Temozolomide is a prodrug that undergoes rapid nonenzymatic conversion to an alkylating compound. It is indicated for the treatment of adults with newly diagnosed glioblastoma multiforme in combination with radiotherapy followed by monotherapy maintenance therapy and for the treatment of anaplastic astrocytoma in adults with refractory disease or as adjuvant therapy in adults with newly diagnosed disease. Severe hematologic toxicity and hepatotoxicity have been reported with temozolomide therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-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.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take temozolomide at the same time each day consistently either with or without food.
-Swallow capsules whole with a glass of water; do not open, chew, or dissolve the contents of the capsules.
-To reduce nausea and vomiting, take on an empty stomach or at bedtime.
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; do not shake.
-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.
Radiation injury (7% vs. 4%) occurred more often in patients with newly diagnosed glioblastoma multiforme who received temozolomide plus radiotherapy (RT) (n = 288) compared with RT alone (n = 285). Radiation injury was also reported in 2% of patients who received maintenance temozolomide therapy (n = 224) in this study.
Nausea (36% to 53%; grade 3 or higher, 1% to 10%), vomiting (20% to 42%; grade 3 or higher, 6% or less), constipation (18% to 33%; grade 3 or higher, 1% or less), diarrhea (6% to 16%; grade 3 or higher, 2% or less), anorexia (27% or less; grade 3 or higher, 1% or less), and abdominal pain (less than 10%) were reported in patients who received temozolomide in clinical trials. Stomatitis and taste perversion/dysgeusia were reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial.
Severe myelosuppression has been reported with temozolomide therapy; some cases were fatal. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop myelosuppression. Continue PCP prophylaxis in patients who develop lymphopenia. Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes, were reported in postmarketing surveillance of temozolomide. Grade 3 or 4 neutrophil abnormalities including neutropenic reactions (8%) and platelet abnormalities including thrombocytopenic reactions (14%) were reported in patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Hematologic toxicity that worsened from baseline, including grade 3 or 4 decreased lymphocyte count/lymphopenia (55%), decreased platelet count/thrombocytopenia (19%), decreased neutrophil count/neutropenia (14%), decreased leukocyte count/leukopenia (11%), and decreased hemoglobin level/anemia (4%), occurred in patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158). In this trial, the median nadirs for neutrophils and platelets occurred at 28 days (range, 1 to 44 days) and 26 days (range, 21 to 40 days), respectively. Grade 4 neutropenia (12% vs. 5%) and thrombocytopenia (9% vs. 3%) occurred more often in the first cycle of temozolomide therapy in female patients compared with male patients with advanced gliomas in clinical trials. Grade 4 thrombocytopenia (10% vs. 6%) occurred more often in the first cycle of temozolomide therapy in geriatric patients aged greater than 70 years compared with younger patients with advanced gliomas in clinical trials (n = 932).
Rash (19% or less; grade 3 or higher, 1% or less) and pruritus (less than 10%) occurred in patients who received temozolomide in clinical trials. Alopecia was reported in 69% of patients newly diagnosed glioblastoma during the temozolomide plus concurrent radiation phase (n = 288) and 55% of patients during the temozolomide maintenance use phase (n = 224) in a randomized trial. Dry skin/xerosis and erythema were each reported in less than 10% of patients with newly diagnosed glioblastoma in this trial. Erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported in postmarketing surveillance of temozolomide. Erythema multiforme typically resolved after temozolomide was discontinued; however, some cases recurred on rechallenge.
New primary malignancy, specifically myelodysplastic syndrome and myeloid leukemia, has been reported in patients who received temozolomide therapy.
Arthralgia was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Back pain and myalgia each occurred in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158).
Cushing's syndrome (adrenal hypercorticism) occurred in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158).
Injection site reaction (i.e., petechiae, hematoma, and pain, skin irritation, pruritus, warmth, swelling, and erythema at the infusion site) occurred with IV temozolomide therapy in 35 patients in clinical trials.
