eks after the last dose of temozolomide. (5.5) fetal harm can occur when administered to a pregnant woman. women should be advised to avoid becoming pregnant when receiving temozolomide. (5.6) 5.1 myelosuppression patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. in some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. prior to dosing, patients must have an absolute neutrophil count (anc) ≥1.5 x 10 9 /l and a platelet count ≥100 x 10 9 /l. a complete blood count should be obtained on day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the anc is above 1.5 x 10 9 /l and platelet count exceeds 100 x 10 9 /l. geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. 5.2 myelodysplastic syndrome cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. 5.3 pneumocystis pneumonia for treatment of newly diagnosed glioblastoma multiforme: prophylaxis against pneumocystis pneumonia (pcp) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen. there may be a higher occurrence of pcp when temozolomide is administered during a longer dosing regimen. however, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of pcp regardless of the regimen. 5.4 laboratory tests for the concomitant treatment phase with rt, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment. for the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on day 1 and on day 22 (21 days after the first dose) of each cycle. blood counts should be performed weekly until recovery if the anc falls below 1.5 x 10 9 /l and the platelet count falls below 100 x 10 9 /l [see recommended dosing and dose modification guidelines (2.1) ] . 5.5 hepatotoxicity fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide. 5.6 use in pregnancy temozolomide can cause fetal harm when administered to a pregnant woman. administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m 2 ), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species [see use in specific populations (8.1) ] .

) followed by maintenance temozolomide capsules for 6 cycles. focal rt includes the tumor bed or resection site with a 2- to 3-cm margin. no dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. the temozolomide capsules dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count ≥1.5 x 10 9 /l, platelet count ≥100 x 10 9 /l, common toxicity criteria (ctc) nonhematological toxicity ≤grade 1 (except for alopecia, nausea, and vomiting). during treatment a complete blood count should be obtained weekly. temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in table 1 . pneumocystis pneumonia (pcp) prophylaxis is required during the concomitant administration of temozolomide capsules and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (ctc grade ≤1). table 1: temozolomide dosing interruption or discontinuation during concomitant radiotherapy and temozolomide toxicity tmz interruption* tmz discontinuation absolute neutrophil count ≥0.5 and <1.5 x 10 9 /l <0.5 x 10 9 /l platelet count ≥10 and <100 x 10 9 /l <10 x 10 9 /l ctc nonhematological toxicity (except for alopecia, nausea, vomiting) ctc grade 2 ctc grade 3 or 4 *treatment with concomitant tmz could be continued when all of the following conditions were met: absolute neutrophil count ≥1.5 x 10 9 /l; platelet count ≥100 x 10 9 /l; ctc nonhematological toxicity ≤grade 1 (except for alopecia, nausea, vomiting). tmz=temozolomide; ctc=common toxicity criteria. maintenance phase: cycle 1: four weeks after completing the temozolomide capsules+rt phase, temozolomide capsules are administered for an additional 6 cycles of maintenance treatment. dosage in cycle 1 (maintenance) is 150 mg/m 2 once daily for 5 days followed by 23 days without treatment. cycles 2 to 6: at the start of cycle 2, the dose can be escalated to 200 mg/m 2 , if the ctc nonhematologic toxicity for cycle 1 is grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (anc) is ≥1.5 x 10 9 /l, and the platelet count is ≥100 x 10 9 /l. the dose remains at 200 mg/m 2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. if the dose was not escalated at cycle 2, escalation should not be done in subsequent cycles. dose reduction or discontinuation during maintenance: dose reductions during the maintenance phase should be applied according to tables 2 and 3 . during treatment, a complete blood count should be obtained on day 22 (21 days after the first dose of temozolomide capsules) or within 48 hours of that day, and weekly until the anc is above 1.5 x 10 9 /l (1500/μl) and the platelet count exceeds 100 x 10 9 /l (100,000/μl). the next cycle of temozolomide capsules should not be started until the anc and platelet count exceed these levels. dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. dose reductions or discontinuations during the maintenance phase should be applied according to tables 2 and 3 . table 2: temozolomide dose levels for maintenance treatment dose level dose (mg/m 2 /day) remarks –1 100 reduction for prior toxicity 0 150 dose during cycle 1 1 200 dose during cycles 2 to 6 in absence of toxicity table 3: temozolomide dose reduction or discontinuation during maintenance treatment toxicity reduce tmz by 1 dose level* discontinue tmz absolute neutrophil count <1.0 x 10 9 /l see footnote † platelet count <50 x 10 9 /l see footnote † ctc nonhematological toxicity (except for alopecia, nausea, vomiting) ctc grade 3 ctc grade 4 † *tmz dose levels are listed in table 2 . † tmz is to be discontinued if dose reduction to <100 mg/m 2 is required or if the same grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. tmz=temozolomide; ctc=common toxicity criteria. patients with refractory anaplastic astrocytoma: for adults the initial dose is 150 mg/m 2 once daily for 5 consecutive days per 28-day treatment cycle. for adult patients, if both the nadir and day of dosing (day 29, day 1 of next cycle) anc are ≥1.5 x 10 9 /l (1500/μl) and both the nadir and day 29, day 1 of next cycle platelet counts are ≥100 x 10 9 /l (100,000/μl), the temozolomide capsules dose may be increased to 200 mg/m 2 /day for 5 consecutive days per 28-day treatment cycle. during treatment, a complete blood count should be obtained on day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the anc is above 1.5 x 10 9 /l (1500/μl) and the platelet count exceeds 100 x 10 9 /l (100,000/μl). the next cycle of temozolomide capsules should not be started until the anc and platelet count exceed these levels. if the anc falls to <1.0 x 10 9 /l (1000/μl) or the platelet count is <50 x 10 9 /l (50,000/μl) during any cycle, the next cycle should be reduced by 50 mg/m 2 , but not below 100 mg/m 2 , the lowest recommended dose (see table 4 ). temozolomide capsules therapy can be continued until disease progression. in the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. table 4: dosing modification table table 5: daily dose calculations by body surface area (bsa) total bsa (m 2 ) 75 mg/m 2 (mg daily) 150 mg/m 2 (mg daily) 200 mg/m 2 (mg daily) 1.0 75 150 200 1.1 82.5 165 220 1.2 90 180 240 1.3 97.5 195 260 1.4 105 210 280 1.5 112.5 225 300 1.6 120 240 320 1.7 127.5 255 340 1.8 135 270 360 1.9 142.5 285 380 2.0 150 300 400 2.1 157.5 315 420 2.2 165 330 440 2.3 172.5 345 460 2.4 180 360 480 2.5 187.5 375 500 table 6: suggested capsule combinations based on daily dose in adults number of daily capsules by strength (mg) total daily dose (mg) 250 mg 180 mg 140 mg 100 mg 20 mg 5 mg 75 0 0 0 0 3 3 82.5 0 0 0 0 4 0 90 0 0 0 0 4 2 97.5 0 0 0 1 0 0 105 0 0 0 1 0 1 112.5 0 0 0 1 0 2 120 0 0 0 1 1 0 127.5 0 0 0 1 1 1 135 0 0 0 1 1 3 142.5 0 0 1 0 0 0 150 0 0 1 0 0 2 157.5 0 0 1 0 1 0 165 0 0 1 0 1 1 172.5 0 0 1 0 1 2 180 0 1 0 0 0 0 187.5 0 1 0 0 0 1 195 0 1 0 0 0 3 200 0 1 0 0 1 0 210 0 0 0 2 0 2 220 0 0 0 2 1 0 225 0 0 0 2 1 1 240 0 0 1 1 0 0 255 1 0 0 0 0 1 260 1 0 0 0 0 2 270 1 0 0 0 1 0 280 0 0 2 0 0 0 285 0 0 2 0 0 1 300 0 0 0 3 0 0 315 0 0 0 3 0 3 320 0 1 1 0 0 0 330 0 1 1 0 0 2 340 0 1 1 0 1 0 345 0 1 1 0 1 1 360 0 2 0 0 0 0 375 0 2 0 0 0 3 380 0 1 0 2 0 0 400 0 0 0 4 0 0 420 0 0 3 0 0 0 440 0 0 3 0 1 0 460 0 2 0 1 0 0 480 0 1 0 3 0 0 500 2 0 0 0 0 0 table 4: dosing modification table 2.2 preparation and administration temozolomide capsules: in clinical trials, temozolomide capsules were administered under both fasting and nonfasting conditions; however, absorption is affected by food [see clinical pharmacology (12.3) ] , and consistency of administration with respect to food is recommended. there are no dietary restrictions with temozolomide capsules. to reduce nausea and vomiting, temozolomide capsules should be taken on an empty stomach. bedtime administration may be advised. antiemetic therapy may be administered prior to and/or following administration of temozolomide capsules. temozolomide capsules should not be opened or chewed. they should be swallowed whole with a glass of water. if capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see how supplied/storage and handling (16.1) ] .

