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  • CLASSES

    Other Alkylating Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Alkylating antineoplastic agent
    Used for the treatment of newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytoma
    Severe hematologic toxicity and hepatotoxicity have been reported

    COMMON BRAND NAMES

    TEMODAR

    HOW SUPPLIED

    TEMODAR Intravenous Inj Pwd F/Sol: 100mg
    TEMODAR/Temozolomide Oral Cap: 5mg, 20mg, 100mg, 140mg, 180mg, 250mg

    DOSAGE & INDICATIONS

    For the treatment of glioblastoma multiforme.
    For the treatment of newly diagnosed GBM in combination with radiotherapy followed by single-agent maintenance therapy.
    Oral dosage
    Adults

    75 mg/m2 orally daily for 42 days with concomitant focal radiotherapy (60 Gray administered in 30 fractions). Administer Pneumocystis carinii pneumonia (PCP) prophylaxis during the concomitant therapy period; continue PCP prophylaxis in patients who develop lymphopenia. Temozolomide may be continued up to 49 days if nonhematologic toxicity is grade 1 or less (except for alopecia, nausea, and vomiting), the absolute neutrophil count (ANC) is 1.5 X 109 cells/L or greater, and the platelet count is 100 X 109 cells/L or greater. Temozolomide therapy interruption or discontinuation may be necessary in patients who develop toxicity. At 4 weeks after completing the concomitant treatment phase, begin 6 cycles of maintenance therapy with temozolomide 150 mg/m2 orally daily for 5 days repeated every 28 days. Starting in cycle 2, the temozolomide dosage may be increased to 200 mg/m2 orally daily for 5 days/cycle if cycle 1 nonhematologic toxicity is grade 2 or less (except for alopecia, nausea, and vomiting), the ANC is 1.5 X 109 cells/L or greater, and the platelet count is 100 X 109 cells/L or greater. If the dosage is not increased in cycle 2, do not increase the dosage in cycles 3 to 6. Interruption, dosage reduction, or discontinuation of maintenance therapy may be necessary in patients who develop toxicity. In a multicenter, randomized trial of 573 patients with newly diagnosed glioblastoma, the addition of oral temozolomide to radiotherapy followed by adjuvant temozolomide therapy significantly prolonged the median overall survival time compared with radiotherapy alone (14.6 months vs. 12.1 months; hazard ratio = 0.63; 95%CI, 0.52 to 0.75; p less than 0.001).

    Intravenous dosage

    NOTE: Bioequivalence to oral temozolomide has been demonstrated for IV temozolomide administer over 90 minutes.

    Adults

    75 mg/m2 IV daily for 42 days with concomitant focal radiotherapy (60 Gray administered in 30 fractions). Administer Pneumocystis carinii pneumonia (PCP) prophylaxis during the concomitant therapy period; continue PCP prophylaxis in patients who develop lymphopenia. Temozolomide may be continued up to 49 days if nonhematologic toxicity is grade 1 or less (except for alopecia, nausea, and vomiting), the absolute neutrophil count (ANC) is 1.5 X 109 cells/L or greater, and the platelet count is 100 X 109 cells/L or greater. Temozolomide therapy interruption or discontinuation may be necessary in patients who develop toxicity. At 4 weeks after completing the concomitant treatment phase, begin 6 cycles of maintenance therapy with temozolomide 150 mg/m2 IV daily for 5 days repeated every 28 days. Starting in cycle 2, the temozolomide dosage may be increased to 200 mg/m2 IV daily for 5 days/cycle if cycle 1 nonhematologic toxicity is grade 2 or less (except for alopecia, nausea, and vomiting), the ANC is 1.5 X 109 cells/L or greater, and the platelet count is 100 X 109 cells/L or greater. If the dosage is not increased in cycle 2, do not increase the dosage in cycles 3 to 6. Interruption, dosage reduction, or discontinuation of maintenance therapy may be necessary in patients who develop toxicity.

