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Medication Safety Issues

Sound-alike/look-alike issues:

Temodar® may be confused with Tambocor®

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Pronunciation

(te moe ZOE loe mide)

U.S. Brand Names

• Temodar®

Index Terms

• TMZ

Generic Available

No

Canadian Brand Names

• Temodal®

Pharmacologic Category

• Antineoplastic Agent, Alkylating Agent (Triazene)

Use: Labeled Indications

Treatment of newly-diagnosed glioblastoma multiforme (initially in combination with radiotherapy, then as maintenance treatment); treatment of refractory anaplastic astrocytoma

Note: The following use is approved in Canada (not an approved indication in the U.S.): Treatment of recurrent glioblastoma multiforme

Use: Unlabeled/Investigational

Treatment of recurrent glioblastoma multiforme, advanced or metastatic melanoma, anaplastic oligodendroglioma, ependymoma, metastatic CNS lesions, cutaneous T-cell lymphomas (mycosis fungoides [MF] and Sézary syndrome [SS]), carcinoid tumors

Pregnancy Risk Factor

D

Pregnancy Considerations

May cause fetal harm when administered to pregnant women. Animal studies, at doses less than used in humans, resulted in numerous birth defects. Testicular toxicity was demonstrated in animal studies using smaller doses than recommended for cancer treatment. There are no adequate and well-controlled studies in pregnant women. Male and female patients should avoid pregnancy while receiving drug.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.

Contraindications

Hypersensitivity (eg, allergic reaction, anaphylaxis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis) to temozolomide or any component of the formulation; hypersensitivity to dacarbazine (both drugs are metabolized to MTIC)

Canadian labeling: Additional contraindications (not in U.S. labeling): Not recommended in patients with severe myelossuppression

Warnings/Precautions

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Myelosuppression: May occur with use; an increased incidence has been reported in geriatric and female patients. Prolonged pancytopenia resulting in aplastic anemia has been reported; concurrent use of temozolomide with medications associated with aplastic anemia may obscure assessment for development of aplastic anemia (eg, carbamazepine, cotrimoxazole, phenytoin) may obscure assessment for development of aplastic anemia.

• Pneumonia: Pneumocystis jiroveci pneumonia (PCP) may occur; risk is increased in those receiving steroids or longer dosing regimens; PCP prophylaxis is required in patients receiving radiotherapy in combination with the 42-day temozolomide regimen.

• Secondary malignancies: Rare cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia have been reported.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment; has not been studied in dialysis patients.

Other warnings/precautions:

• Temozolomide resistance: Increased MGMT (O-6-methylguanine-DNA methyltransferase) activity/levels within tumor tissue is associated with temozolomide resistance. Glioblastoma patients with decreased levels (due to methylated MGMT promoter) may be more likely to benefit from the combination of radiation therapy and temozolomide (Hegi, 2008; Stupp, 2009). Determination of MGMT status may be predictive for response to alklylating agents.

Adverse Reactions

Note: With CNS malignancies, it may be difficult to distinguish between CNS adverse events caused by temozolomide versus the effects of progressive disease.

>10%:

Cardiovascular: Peripheral edema (11%)

Central nervous system: Fatigue (34% to 61%), headache (23% to 41%), seizure (6% to 23%), hemiparesis (18%), fever (13%), dizziness (5% to 12%), coordination abnormality (11%)

Dermatologic: Alopecia (55%), rash (8% to 13%)

Gastrointestinal: Nausea (49% to 53%; grades 3/4: 1% to 10%), vomiting (29% to 42%; grades 3/4: 2% to 6%), constipation (22% to 33%), anorexia (9% to 27%), diarrhea (10% to 16%)

Hematologic: Lymphopenia (grades 3/4: 55%), thrombocytopenia (grades 3/4: adults: 4% to 19%; children: 25%), neutropenia (grades 3/4: adults: 8% to 14%; children: 20%), leukopenia (grades 3/4: 11%)

Neuromuscular & skeletal: Weakness (7% to 13%)