stoma multiforme: during the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+rt arm. the incidence of other adverse reactions was comparable in the two arms. the most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see table 7 ). forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide. *one patient who was randomized to rt only arm received rt+temozolomide. rt+tmz=radiotherapy plus temozolomide; nos=not otherwise specified. note: grade 5 (fatal) adverse reactions are included in the grade ≥3 column. myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. when laboratory abnormalities and adverse reactions were combined, grade 3 or grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and grade 3 or grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide. refractory anaplastic astrocytoma: tables 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. in the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients’ underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. the most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. the adverse reactions were usually nci common toxicity criteria (ctc) grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. the incidence of severe nausea and vomiting (ctc grade 3 or 4) was 10% and 6%, respectively. myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. it usually occurred within the first few cycles of therapy and was not cumulative. myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. the median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. in clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of grade 4 neutropenia (anc<500 cells/μl) and thrombocytopenia (<20,000 cells/μl) in women than men in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively). in the entire safety database for which hematologic data exist (n=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. for patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. pancytopenia, leukopenia, and anemia have also been reported. table 8: adverse reactions in the anaplastic astrocytoma trial in adults (≥5% ) no. (%) of temozolomide patients (n=158) all reactions grade 3/4 any adverse reaction 153 (97) 79 (50) body as a whole headache 65 (41) 10 (6) fatigue 54 (34) 7 (4) asthenia 20 (13) 9 (6) fever 21 (13) 3 (2) back pain 12 (8) 4 (3) cardiovascular edema peripheral 17 (11) 1 (1) central and peripheral nervous system convulsions 36 (23) 8 (5) hemiparesis 29 (18) 10 (6) dizziness 19 (12) 1 (1) coordination abnormal 17 (11) 2 (1) amnesia 16 (10) 6 (4) insomnia 16 (10) 0 paresthesia 15 (9) 1 (1) somnolence 15 (9) 5 (3) paresis 13 (8) 4 (3) urinary incontinence 13 (8) 3 (2) ataxia 12 (8) 3 (2) dysphasia 11 (7) 1 (1) convulsions local 9 (6) 0 gait abnormal 9 (6) 1 (1) confusion 8 (5) 0 endocrine adrenal hypercorticism 13 (8) 0 gastrointestinal system nausea 84 (53) 16 (10) vomiting 66 (42) 10 (6) constipation 52 (33) 1 (1) diarrhea 25 (16) 3 (2) abdominal pain 14 (9) 2 (1) anorexia 14 (9) 1 (1) metabolic weight increase 8 (5) 0 musculoskeletal system myalgia 8 (5) psychiatric disorders anxiety 11 (7) 1 (1) depression 10 (6) 0 reproductive disorders breast pain, female 4 (6) resistance mechanism disorders infection viral 17 (11) 0 respiratory system upper respiratory tract infection 13 (8) 0 pharyngitis 12 (8) 0 sinusitis 10 (6) 0 coughing 8 (5) 0 skin and appendages rash 13 (8) 0 pruritus 12 (8) 2 (1) urinary system urinary tract infection 12 (8) 0 micturition increased frequency 9 (6) 0 vision diplopia 8 (5) 0 vision abnormal* 8 (5) *blurred vision; visual deficit; vision changes; vision troubles table 9: adverse hematologic effects (grade 3 to 4) in the anaplastic astrocytoma trial in adults temozolomide* hemoglobin 7/158 (4%) lymphopenia 83/152 (55%) neutrophils 20/142 (14%) platelets 29/156 (19%) wbc 18/158 (11%) *change from grade 0 to 2 at baseline to grade 3 or 4 during treatment. temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4carboxamide (mtic) as the corresponding temozolomide capsules. adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma. 1 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of temozolomide. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. dermatologic disorders : toxic epidermal necrolysis and stevens-johnson syndrome. immune system disorders: allergic reactions, including anaphylaxis. erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. hematopoietic disorders : prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes [see warnings and precautions (5.1)] . hepatobiliary disorders : fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis [see warnings and precautions (5.5)] . infections and infestations : opportunistic infections including pneumocystis pneumonia (pcp) [ see warnings and precautions (5.3) ], primary and reactivated cytomegalovirus (cmv), and reactivation of hepatitis b infections including some cases with fatal outcomes. pulmonary disorders : interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. endocrine disorders : diabetes insipidus.