    For the treatment of recurrent or relapsed glioblastoma multiforme†.
    Oral dosage
    Adults

    200 mg/m2 orally daily for 5 days repeated every 28 days (150 mg/m2 orally daily for 5 days repeated every 28 days in patients with prior chemotherapy) significantly improved median progression-free survival (PFS) time (12.4 weeks vs. 8.32 weeks; p = 0.0063), 6-month PFS rate (21% vs. 8%; p = 0.008), and 6-month overall survival (OS) rate (60% vs. 44%; p = 0.019) compared with procarbazine in 225 patients with glioblastoma (GBM) in first relapse in a phase 2 study. Treatment with temozolomide (200 mg/m2 orally daily for 5 days or 100 mg/m2 orally daily for 21 days repeated every 28 days for up to 9 cycles) did not significantly improve OS compared with the procarbazine, lomustine, and vincristine (PCV) regimen (hazard ratio = 0.95; 95% CI, 0.75 to 1.19) in 277 chemotherapy-naive patients with recurrent GBM in another randomized clinical trial. Additionally, continuous, low-dose oral temozolomide (50mg/m2 orally daily) produced a 6-month PFS rate of 23.9% and a median OS time of 9.3 months in 91 patients with recurrent or progressive GBM after standard initial therapy for newly diagnosed GBM in a multicenter, phase 2 study (the RESCUE study).

    For the treatment of astrocytoma.
    For the treatment of refractory anaplastic astrocytoma in patients who have experienced disease progression on regimens containing a nitrosourea and procarbazine.
    Oral dosage
    Adults

    150 mg/m2 orally daily for 5 days repeated every 28 days until disease progression. The temozolomide dosage may be increased to 200 mg/m2 orally daily for 5 days per cycle of therapy if both the nadir (at or within 48 hours of day 22) and day of dosing (day 29) absolute neutrophil count is 1.5 X 109 cells/L or greater and the platelet count is 100 X 109 cells/L or greater. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop toxicity. In 54 patients with refractory anaplastic astrocytoma, the overall response rate was 22% (complete response rate, 9%) and the median duration of response was 50 weeks (range, 16 to 114 weeks). Additionally, the median progression-free survival (PFS) time was 4.4 months and the 6- and 12-month PFS rates were 45% and 29%, respectively. The median overall survival (OS) time was 15.9 months and the 6- and 12-month OS rates were 74% and 65%, respectively.

    Intravenous dosage

    NOTE: Bioequivalence to oral temozolomide has been demonstrated for IV temozolomide administer over 90 minutes.

    Adults

    150 mg/m2 IV daily for 5 days repeated every 28 days until disease progression. The temozolomide dosage may be increased to 200 mg/m2 IV daily for 5 days per cycle of therapy if both the nadir (at or within 48 hours of day 22) and day of dosing (day 29) absolute neutrophil count is 1.5 X 109 cells/L or greater and the platelet count is 100 X 109 cells/L or greater. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop toxicity.

    For the treatment of malignant glioma†.
    NOTE: Temozolomide has been designated an orphan drug by the FDA for this indication.
    For the treatment of high-grade glioma in pediatric patients†.
    Oral dosage
    Adults 21 years or younger, Adolescents, and Children 2 years and older

    90 mg/m2 orally daily for 42 days plus radiotherapy (RT) followed by adjuvant temozolomide 200 mg/m2 orally daily for 5 days repeated every 28 days for up to 10 cycles starting 4 weeks after RT led to a 3-year event-free survival rate of 11% and a 3-year overall survival (OS) rate of 22% in 90 pediatric patients with newly diagnosed high-grade glioma in a phase 2 trial. In a multicenter study in 31 pediatric patients with newly diagnosed high-grade glioma, adjuvant temozolomide 200 mg/m2 orally daily for 5 days repeated every 28 days for 6 cycles started 4 weeks after RT resulted in 1- and 2-year progression-free survival (PFS) rates of 43% and 11%, respectively, and 1- and 2-year OS rates of 63% and 21%, respectively. Patients in both trials received Pneumocystis jiroveci pneumonia prophylaxis. In 34 pediatric patients with relapsed or progressive, high-grade glioma, treatment with temozolomide 200 mg/m2 orally daily for 5 days repeated every 28 days resulted in an overall response rate of 12% and a median OS time of 4.8 months in a phase 2 trial. Temozolomide 200 mg/m2 orally 3-times daily for 5 days repeated every 28 days led to an ORR of 0%, a median PFS time of 3 months, and a median OS time of 4 months in 24 pediatric patients with recurrent high-grade glioma in a multicenter, phase 2 trial; additionally, the 6-month PFS and OS rates were 33% and 37.5%, respectively. Patients in both trials were receiving a stable corticosteroid dose prior to study entry.