Miscellaneous: Viral infection (11%)

1% to 10%:

Central nervous system: Amnesia (10%), insomnia (4% to 10%), somnolence (9%), ataxia (8%), paresis (8%), anxiety (7%), memory impairment (7%), depression (6%), confusion (5%)

Dermatologic: Pruritus (5% to 8%), dry skin (5%), radiation injury (2% maintenance phase after radiotherapy), erythema (1%)

Endocrine & metabolic: Hypercorticism (8%), breast pain (females 6%)

Gastrointestinal: Stomatitis (9%), abdominal pain (5% to 9%), dysphagia (7%), taste perversion (5%), weight gain (5%)

Genitourinary: Incontinence (8%), urinary tract infection (8%), urinary frequency (6%)

Hematologic: Anemia (grades 3/4: 4%)

Neuromuscular & skeletal: Paresthesia (9%), back pain (8%), abnormal gait (6%), arthralgia (6%), myalgia (5%)

Ocular: Blurred vision (5% to 8%), diplopia (5%), vision abnormality (visual deficit/vision changes 5%)

Respiratory: Pharyngitis (8%), upper respiratory tract infection (8%), cough (5% to 8%), sinusitis (6%), dyspnea (5%)

Miscellaneous: Allergic reaction (?3%)

<1%, postmarketing, and/or case reports (limited to important or life-threatening): Agitation, alkaline phosphatase increased, anaphylaxis, apathy, aplastic anemia, emotional lability, erythema multiforme, febrile neutropenia, flu-like syndrome, hallucination, hematoma, hemorrhage, herpes simplex, herpes zoster, hyperglycemia, hypokalemia, injection site reactions (erythema, irritation, pain, pruritus, swelling, warmth), interstitial pneumonitis, myelodysplastic syndrome, neuropathy, opportunistic infection (eg, PCP), oral candidiasis, pancytopenia (may be prolonged), peripheral neuropathy, petechiae, pneumonitis, secondary malignancies (including myeloid leukemia), Stevens-Johnson syndrome, toxic epidermal necrolysis, weight loss

Drug Interactions

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination

Valproic Acid: May enhance the adverse/toxic effect of Temozolomide. Valproic Acid may increase the serum concentration of Temozolomide. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Food: Food reduces rate and extent of absorption.

Storage

Injection: Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Reconstituted vials may be stored for up to 14 hours at room temperature of 25°C (77°F); infusion must be completed within 14 hours of reconstitution.

Capsule: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Reconstitution

Bring to room temperature prior to reconstitution. Reconstitute each 100 mg vial with 41 mL sterile water for injection to a final concentration of 2.5 mg/mL. Swirl gently; do not shake. Place dose without further dilution into a 250 mL empty sterile PVC infusion bag. Infusion must be completed within 14 hours of reconstitution. Use appropriate precautions for handling and disposal.

Mechanism of Action

Like dacarbazine, temozolomide (a prodrug) is rapidly and nonenzymatically converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]. Unlike dacarbazine, however, this conversion is spontaneous, nonenzymatic, and occurs under physiologic conditions in all tissues to which the drug distributes. The cytotoxic effects of MTIC are manifested through alkylation of DNA at the O⁶, N⁷ guanine positions.

Pharmacodynamics/Kinetics

Absorption: Oral: Rapid and complete

Distribution: V_d: Parent drug: 0.4 L/kg; penetrates blood brain barrier; CSF levels are ~35% to 39% of plasma levels

Protein binding: 15%

Metabolism: Prodrug, hydrolyzed to the active form, MTIC; MTIC is eventually eliminated as CO₂ and 5-aminoimidazole-4-carboxamide (AIC), a natural constituent in urine; CYP isoenzymes play only a minor role in metabolism (of temozolomide and MTIC)

Bioavailability: Oral: 100% (on a mg-per-mg basis, I.V. temozolomide, infused over 90 minutes, is bioequivalent to an oral dose)

Half-life elimination: Mean: Parent drug: 1.8 hours

Time to peak: Oral: Empty stomach: 1 hour; with food (high-fat meal): 2.25 hours

Excretion: Urine (~38%; parent drug 6%); feces <1%

Dosage

Oral, I.V.: Adults:

Anaplastic astrocytoma (refractory): Initial dose: 150 mg/m²/day for 5 days; repeat every 28 days. Subsequent doses of 100-200 mg/m²/day for 5 days per treatment cycle; based upon hematologic tolerance.