Hepatotoxicity, including elevated hepatic enzymes, hyperbilirubinemia, cholestasis, and hepatitis, has been reported with temozolomide use in postmarketing surveillance; in some cases, hepatotoxicity was fatal. Monitor liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and 2 to 4 weeks after completion of therapy.
Headache (19% to 41%; grade 3 or higher, 2% to 6%), seizures (6% to 23%; grade 3 or higher, 3% to 5%), and dizziness (12% or less; grade 3 or higher, 1% or less) were reported in patients who received temozolomide in clinical trials. Hemiparesis (18%; grade 3 or 4, 6%) and abnormal coordination (11%; grade 3 or 4, 1%) occurred in patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158). Paresthesias, drowsiness/somnolence, paresis, ataxia, dysphagia, and abnormal gait/gait disturbance were each reported in less than 10% of patients with anaplastic astrocytoma in this trial.
Cough was reported in less than 10% of patients who received temozolomide in clinical trials. Additionally, dyspnea was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Interstitial pneumonitis/pneumonitis, alveolitis, and pulmonary fibrosis have been reported postmarketing surveillance of temozolomide.
Pneumocystis pneumonia (PCP) has been reported with temozolomide therapy. Monitor all patients for signs or symptoms of PCP. Viral infection occurred in 11% of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158); additionally, upper respiratory tract infection, pharyngitis, sinusitis, and urinary tract infection each were reported in less than 10% of patients. Serious bacterial, viral (primary and reactivated), fungal, and protozoan opportunistic infections were reported in postmarketing surveillance of temozolomide; some cases were fatal.
Fatigue was reported in 34% to 61% (grade 3 or higher, 4% to 9%) of patients who received temozolomide in clinical trials. Weakness was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Asthenia occurred in 13% (grade 3 or 4, 6%) of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Blurred vision was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Additionally, diplopia and abnormal vision (i.e., blurred vision or visual deficit, changes, and troubles) occurred in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158).
Peripheral edema occurred in 11% (grade 3 or 4, 1%) of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Weight gain occurred in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158).
Mastalgia occurred in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in clinical trial (n = 158).
Urinary incontinence and increased urinary frequency each were reported in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Anxiety and depression were each reported in less than 10% of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Allergic reaction was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Hypersensitivity reactions, including anaphylactoid reactions, were reported in postmarketing surveillance of temozolomide.
Diabetes insipidus was reported in postmarketing surveillance of temozolomide.
Temozolomide is associated with teratogenesis. Spontaneous fetal 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.
Insomnia (10% or less) and confusion (less than 10%) were reported in patients who received temozolomide in clinical trials. Memory impairment was reported in less than 10% of patients with newly diagnosed glioblastoma who received temozolomide plus concurrent radiation followed by temozolomide maintenance therapy in a randomized trial. Amnesia occurred in 10% (grade 3 or 4, 4%) of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Fever occurred in 13% (grade 3 or 4, 2%) of patients with refractory anaplastic astrocytoma who received temozolomide in a clinical trial (n = 158).
Temozolomide is contraindicated in patients who have a history of a serious dacarbazine (DTIC) hypersensitivity reaction, since both drugs are metabolized to the active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).
Bone marrow suppression/myelosuppression (e.g., pancytopenia, leukopenia, and anemia) has been reported with temozolomide therapy; some cases were fatal. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop myelosuppression. Obtain complete blood counts (CBC) with differential prior to starting temozolomide and as clinically indicated during treatment. Do not administer temozolomide until the absolute neutrophil count (ANC) is 1.5 X 109 cells/L or more and the platelet count is 100 X 109 cells/L or more. For the 28-day treatment cycles, monitor CBC prior to treatment on day 1 and on day 22 of each cycle; obtain CBC weekly until recovery if the ANC falls below 1.5 X 109 cells/L and the platelet count falls below 100 X 109 cells/L. When temozolomide is used in combination with radiotherapy, monitor CBC prior to starting and then weekly during treatment. Geriatric patients and females may be at greater risk for developing myelosuppression with temozolomide therapy.
