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Temozolomide

Pronunciation

(te moe ZOE loe mide)

Index Terms

  • SCH 52365
  • TMZ

Dosage Forms

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

Capsule, Oral:

Temodar: 5 mg [contains fd&c blue #2 (indigotine)]

Temodar: 20 mg, 100 mg

Temodar: 140 mg [contains fd&c blue #2 (indigotine)]

Temodar: 180 mg, 250 mg

Generic: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg

Solution Reconstituted, Intravenous:

Temodar: 100 mg (1 ea) [pyrogen free; contains polysorbate 80]

Brand Names: U.S.

  • Temodar

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent (Triazene)

Pharmacology

Temozolomide is a prodrug which is rapidly and nonenzymatically converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]; this conversion is spontaneous, nonenzymatic, and occurs under physiologic conditions in all tissues to which it distributes. The cytotoxic effects of MTIC are manifested through alkylation (methylation) of DNA at the O6, N7 guanine positions which lead to DNA double strand breaks and apoptosis. Non-cell cycle specific.

Absorption

Oral: Rapid and complete

Distribution

Vd: Parent drug: 0.4 L/kg; penetrates blood-brain barrier; CSF levels are ~35% to 39% of plasma levels (Yung 1999)

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)

Excretion

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

5.5 L/hour/m2; women have a ∼5% lower clearance than men (adjusted for body surface area); children 3-17 years have similar temozolomide clearance as adults

Time to Peak

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

Half-Life Elimination

Mean: Parent drug: Children: 1.7 hours; Adults: 1.6-1.8 hours

Protein Binding

15%

Use: Labeled Indications

Anaplastic astrocytoma: Treatment of refractory anaplastic astrocytoma (refractory to a regimen containing a nitrosourea and procarbazine)

Glioblastoma multiforme: Treatment of newly-diagnosed glioblastoma multiforme (initially in combination with radiotherapy, then as maintenance treatment)

Canadian labeling: Treatment of newly-diagnosed glioblastoma multiforme (initially in combination with radiotherapy, then as maintenance treatment), treatment of recurrent or progressive glioblastoma multiforme or anaplastic astrocytoma

Use: Unlabeled

Treatment of recurrent glioblastoma multiforme, low-grade astrocytoma, low-grade oligodendroglioma, anaplastic oligodendroglioma, metastatic CNS lesions, refractory primary CNS lymphoma, advanced or metastatic melanoma, advanced cutaneous T-cell lymphomas (mycosis fungoides [MF] and Sézary syndrome [SS]), advanced neuroendocrine tumors (carcinoid or islet cell), Ewing’s sarcoma (recurrent or progressive), soft tissue sarcomas (extremity/retroperitoneal/intra-abdominal or hemangiopericytoma/solitary fibrous tumor), treatment of pediatric neuroblastoma

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 myelosuppression

Dosing: Adult

Note: Temozolomide is associated with a moderate emetic potential (Roila 2010); antiemetics are recommended to prevent nausea and vomiting. Prior to dosing, ANC should be ≥1,500/mm3 and platelets ≥100,000/mm3.

Anaplastic astrocytoma (refractory): Oral, IV: Initial dose: 150 mg/m2 once daily for 5 consecutive days of a 28-day treatment cycle. If ANC ≥1,500/mm3 and platelets ≥100,000/mm3, on day 1 of subsequent cycles, may increase to 200 mg/m2 once daily for 5 consecutive days of a 28-day treatment cycle. May continue until disease progression.

Dosage modification for toxicity:

ANC <1,000/mm3 or platelets <50,000/mm3 on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1,500/mm3 and platelets >100,000/mm3; reduce dose by 50 mg/m2/day (but not below 100 mg/m2) for subsequent cycle

ANC 1,000 to 1,500/mm3 or platelets 50,000-100,000/mm3 on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1,500/mm3 and platelets >100,000/mm3; maintain initial dose

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

Concomitant phase: 75 mg/m2 once daily for 42 days with focal radiotherapy (60 Gy 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.

Continue at 75 mg/m2 once daily throughout the 42-day concomitant phase (up to 49 days) as long as ANC ≥1,500/mm3, platelet count ≥100,000/mm3, and nonhematologic toxicity ≤grade 1 (excludes alopecia, nausea/vomiting)

Dosage modification for toxicity:

ANC ≥500/mm3 but <1,500/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 on day 22 (or within 48 hours of day 22); hold next cycle and do weekly CBC until ANC >1,500/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 once daily for 5 days of a 28-day treatment cycle

Cycles 2 to 6: May increase to 200 mg/m2 once daily for 5 days; repeat every 28 days (if ANC ≥1,500/mm3, platelets ≥100,000/mm3 and nonhematologic toxicities for cycle 1 are ≤grade 2 [excludes alopecia, nausea/vomiting]); Note: If dose was not escalated at the onset of cycle 2, do not increase for cycles 3 to 6)

Dosage modification (during maintenance phase) for toxicity:

ANC <1,000/mm3, platelet count <50,000/mm3, or grade 3 nonhematologic toxicity (excludes 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 alopecia, nausea/vomiting), or if the same grade 3 nonhematologic toxicity occurs after dose reduction: Discontinue therapy