Dosage modification for toxicity:

ANC <1000/mm³ or platelets <50,000/mm³ on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1500/mm³ and platelets >100,000/mm³; reduce dose by 50 mg/m²/day for subsequent cycle

ANC 1000-1500/mm³ or platelets 50,000-100,000/mm³ on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1500/mm³ and platelets >100,000/mm³; maintain initial dose

ANC >1500/mm³ and platelets >100,000/mm³ on day 22 or day 29 (day 1 of next cycle): Increase dose to or maintain dose at 200 mg/m²/day for 5 days for subsequent cycle

Glioblastoma multiforme (newly diagnosed, high-grade glioma):

Concomitant phase: 75 mg/m²/day for 42 days with focal radiotherapy (60Gy administered in 30 fractions). Note: PCP prophylaxis is required during concomitant phase and should continue in patients who develop lymphocytopenia until lymphocyte recovery to ? grade 1. Obtain weekly CBC.

ANC ?1500/mm³, platelet count ?100,000/mm³, and nonhematologic toxicity ? grade 1 (excludes alopecia, nausea/vomiting): Temodar® 75 mg/m²/day may be continued throughout the 42-day concomitant period up to 49 days

Dosage modification for toxicity:

ANC ?500/mm³ but <1500/mm³ or platelet count ?10,000/mm³ but <100,000/mm³ or grade 2 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Interrupt therapy

ANC <500/mm³ or platelet count <10,000/mm³ or grade 3/4 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Discontinue therapy

Maintenance phase (consists of 6 treatment cycles): Begin 4 weeks after concomitant phase completion. Note: Each subsequent cycle is 28 days (consisting of 5 days of drug treatment followed by 23 days without treatment). Draw CBC within 48 hours of day 22; hold next cycle and do weekly CBC until ANC >1500/mm³ and platelet count >100,000/mm³; dosing modification should be based on lowest blood counts and worst nonhematologic toxicity during the previous cycle.

Cycle 1: 150 mg/m²/day for 5 days; repeat every 28 days

Cycles 2-6: May increase to 200 mg/m²/day for 5 days every 28 days (if ANC >1500/mm³, platelets >100,000/mm³ and nonhematologic toxicities for cycle 1 are ? grade 2; if dose was not escalated at the onset of cycle 2, do not increase for cycles 3-6)

Dosage modification (during maintenance phase) for toxicity:

ANC <1000/mm³, platelet count <50,000/mm³, or grade 3 nonhematologic toxicity (excludes for alopecia, nausea/vomiting) during previous cycle: Decrease dose by 1 dose level (by 50 mg/m²/day for 5 days), unless dose has already been lowered to 100 mg/m²/day, then discontinue therapy.

If dose reduction <100 mg/m²/day is required or grade 4 nonhematologic toxicity (excludes for alopecia, nausea/vomiting), or if the same grade 3 nonhematologic toxicity occurs after dose reduction: Discontinue therapy

Glioblastoma multiforme (recurrent glioma): Canadian labeling (not an approved use in the U.S.): 200 mg/m²/day for 5 days every 28 days; if previously treated with chemotherapy, initiate at 150 mg/m²/day for 5 days every 28 days and increase to 200 mg/m²/day for 5 days every 28 days with cycle 2 if no hematologic toxicity

Metastatic melanoma (unlabeled use): Oral: 200 mg/m²/day for 5 days every 28 days (for up to 12 cycles). For subsequent cycles reduce dose to 75% of the original dose for grade 3/4 hematologic toxicity and reduce the dose to 50% of the original dose for grade 3/4 nonhematologic toxicity (Middletown, 2000).

