelet count >1500/mm3 and >100,000/mm3, respectively, at nadir and day-of-dosing	Administer 200 mg/m2 daily for 5 consecutive days of next 28-day cycle1
If ANC 1000–1500/mm3or platelet count 50,000–100,000/mm3	Postpone therapy until ANC >1500/mm3 and platelet count >100,000/mm3; then administer 150 mg/m2 daily for 5 consecutive days1
If ANC <1000/mm3or 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, but not to <100 mg/m2 daily (lowest recommended dosage)1

Special Populations

Geriatric Patients

Increased risk of developing myelosuppression, but no specific dosage recommendations other than usual adjustment for hematologic toxicity.¹ (See Hematologic Effects under Cautions.)

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.¹

Female Patients

Increased risk of myelosuppression but no specific dosage recommendations other than usual adjustment for hematologic toxicity.¹ (See Hematologic Effects under Cautions.)

Cautions for Temozolomide

Contraindications

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  Known hypersensitivity (e.g., urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome) to temozolomide or any ingredient in the formulation.¹

  
  


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

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Prolonged pancytopenia reported; may result in potentially fatal aplastic anemia.¹ Assessment of patients for such effects may be complicated by concomitant administration of drugs associated with aplastic anemia (i.e., carbamazepine, phenytoin, co-trimoxazole).¹ (See Specific Drugs under Interactions.)

Myelosuppression (dose-limiting thrombocytopenia and neutropenia).¹ Higher incidence of grade 4 thrombocytopenia and/or neutropenia in women and geriatric patients.¹

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 is not cumulative.¹

Hospitalization, blood transfusion, or drug discontinuance may be required.¹

Monitor CBC periodically and adjust dosage and schedule as appropriate.¹ (See Dosage and Administration.)

Secondary Malignancies

Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, reported.¹

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Risk of Pneumocystis jiroveci pneumonia (PCP), particularly with longer dosage regimen.¹

Closely monitor all patients (particularly those receiving corticosteroids) for development of PCP (regardless of regimen).¹

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).^{1 12}

Hepatic Effects

Fatal reactivation of hepatitis B reported.⁹ Consider hepatitis screening and prophylactic antiviral therapy when clinically appropriate.⁹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Teratogenicity and embryolethality demonstrated in animals.¹

Avoid pregnancy during therapy.¹

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.¹

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome reported.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether temozolomide is distributed into milk.¹ Discontinue nursing because of potential risk to nursing infants.¹

Pediatric Use

Safety and efficacy not demonstrated in children.¹ Adverse effects reported in children 3–18 years of age were similar to those in adults in a clinical study.¹

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether geriatric patients respond differently than younger adults.¹ Caution advised.¹ (See Geriatric Patients under Dosage and Administration.)

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.¹

In patients with glioblastoma multiforme, adverse effect profile in those ≥65 years of age similar to that in younger adults.¹

Hepatic Impairment

Use with caution in patients with severe hepatic impairment.¹

Renal Impairment

Use with caution in patients with severe renal impairment.¹

Common Adverse Effects

In patients with glioblastoma multiforme: Alopecia, nausea, vomiting, anorexia, headache, constipation.¹

In patients with refractory anaplastic astrocytoma: Nausea, vomiting, headache, fatigue.¹

With IV therapy, pain, irritation, pruritus, warmth, swelling, erythema at the injection site, petechiae, hematoma.¹

Interactions for Temozolomide

Temozolomide and MTIC only minimally metabolized by CYP isoenzymes.¹

Specific Drugs

Drug	Interaction	Comments
Carbamazepine	Unlikely to affect temozolomide clearance1 Possible additive hematologic toxicity (i.e., aplastic anemia)1	Concomitant administration may complicate assessment of hematologic toxicity 1 (see Hematologic Effects under Cautions)
Co-trimoxazole	Possible additive hematologic toxicity (i.e., aplastic anemia)1	Concomitant administration may complicate assessment of hematologic toxicity 1 (see Hematologic Effects under Cautions)
Dexamethasone	Unlikely to affect temozolomide clearance1
Histamine H2-receptor antagonists	Unlikely to affect temozolomide clearance1 Ranitidine did not affect maximum plasma concentrations or AUC of temozolomide or MTIC1
Ondansetron	Unlikely to affect temozolomide clearance1
Phenobarbital	Unlikely to affect temozolomide clearance1
Phenytoin	Unlikely to affect temozolomide clearance1 Possible additive hematologic toxicity (i.e., aplastic anemia)1	Concomitant administration may complicate assessment of hematologic toxicity 1 (see Hematologic Effects under Cautions)
Prochlorperazine	Unlikely to affect temozolomide clearance1
Valproic acid	5% decrease in temozolomide clearance 1	Clinical importance unknown1

Temozolomide Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration, with nearly 100% bioavailability.^{1 3 10} Peak plasma concentrations usually are attained within 1 hour.^{1 10}

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

Food decreases rate and extent of absorption after oral administration.¹ Modified high fat breakfast decreased mean peak plasma temozolomide concentrations (32%) and AUC (9%).¹

Distribution

Extent

Efficiently crosses the blood brain barrier.¹⁰

Not known whether temozolomide is distributed into milk.¹

Plasma Protein Binding

Approximately 15%.¹

Elimination

Metabolism

Temozolomide is a prodrug;^{1 2 3} undergoes rapid, nonenzymatic hydrolysis at physiologic pH to MTIC.^{1 2 3 4} MTIC 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