Severe hepatotoxicity has been reported with temozolomide therapy; some cases were fatal. Monitor liver function tests at baseline, midway through the first cycle, before each subsequent cycle, and 2 to 4 weeks after the last dose. Temozolomide has not been evaluated in patients with severe hepatic disease/impairment (Child-Pugh class C).
Pneumocystis pneumonia (PCP) infection has been reported with temozolomide therapy. Monitor all patients for the development of lymphopenia and PCP. Administer PCP prophylaxis in patients with newly diagnosed glioblastoma multiforme during the concomitant radiotherapy phase; continue PCP prophylaxis until the infection resolves to grade 1 or less in patients who experience lymphopenia. Patients receiving concomitant corticosteroid therapy or who are on longer treatment regimens may be at greater risk for developing PCP with temozolomide therapy.
Temozolomide may cause fetal harm when administered during pregnancy, based on its mechanism of action, animal studies, and limited data in humans. 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 adverse developmental outcomes have been observed in animal studies with temozolomide doses that were less than the maximum human dose (based on body surface area).
Counsel patients about the reproductive risk and contraception requirements during temozolomide treatment. Patients of reproductive potential require pregnancy testing prior to starting temozolomide. These patients should use effective contraception during temozolomide therapy and for 6 months after the last dose. Patients who become pregnant while receiving temozolomide should be apprised of the potential hazard to the fetus. Due to the potential for male-mediated teratogenicity, patients with a partner who is able to become pregnant should use effective contraception (e.g., condoms) during temozolomide therapy and for 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, sperm donation is not recommended during temozolomide therapy and for 3 months after the last dose.
It is not known if temozolomide or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions (e.g., myelosuppression) in breast-fed children, advise patients against breast-feeding during temozolomide therapy and for 1 week after the last dose.
For the treatment of glioblastoma multiforme (GBM):
-for the treatment of newly diagnosed GBM in combination with radiotherapy followed by single-agent maintenance therapy:
Oral dosage:
Adults: 75 mg/m2 orally once daily for 42 to 49 days with concomitant focal radiotherapy (to the tumor bed or resection site with a 2 to 3 cm margin). Administer Pneumocystis carinii pneumonia (PCP) prophylaxis during the concomitant therapy period; continue PCP prophylaxis in patients who develop lymphopenia. Temozolomide therapy interruption or discontinuation may be necessary in patients who develop toxicity during the concomitant treatment phase. At 4 weeks after completing the concomitant treatment phase, begin 6 cycles of maintenance therapy with temozolomide 150 mg/m2 orally once daily on days 1, 2, 3, 4, and 5 repeated every 28 days. Starting in cycle 2, the temozolomide dosage may be increased to 200 mg/m2 orally once daily for 5 days per cycle if no therapy interruptions or discontinuation was needed in cycle 1. 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:
Adults: 75 mg/m2 IV daily for 42 to 49 days with concomitant focal radiotherapy (to the tumor bed or resection site with a 2 to 3 cm margin). Administer Pneumocystis carinii pneumonia (PCP) prophylaxis during the concomitant therapy period; continue PCP prophylaxis in patients who develop lymphopenia. Temozolomide therapy interruption or discontinuation may be necessary in patients who develop toxicity during the concomitant treatment phase. At 4 weeks after completing the concomitant treatment phase, begin 6 cycles of maintenance therapy with temozolomide 150 mg/m2 IV once daily on days 1, 2, 3, 4, and 5 repeated every 28 days. Starting in cycle 2, the temozolomide dosage may be increased to 200 mg/m2 IV once daily for 5 days per cycle if no therapy interruptions or discontinuation occurred in cycle 1. 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 adjuvant treatment of newly diagnosed anaplastic astrocytoma:
Oral dosage:
Adults: 150 mg/m2 orally once daily on days 1, 2, 3, 4, and 5 repeated every 28 days for 12 cycles starting 4 weeks after the completion of radiotherapy. Starting in cycle 2, increase the temozolomide dosage to 200 mg/m2 orally once daily for 5 days per cycle if there is no or minimal toxicity experienced in cycle 1. If the dosage is not increased in cycle 2, do not increase the dosage in subsequent cycles. Interruption, dosage reduction, or discontinuation of maintenance therapy may be necessary in patients who develop toxicity. The median overall survival time was significantly improved (not reached vs. 41.1 months; hazard ratio = 0.65; 99% to 145% CI, 0.45 to 0.93) in patients with newly diagnosed anaplastic astrocytoma who received adjuvant temozolomide (n = 373) compared with no adjuvant therapy (n = 372) in a planned interim analysis of a randomized, phase 3 (CATNON) trial.