atient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide. 8.3 nursing mothers it is not known whether this drug is excreted in human milk. because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. temozolomide capsules have been studied in 2 open-label studies in pediatric patients (aged 3 to 18 years) at a dose of 160 to 200 mg/m 2 daily for 5 days every 28 days. in one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. all patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. in a second study conducted by the children’s oncology group (cog), 122 patients were enrolled, including patients with medulloblastoma/pnet (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other cns tumors (9), and non-cns tumors (9). the temozolomide toxicity profile in pediatric patients is similar to adults. table 10 shows the adverse reactions in 122 children in the cog study. table 10: adverse reactions reported in the pediatric cooperative group trial (≥10%) no. (%) of temozolomide patients (n=122)* body system/organ class all reactions grade 3/4 adverse reaction subjects reporting an ae 107 (88) 69 (57) body as a whole central and peripheral nervous system central cerebral cns cortex 22 (18) 13 (11) gastrointestinal system nausea 56 (46) 5 (4) vomiting 62 (51) 4 (3) platelet, bleeding and clotting thrombocytopenia 71 (58) 31 (25) red blood cell disorders decreased hemoglobin 62 (51) 7 (6) white cell and res disorders decreased wbc 71 (58) 21 (17) lymphopenia 73 (60) 48 (39) neutropenia 62 (51) 24 (20) *these various tumors included the following: pnet-medulloblastoma, glioblastoma, low grade astrocytoma, brain stem tumor, ependymoma, mixed glioma, oligodendroglioma, neuroblastoma, ewing's sarcoma, pineoblastoma, alveolar soft part sarcoma, neurofibrosarcoma, optic glioma, and osteosarcoma. 8.5 geriatric use clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. in the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of grade 4 neutropenia and grade 4 thrombocytopenia (2/8; 25%, p =0.31 and 2/10; 20%, p =0.09, respectively) in the first cycle of therapy than patients under 70 years of age [see warnings and precautions (5.1) and adverse reactions (6.1) ] . in newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (<65 years) vs. older (≥65 years). 8.6 renal impairment caution should be exercised when temozolomide is administered to patients with severe renal impairment [see clinical pharmacology (12.3) ] . 8.7 hepatic impairment caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see clinical pharmacology (12.3) ] .

ing a single oral dose of 150 mg/m 2 , the geometric mean auc values for temozolomide and mtic were 23.4 mcg·hr/ml and 864 ng·hr/ml, respectively. distribution: temozolomide has a mean apparent volume of distribution of 0.4 l/kg (%cv=13%). it is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%. metabolism and elimination: temozolomide is spontaneously hydrolyzed at physiologic ph to the active species, mtic and to temozolomide acid metabolite. mtic is further hydrolyzed to 5-amino-imidazole-4-carboxamide (aic), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. cytochrome p450 enzymes play only a minor role in the metabolism of temozolomide and mtic. relative to the auc of temozolomide, the exposure to mtic and aic is 2.4% and 23%, respectively. excretion: about 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. the majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), aic (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). overall clearance of temozolomide is about 5.5 l/hr/m 2 . temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m 2 /day. effect of age: a population pharmacokinetic analysis indicated that age (range: 19 to 78 years) has no influence on the pharmacokinetics of temozolomide. effect of gender: a population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men. effect of race: the effect of race on the pharmacokinetics of temozolomide has not been studied. tobacco use: a population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers. effect of renal impairment: a population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 ml/min/m 2 has no effect on the clearance of temozolomide after oral administration. the pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (clcr <36 ml/min/m 2 ). caution should be exercised when temozolomide is administered to patients with severe renal impairment [see use in special populations (8.6) ] . temozolomide has not been studied in patients on dialysis. effect of hepatic impairment: a study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (child-pugh class i - ii) were similar to those observed in patients with normal hepatic function. caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see use in specific populations (8.7) ] . effect of other drugs on temozolomide pharmacokinetics: in a multiple-dose study, administration of temozolomide capsules with ranitidine did not change the c max or auc values for temozolomide or mtic. a population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5% [see drug interactions (7.1) ] . a population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, h 2 -receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.