    For the treatment of newly diagnosed diffuse intrinsic brainstem glioma in pediatric patients†.
    Oral dosage
    Adolescents and Children 3 years and older

    90 mg/m2 orally daily for 42 days plus radiotherapy (RT) followed by adjuvant temozolomide 200 mg/m2 orally daily for 5 days repeated every 28 days up to 10 cycles starting 4 weeks after RT led to a 1-year event-free survival rate of 14%, a 1-year overall survival (OS) rate of 40%, and a median time to progression (TTP) of 6.1 months in 58 pediatric patients with newly diagnosed diffuse intrinsic pontine glioma in a phase 2 trial. In a multicenter study in 33 pediatric patients with newly diagnosed diffuse brainstem glioma, adjuvant temozolomide 200 mg/m2 orally daily for 5 days repeated every 28 days for 6 cycles starting 4 weeks after RT resulted in a median TTP of 8.8 months and a median OS time of 12 months; additionally, 1- and 2-year progression-free survival rates were 27% and 0%, respectively, and the 1-year OS rate was 48%.

    For the first-line treatment of metastatic malignant melanoma†.
    NOTE: Temozolomide has been designated an orphan drug by the FDA for this indication.
    Oral dosage
    Adults

    200 mg/m2 PO daily for 5 days repeated every 28 days has been studied in clinical trials. Treatment with temozolomide led to a nonsignificantly improved median overall survival (OS) time (7.7 months vs. 6.4 months) and overall response rate (ORR) (13.5% vs. 12.1%) and a significantly improved median progression-free survival (PFS) time (1.9 vs. 1.5 months; p = 0.012) compared with dacarbazine in a multicenter, phase 3 trial in 305 patients with metastatic melanoma. Although combination therapy with temozolomide plus interferon alfa-2b significantly increased ORR compared with temozolomide alone (24.1% vs  13.4%; p = 0.036), the median OS (9.7 months vs. 8.4 months) and PFS (3.3 months vs. 2.4 months) times were not significantly different between the study arms in a multicenter, phase 3 trial in 282 patients with metastatic melanoma. Additionally, combination therapy with temozolomide plus cisplatin did not significantly improve ORR (29% vs. 26%), median OS time (12 months vs. 11.5 months), or median time to progression (5.8 months vs. 3.8 months) compared with temozolomide alone in a phase 2 trial in 127 patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Glioblastoma multiforme: 75 mg/m2 PO/IV daily with concomitant radiation therapy for 42 to 49 days; 200 mg/m2 PO/IV daily for 5 days per cycle as maintenance therapy.
    Anaplastic astrocytoma: 200 mg/m2 PO/IV daily for 5 days per cycle.

    Geriatric

    Glioblastoma multiforme: 75 mg/m2 PO/IV daily with concomitant radiation therapy for 42 to 49 days; 200 mg/m2 PO/IV daily for 5 days per cycle as maintenance therapy.
    Anaplastic astrocytoma: 200 mg/m2 PO/IV daily for 5 days per cycle.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.Severe hepatic impairment (Child-Pugh class C): Specific guidelines are not available for dosage adjustments in patients with baseline severe hepatic impairment; temozolomide has not been evaluated in these patients.

    Renal Impairment

    Mild to moderate renal impairment: Dosage adjustment not necessary.Severe renal impairment (creatinine clearance less than 36 mL/min/m2): Specific guidelines are not available for dosage adjustments in patients with baseline severe renal impairment or end-stage renal disease on dialysis; temozolomide has not been evaluated in these patients.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Avoid contact with temozolomide powder. If capsules or vials open, avoid inhalation or contact with skin or mucous membranes.
    Emetic Risk
    Pediatrics:
    Oral Doses 200 mg/m2: Low
    Administer prn antiemetics as necessary.
    Adults:
    Oral Doses: Moderate/High
    Administer routine antiemetic prophylaxis prior to treatment.

