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temozolomide 5 mg capsule generic temodar

In stock Manufacturer ACCORD HEALTHCA 16729004854
$1.47 / Capsule

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Uses

Brain Tumors

Glioblastoma Multiforme

Temozolomide is used concomitantly with radiation therapy for the treatment of newly diagnosed glioblastoma multiforme in adults; temozolomide also is used as maintenance therapy for glioblastoma multiforme.

The current indication is based on a randomized trial involving 573 patients with newly diagnosed glioblastoma multiforme. Treatment consisted of temozolomide 75 mg/m once daily with radiation therapy for 42 days (up to a maximum of 49 days) followed by a 4-week rest period and then maintenance therapy with up to 6 cycles of temozolomide (150 or 200 mg/m) on days 1-5 of every 28-day cycle; or radiation therapy alone. Salvage therapy with temozolomide was administered upon disease progression to 22% of patients receiving initial therapy with temozolomide and radiation therapy and 57% of patients receiving initial therapy with radiation therapy alone.

Overall survival was prolonged (unadjusted hazard ratio for death: 0.63) and median survival was increased by 2.5 months (14.6 versus 12.1 months) in patients receiving concomitant temozolomide and radiation therapy followed by maintenance therapy with temozolomide compared with those receiving radiation therapy alone as initial therapy for glioblastoma multiforme. Nausea (36 versus 16%), vomiting (20 versus 6%), anorexia (19 versus 9%), constipation (18 versus 6%), and thrombocytopenia (4 versus 1%) occurred more frequently in patients receiving concomitant temozolomide and radiation therapy than in those receiving radiation therapy alone.

Anaplastic Astrocytoma

Temozolomide is used in the treatment of refractory anaplastic astrocytoma in adults whose disease has progressed after initial therapy with a nitrosourea and procarbazine. The current indication is based on tumor response rates in this population from an uncontrolled phase 2 study. In a single-arm, multicenter study in 162 patients with relapsed anaplastic astrocytoma who had a baseline Karnofsky performance status of 70 or greater, efficacy in a subgroup of 54 patients with refractory disease (i.e., progression following treatment with a nitrosourea and procarbazine) was demonstrated by an overall (complete plus partial) tumor response rate of 22% and a complete response rate of 9%. Median durations of all responses and complete responses were 50 and 64 weeks, respectively. Progression-free survival at 6 and 12 months was 45 and 29%, respectively; median progression-free survival was 4.4 months; 12-month overall survival was 65%; and median overall survival was 15.9 months.

Dosage and Administration

General

Temozolomide is administered orally or by IV infusion.

The recommended dosage of temozolomide by IV infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence of oral and IV doses of temozolomide has been established only when temozolomide for injection is administered by IV infusion over 90 minutes; infusion over a shorter or longer duration may result in suboptimal dosing or an increase in infusion-related adverse reactions.

Opportunistic infections, such as Pneumocystis jiroveci (formerly P. carinii) pneumonia (PCP), may occur in patients receiving temozolomide. The risk of PCP is higher when temozolomide is administered as a longer dosage regimen. Prophylaxis for PCP (e.g., inhaled pentamidine or oral co-trimoxazole) is required for all patients receiving concomitant temozolomide and radiation therapy for the 42-day regimen. For patients experiencing lymphocytopenia during the concomitant phase of therapy, PCP prophylaxis should be continued until recovery from lymphocytopenia occurs. Regardless of the regimen, all patients receiving temozolomide, particularly those receiving concomitant corticosteroids, should be monitored closely for the development of PCP.

Reconstitution and Administration

When given orally, temozolomide is administered once daily and should be swallowed intact with a full glass of water. If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation of capsule contents or contact with the skin or mucous membranes. The manufacturer recommends use of gloves and safety glasses to avoid exposure in case of breakage of the capsules. Although the drug may be administered with food, administration on an empty stomach may reduce the incidence of nausea and vomiting. Because food may decrease the rate and extent of absorption of temozolomide, the drug should be administered in a consistent manner relative to food intake.(See Advice to Patients.) Bedtime administration may be advisable. Antiemetics may be administered prior to and/or following temozolomide administration.

Based on the dose prescribed, the number of each strength capsules needed (e.g., for a dose of 275 mg daily for 5 days, dispense five 250-mg capsules, five 20-mg capsules, and five 5-mg capsules) should be determined. Each strength of capsules should be dispensed in a separate container. Each container should be labeled with the strength per capsule and with the appropriate number of capsules to be taken each day. The patient should be instructed to take the appropriate number of capsules from each container to equal the total daily dose.