Elderly: Refer to adult dosing. Note: Patients ?70 years of age had a higher incidence of grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than patients <70 years of age.

Dosage adjustment in renal impairment: Oral:

Cl_cr ?36 mL/minute: No effect on temozolomide clearance was demonstrated

Severe renal impairment (Cl_cr <36 mL/minute): Use with caution

Dialysis patients: Use has not been studied

Dosage adjustment in hepatic impairment: Severe hepatic impairment: Use with caution

Administration: Oral

Swallow capsules whole with a glass of water. Absorption is affected by food. Administer consistently either with food or without food (was administered in studies under fasting and non-fasting conditions). May administer on an empty stomach or at bedtime to reduce nausea and vomiting. Standard antiemetics may be administered if needed. Do not repeat dose if vomiting occurs after dose is administered, wait until the next scheduled dose. Do not open or chew capsules; avoid contact with skin if capsules are accidentally opened or damaged.

Administration: I.V.

Infuse over 90 minutes. Flush line before and after administration. Do not administer other medications through the same I.V. line. Standard antiemetics may be administered if needed.

Monitoring Parameters

CBC with differential and platelets (prior to each cycle; weekly during glioma concomitant phase treatment; at or within 48 hours of day 22 and weekly until ANC >1500/mm³ for glioma maintenance and astrocytoma treatment)

Dietary Considerations

The incidence of nausea/vomiting is decreased when the drug is taken on an empty stomach. Take capsules consistently either with food or without food (absorption is affected by food).

Patient Education

Do not take any new prescription or OTC medications or herbal products during therapy unless approved by prescriber. If administered I.V., report immediately any swelling, pain, or burning at infusion site. May cause headache, dizziness, confusion, fatigue, anxiety, insomnia, or impaired coordination (use caution when driving or engaging in tasks requiring alertness until response to medication is known); nausea, vomiting, or loss of appetite (small, frequent meals, good mouth care, chewing gum, or sucking hard candy may help); constipation (increased fiber and fluids and regular exercise may help); or diarrhea (yogurt may help; consult prescriber if persistent). Report chest pain or palpitations; acute headache; unusual swelling of legs or feet; visual disturbances; unresolved GI problems; itching or burning on urination or vaginal discharge; acute joint, back, bone, or muscle pain or unusual weakness; difficulty breathing, cough, or signs of respiratory infection; or other adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you pregnant. Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures. Breast-feeding is not recommended.

Oral: Take always with food or always without food; taking at bedtime may reduce nausea or vomiting. Swallow whole with 8 ounces of water. Do not open, crush, or chew capsules; if capsule is accidentally broken, do not inhale powder (wash hands thoroughly if powder gets on skin).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis, dysphagia, and taste perversion.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Fatigue, dizziness, amnesia, and insomnia are common; may cause somnolence, confusion, anxiety, depression

Mental Health: Effects on Psychiatric Treatment

Myelosuppression is common, use caution with clozapine and carbamazepine; nausea is very common, avoid use with SSRIs

Nursing: Physical Assessment/Monitoring

Assess results of laboratory tests at recommended intervals. See Administration for infusion specifics. Evaluate therapeutic effectiveness (reduction in symptoms), and adverse effects (eg, CNS effects, gastrointestinal disturbance, myelosuppression, opportunistic infection, vision disturbance, cough) on a regular basis throughout therapy (dosage adjustments may be necessary for toxicity). Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report.