    Oral Administration
    Oral Solid Formulations

    Take temozolomide at the same time each day consistently either with or without food.
    To reduce nausea and vomiting, take on an empty stomach or at bedtime.
    Swallow capsules whole; do not chew, open, or split capsules.
    If vomiting occurs after a dose, skip that dose and take the next dose at the regularly scheduled time.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Allow the lyophilized powder vial to acclimate to room temperature prior to reconstitution.
    Add 41 mL of Sterile Water for injection to the 100-mg vial for a final vial concentration of 2.5 mg/mL; gently swirl the vial to dissolve the powder.
    Withdraw the appropriate amount (up to 40 mL per vial) from the reconstituted vial and add to an empty 250 mL infusion bag; do not dilute further.
    Storage following reconstitution: store at room temperature (25 degrees C; 77 degrees F) for up to 14 hours (includes infusion time).
    Intravenous Infusion:
    Administer IV over 90 minutes via an infusion pump; flush the IV line prior to and after the infusion.
    Temozolomide may be administered in the same IV line with 0.9% Sodium Chloride injection; do not administer in the same IV line with other fluids, additives, or medications.

    STORAGE

    TEMODAR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Aplastic anemia, bone marrow suppression, females, geriatric, neutropenia, thrombocytopenia

    Bone marrow suppression including prolonged pancytopenia, aplastic anemia, and severe neutropenia and thrombocytopenia has been reported with temozolomide therapy; some cases were fatal. For the 28-day treatment cycles, monitor complete blood counts (CBC) prior to therapy, on day 22 (21 days after the first dose) or within 48 hours of day 22, and then weekly until the absolute neutrophil count (ANC) is greater than 1.5 X 109 cells/L and the platelet count is greater than 100 X 109 cells/L. For the concomitant treatment phase with radiotherapy, a CBC should be obtained prior to start of and weekly during treatment. Do not administer temozolomide if the ANC is less than 1.5 X 109 cells/L or the platelet count is less than 100 X 109 cells/L. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop myelosuppression. Geriatric patients and females may be at greater risk for developing myelosuppression with temozolomide therapy.

    Dacarbazine (DTIC) hypersensitivity, gelatin hypersensitivity, mannitol hypersensitivity, serious rash, urticaria

    Temozolomide is contraindicated in patients who have a history of severe hypersensitivity reaction (e.g., urticaria) including serious rash (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) to any of its components. It is also contraindicated in patients who have a history of dacarbazine (DTIC) hypersensitivity, since both drugs are metabolized to the active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). Temozolomide capsules contain gelatin; use this formulation with caution in patients with a gelatin hypersensitivity. Temozolomide vials for injection contain mannitol; use this formulation with caution in patients with a mannitol hypersensitivity.

    Hepatic disease, hepatotoxicity

    Severe hepatotoxicity has been reported with temozolomide therapy; some cases were fatal. Monitor liver function tests at baseline, halfway through the first cycle, before each subsequent cycle, and about every 2 to 4 weeks after the last dose. Temozolomide has not been evaluated in patients with severe hepatic disease/impairment (Child-Pugh class C).

    Renal disease, renal impairment

    Temozolomide has not been evaluated in patients with baseline severe renal impairment (creatinine clearance of less than 36 mL/min/m2) or end-stage renal disease on dialysis.

    Glioblastoma multiforme, infection

    Infection has been reported with temozolomide therapy, including opportunistic infections; some cases were fatal. Monitor all patients for signs and symptoms of pneumocystis pneumonia (PCP) infection and the development of lymphopenia. Patients with glioblastoma multiforme who are receiving concomitant temozolomide and radiotherapy (42-day regimen) should receive PCP prophylaxis; continue prophylaxis in patients who develop lymphopenia until the toxicity resolves to grade 1 or less. Patients receiving a prolonged course of temozolomide or who are receiving concomitant corticosteroids may be at increased risk for developing lymphopenia and PCP.

    Children, infants, neonates

    The safety and efficacy of temozolomide have not been established in neonates, infants, children, and adolescents. However, the toxicity profile of temozolomide was similar in pediatric patients compared with adults in 2 open-label studies in pediatric patients aged 3 to 18 years.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk, sperm donation

    Counsel patients about the reproductive risk and contraception requirements during temozolomide treatment. Female patients of reproductive potential require pregnancy testing prior to starting temozolomide. These women should use effective contraception during temozolomide therapy and for at least 6 months after the last dose. Women who become pregnant while receiving temozolomide should be apprised of the potential hazard to the fetus. Due to the potential for male-mediated teratogenicity, male patients with a female partner who is able to become pregnant should use effective contraception (e.g., condoms) during temozolomide therapy and for at least 3 months after the last dose. Based on limited data from case reports, infertility may occur in male patients who receive temozolomide; it is not known if sperm changes are reversible. Additionally, male patients should be warned against sperm donation during temozolomide therapy and for 3 months after the last dose.