olic activation. temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation. temozolomide impairs male fertility. temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m 2 ) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m 2 ). 13.2 animal toxicology and/or pharmacology toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m 2 ). these changes were most commonly seen at doses where mortality was observed.

ered as salvage therapy in 161 patients of the 282 (57%) in the rt alone arm, and 62 patients of the 277 (22%) in the temozolomide+rt arm. the addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed gbm showed a statistically significant improvement in overall survival compared to radiotherapy alone ( figure 1 ). the hazard ratio (hr) for overall survival was 0.63 (95% ci for hr=0.52 to 0.75) with a log-rank p <0.0001 in favor of the temozolomide arm. the median survival was increased by 2.5 months in the temozolomide arm. figure 1: kaplan-meier curves for overall survival (itt population) f696f63e-figure-03 14.2 refractory anaplastic astrocytoma a single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline karnofsky performance status of 70 or greater. patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine, and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). median age of this subgroup of 54 patients was 42 years (19 to 76). sixty-five percent were male. seventy-two percent of patients had a kps of >80. sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. eighteen percent of patients had surgery at the time of first relapse. the median time from initial diagnosis to first relapse was 13.8 months (4.2 to 75.4). temozolomide capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m 2 /day. if the nadir and day of dosing (day 29, day 1 of next cycle) absolute neutrophil count was ≥1.5 x 10 9 /l (1500/μl) and the nadir and day 29, day 1 of next cycle platelet count was ≥100 x 10 9 /l (100,000/μl), the temozolomide dose was increased to 200 mg/m 2 /day for the first 5 consecutive days of a 28-day cycle. in the refractory anaplastic astrocytoma population, the overall tumor response rate (cr + pr) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). the median duration of all responses was 50 weeks (range: 16 to 114 weeks) and the median duration of complete responses was 64 weeks (range: 52 to 114 weeks). in this population, progression-free survival at 6 months was 45% (95% ci: 31% to 58%) and progression-free survival at 12 months was 29% (95% ci: 16% to 42%). median progression-free survival was 4.4 months. overall survival at 6 months was 74% (95% ci: 62% to 86%) and 12-month overall survival was 65% (95% ci: 52% to 78%). median overall survival was 15.9 months.

es imprinted “802” with black ink. they are available as follows: ndc 50268-761-12 (5 capsules per card, 4 cards per carton). temozolomide capsules 100 mg are supplied as size “1” hard gelatin capsules with pink opaque color caps imprinted “amneal” and white opaque color bodies imprinted “803” with black ink.they are available as follows: ndc 50268-762-12 (5 capsules per card, 4 cards per carton). temozolomide capsules 140 mg are supplised as size “0” hard gelatin capsules with blue opaque color caps imprinted “amneal” and white opaque color bodies imprinted “804” with black ink. they are available as follows: ndc 50268-763-12 (5 capsules per card, 4 cards per carton). temozolomide capsules 180 mg are supplied as size “0” hard gelatin capsules with red opaque color caps imprinted “amneal” and white opaque color bodies imprinted “805” with black ink. temozolomide capsules 250 mg are supplied as size “0” hard gelatin capsules with white opaque color caps imprinted “amneal” and white opaque color bodies imprinted “806” with black ink. 16.3 storage store temozolomide capsules at 20° to 25°c (68° to 77°f); excursions permitted to 15° to 30°c (59° to 86°f) [see usp controlled room temperature].