Temozolomide

TEMODAR is an alkylating drug indicated for the treatment of adults with: Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) Anaplastic astrocytoma. ( 1.2 ) Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma. ( 1.2 ) Treatment of adults with refractory anaplastic astrocytoma. ( 1.2 )

1.1 Newly Diagnosed Glioblastoma TEMODAR is indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment.

1.2 Anaplastic Astrocytoma TEMODAR is indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma.

Capsules: – 5 mg: opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” – 20 mg: opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” – 100 mg: opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” – 140 mg: opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” – 180 mg: opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” – 250 mg: opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with “TEMODAR.” For injection: 100 mg white to light tan or light pink lyophilized powder for reconstitution in a single-dose vial. Capsules: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. ( 3 ) For injection: 100 mg as a lyophilized powder in single-dose vial for reconstitution. ( 3 )

TEMODAR is contraindicated in patients with a history of serious hypersensitivity reactions to: temozolomide or any other ingredients in TEMODAR; and dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide. Reactions to TEMODAR have included anaphylaxis [see Adverse Reactions (6.2) ]. History of serious hypersensitivity to temozolomide or any other ingredients in TEMODAR and dacarbazine. ( 4 )

Myelosuppression : Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have a higher risk of developing myelosuppression. ( 5.1 , 8.5 ) Hepatotoxicity : Fatal and severe hepatotoxicity have been reported. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of TEMODAR. ( 5.2 ) Pneumocystis Pneumonia (PCP) : Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. ( 5.3 ) Secondary Malignancies: Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ( 5.4 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. ( 5.5 , 8.1 , 8.3 ) Exposure to Opened Capsules: TEMODAR capsules should not be opened, chewed, or dissolved but should be swallowed whole with a glass of water. ( 5.6 )

5.1 Myelosuppression Myelosuppression, including pancytopenia, leukopenia, and anemia, some with fatal outcomes, have occurred with TEMODAR [see Adverse Reactions (6.1 , 6.2) ] . In MK-7365-006, myelosuppression usually occurred during the first few cycles of therapy and was generally not cumulative. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Approximately 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Obtain a complete blood count and monitor ANC and platelet counts before initiation of treatment and as clinically indicated during treatment. When TEMODAR is used in combination with radiotherapy, obtain a complete blood count prior to initiation of treatment, weekly during treatment, and as clinically indicated [see Dosage and Administration (2.1 , 2.2 , 2.3) ]. For severe myelosuppression, withhold TEMODAR and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.1 , 2.2 , 2.3) ] .

5.2 Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving TEMODAR. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of TEMODAR.

5.3 Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) has been reported in patients receiving TEMODAR. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens of TEMODAR. For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue PCP prophylaxis in patients who experience lymphopenia, until resolution to Grade 1 or less [see Dosage and Administration (2.1) ] . Monitor all patients receiving TEMODAR for the development of lymphopenia and PCP.

5.4 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with TEMODAR-containing regimens. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following TEMODAR administration.

5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TEMODAR can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than the maximum human dose based on body surface area. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TEMODAR and for 6 months after the last dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with TEMODAR and for 3 months after the last dose. Advise male patients not to donate semen during treatment with TEMODAR and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ].

5.6 Exposure to Opened Capsules Advise patients not to open, chew or dissolve the contents of the TEMODAR capsules. Swallow capsules whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membranes. In case of powder contact, wash affected area with water immediately [see Dosage and Administration (2.4) ] . If TEMODAR capsules must be opened or the contents must be dissolved, this should be done by a professional trained in safe handling of hazardous drugs using appropriate equipment and safety procedures.