    Pregnancy

    Temozolomide may cause fetal harm when administered during pregnancy, based on its mechanism of action, animal studies, and limited data in humans. Advise females of reproductive potential to avoid pregnancy while taking temozolomide. Discuss the potential hazard to the fetus if temozolomide is used during pregnancy. Spontaneous abortion and congenital malformations including central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies have been reported in postmarketing surveillance of temozolomide-exposed pregnant women. Similar fetal abnormalities have been observed in animal studies with temozolomide doses that were less than the maximum human dose (based on BSA).

    Breast-feeding

    It is not known if temozolomide or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions (e.g., myelosuppression) in a nursing child, advise woman against breast-feeding during temozolomide therapy and for at least 1 week after the last dose.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 55.0-55.0
    seizures / Delayed / 6.0-23.0
    thrombocytopenia / Delayed / 4.0-14.0
    neutropenia / Delayed / 8.0-14.0
    nausea / Early / 1.0-10.0
    fatigue / Early / 4.0-9.0
    vomiting / Early / 0-6.0
    paresis / Delayed / 3.0-6.0
    headache / Early / 2.0-6.0
    visual impairment / Early / 5.0-5.0
    anemia / Delayed / 4.0-4.0
    amnesia / Delayed / 4.0-4.0
    back pain / Delayed / 3.0-3.0
    drowsiness / Early / 3.0-3.0
    diarrhea / Early / 1.0-2.0
    ataxia / Delayed / 2.0-2.0
    confusion / Early / 1.0-2.0
    dyspnea / Early / 0-2.0
    fever / Early / 2.0-2.0
    asthenia / Delayed / 2.0-2.0
    weakness / Early / 2.0-2.0
    urinary incontinence / Early / 2.0-2.0
    stomatitis / Delayed / 1.0-1.0
    abdominal pain / Early / 0-1.0
    constipation / Delayed / 1.0-1.0
    anorexia / Delayed / 1.0-1.0
    rash / Early / 1.0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    xerosis / Delayed / 0-1.0
    pruritus / Rapid / 1.0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    dysphagia / Delayed / 1.0-1.0
    dizziness / Early / 1.0-1.0
    paresthesias / Delayed / 1.0-1.0
    memory impairment / Delayed / 0-1.0
    pulmonary fibrosis / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    blurred vision / Early / 1.0-1.0
    peripheral edema / Delayed / 1.0-1.0
    anxiety / Delayed / 1.0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    Cushing's syndrome / Delayed / 8.0-8.0
    depression / Delayed / 6.0-6.0
    erythema / Early / 1.0-5.0
    pneumonitis / Delayed / 0-1.0
    leukopenia / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    edema / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 55.0-69.0
    infection / Delayed / 6.0-11.0
    insomnia / Early / 4.0-10.0
    pharyngitis / Delayed / 8.0-8.0
    dysgeusia / Early / 5.0-6.0
    sinusitis / Delayed / 6.0-6.0
    mastalgia / Delayed / 6.0-6.0
    increased urinary frequency / Early / 6.0-6.0
    myalgia / Early / 5.0-5.0
    diplopia / Early / 5.0-5.0
    weight gain / Delayed / 5.0-5.0
    petechiae / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL 2 in combination with any antineoplastic agents have not been established. Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin, IL 2 and dacarbazine. Aldesleukin, IL 2 can decrease dacarbazine serum concentrations by increasing the volume of distribution of dacarbazine by 36 percent via an unknown mechanism.
    Amlodipine; Celecoxib: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bupivacaine; Meloxicam: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Celecoxib: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Celecoxib; Tramadol: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cyclosporine: (Minor) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Daclizumab: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Diclofenac: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Etodolac: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Flurbiprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocodone; Ibuprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketoprofen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Methotrexate: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as methotrexate may result in additive effects.
    Mycophenolate: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Nabumetone: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nanoparticle Albumin-Bound Sirolimus: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Naproxen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Esomeprazole: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Piroxicam: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rofecoxib: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sirolimus: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Sulindac: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sumatriptan; Naproxen: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tacrolimus: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Tolmetin: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid decreases the oral clearance of temozolomide. The clinical implication of this effect is not known.