Glioblastoma multiforme (recurrent glioma): Canadian labeling (off-label use in the U.S.): 200 mg/m2 once daily for 5 days every 28 days; if previously treated with chemotherapy, initiate at 150 mg/m2 once daily for 5 days every 28 days and increase to 200 mg/m2 once daily for 5 days every 28 days with cycle 2 if no hematologic toxicity (Brada 2001; Yung 2000)

Cutaneous T-cell lymphoma, advanced (mycosis fungoides [MF] and Sézary syndrome [SS]; off-label use): Oral: 200 mg/m2 once daily for 5 days every 28 days for up to 1 year (Querfeld 2011)

Ewing’s sarcoma, recurrent or progressive (off-label use): Oral: 100 mg/m2/dose days 1 to 5 every 21 days (in combination with irinotecan) (Casey 2009). Additional data may be necessary to further define the role of temozolomide in this condition

Melanoma, advanced or metastatic (off-label use): Oral: 200 mg/m2 once daily 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 (Middleton 2000).

Neuroendocrine tumors, advanced (off-label use): Oral: 150 mg/m2 once daily for 7 days every 14 days (in combination with thalidomide) until disease progression (Kulke 2006) or 200 mg/m2 once daily (at bedtime) days 10 to 14 of a 28-day treatment cycle (in combination with capecitabine) (Strosberg 2011)

Primary CNS lymphoma, refractory (off-label use): Oral: 150 mg/m2 once daily for 5 days every 28 days, initially in combination with rituximab (for 4 cycles), followed by temozolomide monotherapy: 150 mg/m2 once daily for 5 days every 28 days for 8 cycles (Wong 2004) or 150 mg/m2 once daily on days 1 to 7 and 15 to 21 every 28 days (initially in combination with rituximab for 1 or 2 cycles), followed by temozolomide maintenance monotherapy: 150 mg/m2 once daily for 5 days every 28 days (Enting 2004). However, additional data may be necessary to further define the role of temozolomide in this condition.

Soft tissue sarcoma (off-label use): Oral:

Soft tissue sarcoma, metastatic or unresectable: 75 mg/m2 once daily for 6 weeks (Garcia del Muro 2005)

Hemangiopericytoma/solitary fibrous tumor: 150 mg/m2 once daily days 1 to 7 and days 15 to 21 of a 28-day treatment cycle (in combination with bevacizumab) (Park 2011). Additional data may be necessary to further define the role of temozolomide in this condition

Dosing: Geriatric

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

Dosing: Pediatric

Note: Temozolomide is associated with a moderate emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting.

Ewing’s sarcoma, recurrent or progressive (off-label use): Children and Adolescents: Oral: Refer to adult dosing.

Neuroblastoma, relapsed or refractory (off-label use):

Children and Adolescents: Oral: 100 mg/m2/dose days 1 to 5 every 21 days (in combination with irinotecan) for up to 6 cycles (Bagatell 2011)

Children ≥6 months and Adolescents: Oral: 150 mg/m2/dose days 1 to 5 every 28 days (in combination with topotecan) until disease progression or unacceptable toxicity (Di Giannatale 2014)

Dosing: Renal Impairment

Oral:

CrCl ≥36 mL/minute/m2: There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustment is not likely needed as no effect on temozolomide clearance was demonstrated.

Severe renal impairment (CrCl <36 mL/minute/m2): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (has not been studied).

Dialysis patients: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetics are similar to patients with normal hepatic function.

Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (has not been studied).

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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 infusion bag. Infusion must be completed within 14 hours of reconstitution.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

A 10 mg/mL temozolomide oral suspension may be compounded in a vertical flow hood. Mix the contents of ten 100 mg capsules and 500 mg of povidone K-30 powder in a glass mortar; add 25 mg anhydrous citric acid dissolved in 1.5 mL purified water and mix to a uniform paste; mix while adding 50 mL Ora-Plus in incremental proportions. Transfer to an amber plastic bottle, rinse mortar 4 times with small portions of either Ora-Sweet or Ora-Sweet SF, and add quantity of Ora-Sweet or Ora-Sweet SF sufficient to make 100 mL. Store in plastic amber prescription bottles; label "shake well" and "refrigerate"; include the beyond-use date. Stable for 7 days at room temperature or 60 days refrigerated (preferred).

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

Administration

Temozolomide is associated with a moderate emetic potential (Dupuis 2011; Roila 2010); antiemetics are recommended to prevent nausea and vomiting.

Oral:

US labeling: Swallow capsules whole with a glass of water. Absorption is affected by food; therefore, administer consistently either with food or without food (was administered in studies under fasting and nonfasting conditions). May administer on an empty stomach and/or at bedtime to reduce nausea and vomiting. 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 or mucous membranes if capsules are accidentally opened or damaged.

Canadian labeling: Administer on an empty stomach at least one hour before a meal. Swallow capsules whole with a glass of water. 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 or mucous membranes if capsules are accidentally opened or damaged.

