Temodar Drug Information

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

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

Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer TEMODAR either orally or intravenously once daily for 42 to 49 consecutive days during the concomitant use phase with focal radiotherapy, and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance use phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant use phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less. Focal radiotherapy includes the tumor bed or resection site with a 2 to 3 cm margin.

Other administration schedules have been used. Obtain a complete blood count weekly. The recommended dosage modifications due to adverse reactions during concomitant use phase are provided in Table 1.

If the dose is not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6. Do not start the next cycle until the ANC and platelet count exceed these levels. The recommended dosage modifications due to adverse reactions during the maintenance use phase are provided in Table 2.

If TEMODAR is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMODAR in patients who are unable to tolerate a dose of 100 mg/m 2 per day. TABLE 2: Dosage Modifications Due to Adverse Reactions During Maintenance and Adjuvant Treatment

Recommended Dosage and Dosage Modifications for Anaplastic Astrocytoma Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma Beginning 4 weeks after the end of radiotherapy, administer TEMODAR orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. Cycles per day on days 1 to 5 if patient experienced no or minimal toxicity in Cycle 1. If the dose was not escalated at the onset of Cycle 2, do not increase the dose during Cycles 3 to 6.

Continue TEMODAR until disease progression or unacceptable toxicity.

Preparation and Administration TEMODAR is a hazardous drug

Follow applicable special handling and disposal procedures. 1 TEMODAR capsules Take TEMODAR at the same time each day. Administer TEMODAR consistently with respect to food (fasting vs. nonfasting). To reduce nausea and vomiting, take TEMODAR on an empty stomach or at bedtime and consider antiemetic therapy prior to and following TEMODAR administration.

Swallow TEMODAR capsules whole with water. Advise patients not to open, chew, or dissolve the contents of the capsules. If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes.

In case of powder contact, wash the affected area with water immediately. TEMODAR for injection Bring the vial to room temperature prior to reconstitution with Sterile Water for Injection. Reconstitute the vial with 41 mL of Sterile Water for Injection to yield a TEMODAR solution with a concentration of 2.5 mg/mL temozolomide.

Reconstituted TEMODAR is a clear solution and essentially free of visible particles. Gently swirl vial. Do not shake.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if particulate matter or discoloration is observed. Do not further dilute the reconstituted solution.

Store reconstituted solution at room temperature (25°C ). Discard reconstituted solution if not used within 14 hours, including infusion time. Withdraw up to 40 mL from each vial to make up the total dose and discard any unused portion.

Transfer reconstituted solution from each vial into an empty 250 mL infusion bag. Administer reconstituted solution using a pump over a period of 90 minutes. Administer TEMODAR by intravenous infusion only.

Infusion over a shorter or longer period of time may result in suboptimal dosing. Flush the lines before and after each infusion. TEMODAR for injection may be administered in the same intravenous line with 0.9% Sodium Chloride injection only.

Because no data are available on the compatibility of TEMODAR for injection with other intravenous substances or additives, do not infuse other medications simultaneously through the same intravenous line.

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. 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 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.

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. 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 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. In the entire safety database for which hematologic data exist (N=932), of patients >70 years 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.

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.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, 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 respectively.

Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 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.

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, high grade astrocytoma, low grade astrocytoma, brain stem glioma, ependymoma, other CNS tumors, and non-CNS tumors. The adverse reaction profile in pediatric patients was similar to adults.

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.

Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death.

In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.