Elimination Route

About 38% of administered dose is recovered over 7 days, principally in urine with <1% in feces.¹

Half-life

Approximately 1.8 hours.^{1 3 10} Apparent half-lives for metabolites MTIC and AIC are 2.1 and 2.6 hours, respectively.³

Special Populations

In patients with mild to moderate hepatic impairment, pharmacokinetic profile resembles that in patients with normal hepatic function.¹

Clearance is not affected by renal function in patients with Cl_cr 36–130 mL/minute per m².¹ Not studied in patients with severe renal impairment (Cl_cr<36 mL/minute per m²) or patients receiving dialysis.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Parenteral

Powder for Injection

2–8°C.¹ Store reconstituted solution at 25°C and use within 14 hours (including infusion time).¹

ActionsActions

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  Temozolomide is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to MTIC.¹

  
  


• 
  

  MTIC is further hydrolyzed to active metabolites that may alkylate DNA at the O⁶ and N⁷ positions of guanine.^{1 2 3 4 10}

  
  

Advice to Patients

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  Importance of adhering to dosage and laboratory appointment schedules.¹

  
  


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  Importance of PCP prophylaxis for patients with glioblastoma multiforme.¹ (See Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia (PCP), under Cautions.) Importance of patients informing clinicians of signs and symptoms of PCP infection (e.g., shortness of breath, fever, chills, dry cough).⁷

  
  


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  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.¹ Advise women and men to avoid pregnancy during therapy.¹ Advise pregnant women of risk to the fetus.¹

  
  


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  Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹

  
  


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  Importance of taking temozolomide in a consistent manner relative to food.¹

  
  


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  Importance of swallowing capsules whole without chewing.¹

  
  


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  Importance of avoiding exposure to capsule contents and of correct, safe storage and disposal away from children and pets.¹

  
  


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  Risk of nausea and vomiting.¹ Premedication with antiemetics and bedtime administration recommended.¹

  
  


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  Advise of risk of low platelet counts and possible risk of bleeding.⁷ Importance of patients informing clinicians of any unusual bruising or bleeding.⁷

  
  


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  Importance of providing patient a copy of manufacturer’s patient information, including written, patient-specific instructions on how to take temozolomide.⁷

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Temozolomide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	5 mg	Temodar	Schering
		20 mg	Temodar	Schering
		100 mg	Temodar	Schering
		140 mg	Temodar	Schering
		180 mg	Temodar	Schering
		250 mg	Temodar	Schering
Parenteral	For injection, for IV infusion	100 mg	Temodar for Injection	Schering

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Temodar 100MG Capsules (SCHERING): 5/$929.6 or 15/$2777.89

Temodar 180MG Capsules (SCHERING): 14/$4786.94 or 28/$9459.2

Temodar 20MG Capsules (SCHERING): 5/$201.33 or 15/$569.39

Temodar 250MG Capsules (SCHERING): 5/$2300.06 or 15/$6859.96

Temodar 5MG Capsules (SCHERING): 5/$54.19 or 15/$136.54

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Schering Corp. Temodar (temozolomide) capsules, Temodar (temozolomide) for injection prescribing information. Kenilworth, NJ: 2009 Apr.

2. Anon. Temozolomide. Drugs Future. 1994; 19:746-9.

3. Baker SD, Wirth M, Statkevich P et al. Absorption, metabolism, and excretion of¹⁴C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res. 1999; 5:309-17. [IDIS 424069] [PubMed 10037179]

4. Yung WKA, Prados MD, Yaya-Tur R et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol. 1999; 17:2762-71. [IDIS 435278] [PubMed 10561351]

5. Schering Corp, Kenilworth, NJ. Personal communication.

7. Schering Corp. Temodar (temozolomide) capsules, Temodar (temozolomide) for injection patient package insert. Kenilworth, NJ: 2009 Feb.

8. Stupp R, Mason WP van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide. N Engl J Med. 2007; 356:1591-2. [PubMed 17429098]

9. Grewal J, Dellinger CA, Yung WK. Fatal reactivation of hepatitis B with temozolomide. N Engl J Med. 2007;356:1591-2.

10. Baker SD, Wirth M, Statkevich P et al. Absorption, metabolism, and excretion of¹⁴C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res. 1999; 5:309-17. [IDIS 424069] [PubMed 10037179]

11. Agarwala SS, Kirkwood JM. Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist. 2000; 5:144-51. [PubMed 10794805]

12. Schering Corporation. Temodar (temozolomide) capsules pharmacist information sheet. Kenilworth, NJ: 2009 Feb

More Temozolomide resources

• Temozolomide Side Effects (in more detail)
• Temozolomide Use in Pregnancy & Breastfeeding
• Temozolomide Drug Interactions
• Temozolomide Support Group
• 4 Reviews for Temozolomide - Add your own review/rating

• Temozolomide MedFacts Consumer Leaflet (Wolters Kluwer)


• Temozolomide Professional Patient Advice (Wolters Kluwer)


• temozolomide Advanced Consumer (Micromedex) - Includes Dosage Information


• Temodar Prescribing Information (FDA)


• Temodar Consumer Overview

Compare Temozolomide with other medications

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