-for the treatment of refractory anaplastic astrocytoma:
Oral dosage:
Adults: 150 mg/m2 orally once daily on days 1, 2, 3, 4, and 5 repeated every 28 days until disease progression. Increase the temozolomide dosage to 200 mg/m2 orally once daily for 5 days per cycle if the absolute neutrophil count is 1.5 X 109 cells/L or greater and the platelet count is 100 X 109 cells/L or greater at both the nadir and on day 1 of the next cycle. 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:
Adults: 150 mg/m2 IV once daily on days 1, 2, 3, 4, and 5 repeated every 28 days until disease progression. Increase the temozolomide dosage to 200 mg/m2 IV once daily for 5 days per cycle of therapy if the absolute neutrophil count is 1.5 X 109 cells/L or greater and the platelet count is 100 X 109 cells/L or greater at both the nadir and on day 1 of the next cycle. 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.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicities
Glioblastoma Concomitant Radiotherapy Phase:
Hematologic Toxicity
-Neutropenia
Absolute neutrophil count (ANC) of 0.5 X 109 cells/L to less than 1.5 X 109 cells/L: Hold temozolomide until the ANC is 1.5 X 109 cells/L or higher. Resume therapy at the same dosage.
ANC less than 0.5 X 109 cells/L: Discontinue temozolomide therapy.
-Thrombocytopenia
Platelet count of 10 X 109 cells/L to less than 100 X 109 cells/L: Hold temozolomide until the platelet count is 100 X 109 cells/L or higher. Resume therapy at the same dosage.
Platelet count less than 10 X 109 cells/L: Discontinue temozolomide therapy.
Nonhematologic Toxicity (except alopecia, nausea, or vomiting)
Grade 2 toxicity: Hold temozolomide until the toxicity resolves to grade 1 or less. Resume therapy at the same dosage.
Grade 3 or 4 toxicity: Discontinue temozolomide therapy.
Glioblastoma Maintenance Phase OR Anaplastic Astrocytoma:
Hematologic Toxicity
-Neutropenia
ANC less than 1 X 109 cells/L: Hold temozolomide until the ANC is above 1.5 X 109 cells/L, then reduce the dose by 50 mg/m2 per day for the next cycle. Discontinue temozolomide in patients who are unable to tolerate the 100 mg/m2 per day dosage.
-Thrombocytopenia
Platelet count less than 50 X 109 cells/L: Hold temozolomide until the platelet count is above 100 X 109 cells/L or higher, then reduce the dose by 50 mg/m2 per day for the next cycle. Discontinue temozolomide in patients who are unable to tolerate the 100 mg/m2 per day dosage.
Nonhematologic Toxicity (except alopecia, nausea, or vomiting)
Grade 3 toxicity: Hold temozolomide until the toxicity resolves to grade 1 or less, then reduce the dose by 50 mg/m2 per day for the next cycle. Discontinue temozolomide in patients who are unable to tolerate the 100 mg/m2 per day dosage or in patients who experience recurrent grade 3 toxicity after a dosage reduction.
Grade 4 toxicity: Discontinue temozolomide therapy.
Maximum Dosage Limits:
-Adults
75 mg/m2 PO/IV daily with concomitant radiation therapy OR 200 mg/m2 PO/IV daily for 5 days per 28-day cycle.