    PREGNANCY AND LACTATION

    Pregnancy

    Temozolomide may cause fetal harm when administered during pregnancy, based on its mechanism of action, animal studies, and limited data in humans. Advise females of reproductive potential to avoid pregnancy while taking temozolomide. Discuss the potential hazard to the fetus if temozolomide is used during pregnancy. Spontaneous abortion and congenital malformations including central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies have been reported in postmarketing surveillance of temozolomide-exposed pregnant women. Similar fetal abnormalities have been observed in animal studies with temozolomide doses that were less than the maximum human dose (based on BSA).

    Counsel patients about the reproductive risk and contraception requirements during temozolomide treatment. Female patients of reproductive potential require pregnancy testing prior to starting temozolomide. These women should use effective contraception during temozolomide therapy and for at least 6 months after the last dose. Women who become pregnant while receiving temozolomide should be apprised of the potential hazard to the fetus. Due to the potential for male-mediated teratogenicity, male patients with a female partner who is able to become pregnant should use effective contraception (e.g., condoms) during temozolomide therapy and for at least 3 months after the last dose. Based on limited data from case reports, infertility may occur in male patients who receive temozolomide; it is not known if sperm changes are reversible. Additionally, male patients should be warned against sperm donation during temozolomide therapy and for 3 months after the last dose.

    MECHANISM OF ACTION

    Temozolomide is an imidazotetrazine derivative prodrug that undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). It is a second-generation DNA alkylating agent that causes crosslinking of double-stranded DNA resulting in calcium-dependent apoptosis and cell death. Alkylation via methylation occurs primarily at the O6 and N7 positions of guanine and cycle arrest usually occurs between the G2- and M-phases. Temozolomide is a lipophilic molecule that crosses the blood-brain barrier and effectively penetrates into glioma cells. A mechanism of temozolomide resistance includes the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is expressed in glioma cells; loss of DNA mismatch repair appears to be another resistance mechanism. Temozolomide exhibits synergy with radiotherapy.

    PHARMACOKINETICS

    Temozolomide is administered orally and intravenously. It is minimally bound to plasma proteins (15%) and has a mean steady-state volume of distribution of 0.4 L/kg (coefficient of variation (CV), 13%), an overall clearance of 5.5 L/hour/m2, and a mean elimination half-life of 1.8 hours. Temozolomide exhibits linear kinetics over a dose range of 75 to 250 mg/m2. It is spontaneously hydrolyzed at physiologic pH to an active metabolite, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and methylhydrazine, the active alkylating substance. AIC is known to be an intermediate in purine and nucleic acid biosynthesis. Temozolomide and MTIC are not significantly metabolized via cytochrome P450 enzymes. About 38% of a radioactive dose of temozolomide was recovered after 7 days, 37.7% in urine and 0.8% in feces. Most of the radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolites (17%).

    Oral Route

    Temozolomide is rapidly and completely absorbed following oral administration; the Cmax occurs at a median Tmax of 1 hour. In a pharmacokinetic study in 19 patients with primary central nervous system malignancies, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively, following a single oral dose of temozolomide 150 mg/m2; the mean geometric AUC values were 23.4 mcg X hour/mL and 864 ng X hour/mL, respectively.
    Effects of food: Food reduces the rate and extent of temozolomide absorption. When temozolomide was given after a modified high-fat breakfast, the mean Cmax and AUC values decreased by 32% and 9%, respectively; additionally, the median Tmax increased from 1.1 to 2.25 hours.

    Intravenous Route

    In a pharmacokinetic study in 19 patients with primary central nervous system malignancies, temozolomide given as 150 mg/m2 orally or 150 mg/m2 IV over 90 minutes resulted in bioequivalent Cmax and AUC values for both temozolomide and the active metabolite, MTIC. Following a single IV dose of temozolomide 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively, and the mean geometric AUC values were 24.6 mcg X hour/mL and 891 ng X hour/mL, respectively.