Oncology: Emetic Potential

Moderate (30% to 90%)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule:

Temodar®: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg

Injection, powder for reconstitution:

Temodar®: 100 mg [contains polysorbate 80]

Pricing: U.S. (www.drugstore.com)

Capsules (Temodar)

5 mg (5): $54.18

20 mg (5): $189.70

100 mg (5): $893.49

180 mg (14): $4601.16

250 mg (5): $2009.84

Extemporaneously Prepared

Temozolomide 10 mg/mL oral suspension: In a glass mortar, mix the contents of ten 100-mg capsules and 500 mg of povidine K-30 powder; add 25 mg anhydrous citric acid dissolved in 1.5 mL purified water; mix to form a paste; add 50 mL Ora-Plus® (add a small amount at first, mix, add balance); mix; transfer to amber plastic bottle; add enough Ora-Sweet® or Ora-Sweet® SF to bring a total volume of 100 mL by rinsing the mortar with small amounts of Ora-Sweet®; repeat rinsing 3 more times. The suspension is stable for 7 days at room temperature or 60 days refrigerated in plastic amber prescription bottles. Note: Use appropriate handling precautions during preparation.

Trissel LA, Yanping Z, and Koontz SE. “Temozolomide Stability in Extemporaneously Compounded Oral Suspension,” Int J Pharm Compounding, 2006, 10(5):396-9.

References

Agarwala SS, Kirkwood JM, Gore M, et al, “ Temozolomide for the Treatment of Brain metastases Associated With Metastatic Melanoma: A Phase II Study,” J Clin Oncol, 2004, 22(11):2101-7.

Agarwala SS and 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(2):144-51.

Gaya A, Rees J, Greenstein A, et al, “The Use of Temozolomide in Recurrent Malignant Gliomas,” Cancer Treat Rev, 2002, 28(2):115-20.

Hegi ME, Diserens AC, Gorlia T, et al, “MGMT Gene Silencing and Benefit From Temozolomide in Glioblastoma,” N Engl J Med, 2005, 352(10):997-1003.

Hegi ME, Liu L, Herman JG, et al, “Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity,” J Clin Oncol, 2008, 26(25):4189-99.

Jalali R, Singh P, Menon H, et al, “Unexpected Case of Aplastic Anemia in a Patient With Glioblastoma Multiforme Treated With Temozolomide,” J Neurooncol, 2007, 85(1):105-7.

Middleton MR, Grob JJ, Aaronson N, et al, “Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma,” J Clin Oncol, 2000, 18(1):158-66.

National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Central Nervous System Cancers,” Version 1.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf

National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Hodgkin's Lymphomas,” Version 1.2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf

Newlands ES, Stevens MF, Wedge SR, et al, “Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials,” Cancer Treat Rev, 1997, 23(1):35-61.

Schwenka J and Ignoffo RJ, “Temozolomide. A New Option for High-Grade Astrocytomas,” Cancer Pract, 2000, 8(6):311-3.

Stupp R, Dietrich PY, Ostermann Kraljevic S, et al, “Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide,” J Clin Oncol, 2002, 20(5):1375-82.

Stupp R, Gander M, Leyvraz S, et al, “Current and Future Developments in the Use of Temozolomide for the Treatment of Brain Tumours,” Lancet Oncol, 2001, 2(9):552-60.

Stupp R, Hegi ME, Mason WP, et al, “Effects of Radiotherapy With Concomitant and Adjuvant Temozolomide Versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-year Analysis of the EORTC-NCIC Trial,” Lancet Oncol, 2009 [epub ahead of print]

Stupp R, Mason WP, van den Bent MJ, et al, “Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma,” N Engl J Med, 2005, 352(10):987-96.

Villano JL, Collins CA, Manasanch EE, et al, “Aplastic Anaemia in Patient With Glioblastoma Multiforme Treated With Temozolomide,” Lancet Oncol, 2006, 7(5):436-8.

Yung WK, 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(9):2762-71.

International Brand Names

• Temodal (AE, AR, AT, AU, BE, BG, BH, BO, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EG, ES, FI, FR, GB, GR, GT, HK, HN, ID, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, NI, NL, NO, OM, PA, PE, PH, PL, PR, PT, PY, QA, RU, SA, SE, SG, SV, SY, TH, TR, TW, UY, VE, YE)
• Temozam (PH)

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Last full review/revision October 2009

Content last modified October 2009