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Pneumocystis Pneumonia [see Warnings and Precautions (5.3) ] Secondary Malignancies [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥20%) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10%) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Glioblastoma The safety of TEMODAR was evaluated in study MK-7365-051 [see Clinical Studies (14.1) ]. Severe or life-threatening adverse reactions occurred in 49% of patients treated with TEMODAR; the most common were fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). The most common adverse reactions (≥20%) in patients treated with TEMODAR were alopecia, fatigue, nausea, anorexia, headache, constipation, and vomiting. Table 3 summarizes the adverse reactions in MK-7365-051. TABLE 3: Adverse Reactions (≥10%) in Patients with Newly Diagnosed Glioblastoma Adverse Reactions Concomitant Use Phase Maintenance Use Phase Radiation Therapy and TEMODAR N=288 One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMODAR. Radiation Therapy Alone N=285 TEMODAR N=224 All Grades (%) Grade ≥3 (%) All Grades (%) Grades ≥3 (%) All Grades (%) Grade ≥3 (%) Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. Skin and Subcutaneous Tissue Alopecia 69 0 63 0 55 0 Rash 19 1 15 0 13 1 General Fatigue 54 7 49 5 61 9 Anorexia 19 1 9 <1 27 1 Headache 19 2 17 4 23 4 Gastrointestinal System Nausea 36 1 16 <1 49 1 Vomiting 20 <1 6 <1 29 2 Constipation 18 1 6 0 22 0 Diarrhea 6 0 3 0 10 1 Central and Peripheral Nervous System Convulsions 6 3 7 3 11 3 Clinically relevant adverse reactions in <10% of patients are presented below: Central & Peripheral Nervous System: memory impairment, confusion Eye: v ision blurred Gastrointestinal System: stomatitis, abdominal pain General: weakness, dizziness Immune System: allergic reaction Injury: radiation injury not otherwise specified Musculoskeletal System: arthralgia Platelet, Bleeding, & Clotting: thrombocytopenia Psychiatric: insomnia Respiratory System: coughing, dyspnea Special Senses Other: taste perversion Skin & Subcutaneous Tissue: dry skin, pruritus, erythema When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients. Newly Diagnosed Anaplastic Astrocytoma The safety of TEMODAR for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma was derived from published literature [see Clinical Studies (14.2) ]. The safety of TEMODAR for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was consistent with the known safety profile of TEMODAR. Refractory Anaplastic Astrocytoma The safety of TEMODAR was evaluated in study MK-7365-006 [see Clinical Studies (14.2) ]. The most common adverse reactions (≥20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions. Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in MK-7365-006. TABLE 4: Adverse Reactions (≥10%) in Patients with Refractory Anaplastic Astrocytoma Adverse Reactions TEMODAR N=158 All Reactions (%) Grades 3-4 (%) Gastrointestinal System Nausea 53 10 Vomiting 42 6 Constipation 33 1 Diarrhea 16 2 General Headache 41 6 Fatigue 34 4 Asthenia 13 6 Fever 13 2 Central and Peripheral Nervous System Convulsions 23 5 Hemiparesis 18 6 Dizziness 12 1 Coordination abnormal 11 1 Amnesia 10 4 Insomnia 10 0 Cardiovascular Edema peripheral 11 1 Resistance Mechanism Infection viral 11 0 Clinically relevant adverse reactions in <10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric : anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal This term includes blurred vision; visual deficit; vision changes; and vision troubles. TABLE 5: Grade 3 to 4 Hematologic Laboratory Abnormalities That Worsened from Baseline in Patients with Refractory Anaplastic Astrocytoma TEMODAR Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. , Denominator range= 142, 158 (%) Decreased lymphocytes 55 Decreased platelets 19 Decreased neutrophils 14 Decreased leukocytes 11 Decreased hemoglobin 4 Hematological Toxicities for Advanced Gliomas In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC <0.5 × 10 9 /L) and thrombocytopenia (<20 × 10 9 /L) than males 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 10% (6/63) of patients >70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. Injection Site Reactions Adverse reactions that were reported in 35 patients who received TEMODAR for injection were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TEMODAR. 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 : Toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune System : Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMODAR and, in some cases, recurred upon rechallenge. Hematopoietic : Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary : Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Infections : Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary : Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine : Diabetes insipidus.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , TEMODAR can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to TEMODAR during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of TEMODAR to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data ) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions.

8.2 Lactation There are no data on the presence of TEMODAR or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed children, advise women not to breastfeed during treatment with TEMODAR and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential TEMODAR can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TEMODAR [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TEMODAR and for 6 months after the last dose. Males Because of the potential for embryofetal toxicity and genotoxic effects on sperm cells, advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with TEMODAR and for 3 months after the last dose [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ] . Advise male patients not to donate semen during treatment with TEMODAR and for 3 months after the last dose. Infertility TEMODAR may impair male fertility [see Nonclinical Toxicology (13.1) ] . Limited data from male patients show changes in sperm parameters during treatment with TEMODAR; however, no information is available on the duration or reversibility of these changes.

8.4 Pediatric Use Safety and effectiveness of TEMODAR have not been established in pediatric patients. Safety and effectiveness of TEMODAR capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to 18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. 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 adverse reaction profile in pediatric patients was similar to adults.

8.5 Geriatric Use In MK-7365-051, 15% of patients with newly diagnosed glioblastoma were 65 years and older. This study did not include sufficient numbers of patients aged 65 years and older to determine differences in effectiveness from younger patients. No overall differences in safety were observed between patients ≥65 years and younger patients. The CATNON trial did not include sufficient numbers of patients aged 65 years and older to determine differences in safety or effectiveness when compared to younger patients. In MK-7365-006, 4% of patients with refractory anaplastic astrocytoma were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger patients. Patients 70 years and older had a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients >70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred.

8.6 Renal Impairment No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 [see Clinical Pharmacology (12.3) ] . The recommended dose of TEMODAR has not been established for patients with severe renal impairment (CLcr <36 mL/min/m 2 ) or for patients with end-stage renal disease on dialysis.

8.7 Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child Pugh class A and B) [see Clinical Pharmacology (12.3) ] . The recommended dose of TEMODAR has not been established for patients with severe hepatic impairment (Child-Pugh class C).

Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to DNA alkylation, mainly at the O 6 and N 7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death.