IV: Infuse over 90 minutes. Flush line before and after administration. May be administered through the same IV line as sodium chloride 0.9%; do not administer other medications through the same IV line.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of intact capsules. Although the manufacturer does not recommend opening capsules, if necessary to manipulate the capsules (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

The incidence of nausea/vomiting is decreased when taken on an empty stomach. Take capsules consistently either with food or without food (absorption is affected by food). The Canadian labeling recommends taking capsules on an empty stomach one hour before a meal.

Compatibility

Y-site administration: Incompatible with D5W

Storage

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

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.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

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

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). 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. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

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

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

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

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

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

Valproate Products: May enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (11%)

Central nervous system: Fatigue (34% to 61%), headache (23% to 41%), convulsions (6% to 23%), hemiparesis (18%), dizziness (5% to 12%), ataxia (8% to 11%)

Dermatologic: Alopecia (55%), skin 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 & oncologic: Lymphocytopenia (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%)

Infection: Viral infection (11%)

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

Miscellaneous: Fever (13%)

1% to 10%:

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

Dermatologic: Pruritus (5% to 8%), xeroderma (5%), erythema (1%)

Endocrine & metabolic: Hypercorticoidism (8%), weight gain (5%)

Gastrointestinal: Stomatitis (9%), abdominal pain (5% to 9%), dysphagia (7%), dysgeusia (5%)

Genitourinary: Urinary incontinence (8%), urinary tract infection (8%), mastalgia (females 6%), urinary frequency (6%)

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

Hypersensitivity: Hypersensitivity reaction (≤3%)

Neuromuscular & skeletal: Back pain (8%), arthralgia (6%), myalgia (5%)

Ophthalmic: Blurred vision (5% to 8%), diplopia (5%), visual disturbance (visual deficit/vision changes 5%)

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

Miscellaneous: Radiation injury (2% maintenance phase after radiotherapy)

<1% (Limited to important or life-threatening): Alveolitis, anaphylaxis, aplastic anemia, cytomegalovirus disease (primary and reactivation), diabetes insipidus, emotional lability, erythema multiforme, febrile neutropenia, flu-like symptoms, hallucination, hematoma, hemorrhage, hepatitis, hepatitis B (reactivation), hepatotoxicity, herpes simplex infection, herpes zoster, hyperbilirubinemia, hyperglycemia, hypersensitivity pneumonitis, hypokalemia, metastases (including myeloid leukemia), myelodysplastic syndrome, opportunistic infection (including pneumocystosis), oral candidiasis, pancytopenia (may be prolonged), peripheral neuropathy, petechia, pneumonitis, pulmonary fibrosis, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Myelosuppression may occur; may require treatment interruption, dose reduction and/or discontinuation; monitor blood counts. An increased incidence has been reported in geriatric and female patients. Prolonged pancytopenia resulting in aplastic anemia has been reported (may be fatal); concurrent use of temozolomide with medications associated with aplastic anemia (eg, carbamazepine, co-trimoxazole, phenytoin) may obscure assessment for development of aplastic anemia. ANC should be ≥1,500/mm3 and platelets ≥100,000/mm3 prior to treatment.

• Gastrointestinal toxicity: Temozolomide is associated with a moderate emetic potential (Dupuis 2011; Roila 2010); antiemetics are recommended to prevent nausea and vomiting.

• Hepatotoxicity: Hepatotoxicity has been reported; may be severe or fatal. Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose. Postmarketing reports of hepatotoxicity have included liver function abnormalities, hepatitis, hepatic failure, cholestasis, hepatitis cholestasis, jaundice, cholelithiasis, hepatic steatosis , hepatic necrosis, hepatic lesion, and hepatic encephalopathy (Sarganas 2012).

• Pneumonia: Pneumocystis jirovecii pneumonia (PCP) may occur; risk is increased in those receiving steroids or longer dosing regimens. Monitor all patients for development of PCP (particularly if also receiving corticosteroids). 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Infusion time: Bioequivalence has only been established when IV temozolomide is administered over 90 minutes; shorter or longer infusion times may result in suboptimal dosing.

• 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 alkylating agents.

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 >1,500/mm3 and platelets >100,000/mm3 for glioma maintenance and astrocytoma treatment). Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose. The Canadian labeling additionally recommends HBV screening at baseline (all patients) and monitoring for hepatitis or HBV reactivation during therapy and for several months after discontinuation (patients with evidence of current or prior HBV infection).

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. May cause fetal harm when administered to pregnant women. Male and female patients should avoid pregnancy while receiving temozolomide. The Canadian labeling recommends that male and female patients also avoid pregnancy for 6 months after discontinuation of therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, lack of appetite, dizziness, fatigue, hair loss, abdominal pain, nausea, vomiting, insomnia, muscle pain, joint pain, dry skin, change in taste, back pain, weight gain, or constipation. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), bruising, bleeding, shortness of breath, excessive weight gain, swelling of arms or legs, confusion, mood changes, dysphagia, urinary incontinence, memory impairment, burning or numbness feeling, seizures, severe headache, vision changes, pinpoint red spots on skin, pale skin, severe loss of strength and energy, or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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