-Geriatric
75 mg/m2 PO/IV daily with concomitant radiation therapy OR 200 mg/m2 PO/IV daily for 5 days per 28-day cycle.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
Creatinine clearance (CrCl) of 36 mL/min/m2 or more: Dosage adjustment not necessary.
CrCl less than 36 mL/min/m2 OR end-stage renal disease requiring dialysis: Specific guidelines are not available; temozolomide use has not been evaluated in these patients.
*non-FDA-approved indication
Acetaminophen; 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.
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.
Bacillus Calmette-Guerin Vaccine, BCG: (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.
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.
Chikungunya Vaccine, Live: (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.
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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
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.
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.
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; Famotidine: (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.
Intranasal Influenza Vaccine: (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.
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.
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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (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.
Measles/Mumps/Rubella Vaccines, MMR: (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.
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.
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.
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.
Rotavirus Vaccine: (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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (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.
Smallpox Vaccine, Vaccinia Vaccine: (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.
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.
Typhoid Vaccine: (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.
Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid decreases the oral clearance of temozolomide. The clinical implication of this effect is not known.
Varicella-Zoster Virus Vaccine, Live: (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.
Yellow Fever Vaccine, Live: (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.
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.
Temozolomide is administered orally and intravenously. It is minimally bound to plasma proteins (15%) and has a mean apparent Vd of 0.4 L/kg (coefficient of variation, 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 daily 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. Relative to temozolomide, the exposure of MTIC and AIC is 2.4% and 23%, respectively. Temozolomide and MTIC are not significantly metabolized via CYP450 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 (6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolites (17%).
-Route-Specific Pharmacokinetics
Oral Route
Temozolomide is rapidly absorbed following oral administration; it has a systemic bioavailability of nearly 100%. Following a single oral dose of temozolomide 150 mg/m2, the mean Cmax values for temozolomide and MTIC were 7.68 (coefficient of variation (CV), 19%) and 0.33 (CV, 62%) micrograms (mcg)/mL, respectively, and the mean AUC(0 to inf) values were 23.6 (CV, 15%) and 1 (CV, 60%) mcg X hour/mL, respectively. The Tmax was reached at a median of 1 (range, 0.25 to 2) hour.
Effects of food: When temozolomide was given after a modified high-fat breakfast (587 total calories), the mean Cmax and AUC values decreased by 32% and 9%, respectively; additionally, the median Tmax increased from 1 to 2.25 hours.
Intravenous Route
Administering temozolomide 150 mg/m2 orally or as a 90-minute IV infusion met exposure equivalence criteria for Cmax and AUC values for both temozolomide and the active metabolite, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) in a pharmacokinetic study in 19 subjects. Following a single IV dose of temozolomide 150 mg/m2, the mean Cmax values for temozolomide and MTIC were 7.44 (coefficient of variation (CV), 21%) and 0.32 (CV, 61%) micrograms (mcg)/mL, respectively, and the mean AUC(0 to inf) values were 25 (CV, 16%) and 1 (CV, 54%) mcg X hour/mL, respectively.
-Special Populations
Hepatic Impairment
Mild to moderate hepatic impairment (Child Pugh class A and B) does not significantly impact the pharmacokinetic (PK) parameters of temozolomide. The PK parameters of temozolomide were not evaluated in patients with severe hepatic impairment (Child Pugh class C).
Renal Impairment
A creatinine clearance (CrCl) range of 36 to 130 mL/min/m2 did not significantly impact the pharmacokinetic (PK) parameters of temozolomide. The PK parameters of temozolomide were not evaluated in patients with a CrCl less than 36 mL/min/m2, end-stage renal disease, or receiving dialysis.
Geriatric
Age (range, 19 to 78 years) does not significantly impact the pharmacokinetic parameters of temozolomide.
Gender Differences
Gender does not significantly impact the pharmacokinetic parameters of temozolomide.
Other
Smoking Status
Smoking status (smoker vs. non-smoker) does not significantly impact the pharmacokinetic parameters of temozolomide.