Temozolomide for injection should be stored at 2-8°C and must be reconstituted prior to administration. If vials are accidentally opened or damaged, precautions should be taken to avoid inhalation of vial contents or contact with the skin or mucous membranes. The manufacturer recommends use of gloves and safety glasses to avoid exposure in case of breakage of the vial. Prior to reconstitution, temozolomide for injection should be brought to room temperature. Temozolomide for injection should be reconstituted by adding 41 mL of sterile water for injection to a vial labeled as containing 100 mg of temozolomide to provide a solution containing 2.5 mg/mL of the drug; reconstituted vials should be gently swirled but not shaken. The reconstituted solution may be stored at room temperature (25°C) for up to 14 hours (including infusion time). Reconstituted temozolomide for injection should be inspected visually for particulate matter prior to administration; the drug should be discarded if the solution contains visible particulate matter. The reconstituted solution should not be further diluted prior to administration. Using aseptic technique, up to 40 mL from each vial of reconstituted solution needed to reach the calculated dosage should be transferred to an empty 250-mL polyvinylchloride (PVC) infusion bag; compatibility studies with non-PVC bags have not been conducted. Temozolomide for injection should be administered by IV infusion over 90 minutes using an infusion pump. IV lines should be flushed before and after each temozolomide infusion. The manufacturer states that other drugs should not be infused through the same IV line.

Dosage

Glioblastoma Multiforme

Concomitant Phase

During the concomitant phase of therapy, the initial oral or IV dosage of temozolomide for the treatment of newly diagnosed glioblastoma multiforme is 75 mg/m daily. Temozolomide is to be administered daily for 42 days concomitantly with focal radiation therapy (60 Gy administered in 30 fractions). No dosage reductions for temozolomide are recommended during the concomitant phase of therapy, but interruptions or discontinuance may be required according to toxicity.

A complete blood cell count (CBC) should be obtained prior to treatment and weekly during treatment. Criteria for the continuance of temozolomide dosing are as follows: absolute neutrophil count (ANC) of at least 1500/mm, platelet count of at least 100,000/mm, and nonhematologic toxicities that are grade 1 or less in severity (except alopecia, nausea, and vomiting). If these criteria are met, the daily temozolomide dose should be continued throughout the 42-day concomitant phase of therapy (for up to 49 days) in the treatment period.

Temozolomide dosing should be interrupted for any of the following criteria: ANC of 500-1499/mm, platelet count of 10,000-99,000/mm, or any grade 2 nonhematologic toxicity (except alopecia, nausea, and vomiting). Temozolomide therapy may be resumed when all of the criteria for the continuance of temozolomide dosing are met.

Temozolomide dosing should be discontinued for any of the following criteria: ANC less than 500/mm, platelet count less than 10,000/mm, or any grade 3 or 4 nonhematologic toxicity (except alopecia, nausea, and vomiting). Patients experiencing any of these toxicities should not receive any further concomitant therapy with temozolomide and are not eligible for maintenance therapy.

Maintenance Phase

For patients who complete the concomitant phase of therapy, the maintenance phase of therapy is initiated after a 4-week rest period following completion of temozolomide and radiation therapy. The maintenance phase of therapy consists of up to 6 cycles of temozolomide therapy as tolerated.

During the maintenance phase of therapy, the temozolomide dose is administered once daily for 5 days followed by a 23-day rest period for a 28-day cycle. The initial oral or IV dosage of temozolomide (for cycle 1) is 150 mg/m once daily for 5 days followed by a 23-day rest period. The dose level for subsequent cycles of therapy depends on toxicity.

A CBC should be obtained prior to treatment on day 1 and on day 22 (21 days following the first dose of temozolomide) or within 48 hours of that day and then weekly, and dosing should not resume until the dosing criteria for continuance of therapy are met. Criteria for the continuance of maintenance temozolomide dosing are as follows: ANC that exceeds 1500/mm, platelet count that exceeds 100,000/mm, and nonhematologic toxicities that are grade 2 or less in severity (except alopecia, nausea, and vomiting).

For patients who meet the dosing criteria following cycle 1, the dosage of temozolomide may be increased to 200 mg/m once daily for 5 days for cycle 2 and maintained at this level for each subsequent cycle for which the dosing criteria are met. For patients who experience toxicity during cycle 1, the temozolomide dose should not be increased for cycle 2 or any subsequent cycle of therapy.

The temozolomide dose (administered once daily for 5 days) should be reduced by 50 mg/m (for example, from 150 mg/m to 100 mg/m, or from 200 mg/m to 150 mg/m) for the subsequent cycle of therapy for any of the following criteria: ANC less than 1000/mm, platelet count less than 50,000/mm, or any grade 3 nonhematologic toxicity (except alopecia, nausea, and vomiting). Dose reductions for the next cycle of therapy should be based on the lowest blood count or the worst nonhematologic toxicity that occurred during the previous cycle of therapy.

Temozolomide dosing should be discontinued for any of the following criteria: the dose reduction for toxicity during a previous cycle would result in a dose lower than temozolomide 100 mg/m for the subsequent cycle, recurrence of the same grade 3 nonhematologic toxicity (except alopecia, nausea, and vomiting) following dose reduction, or any grade 4 nonhematologic toxicity (except alopecia, nausea, and vomiting).

Anaplastic Astrocytoma

The initial oral or IV dosage of temozolomide for the treatment of refractory anaplastic astrocytoma in adults is 150 mg/m daily for 5 consecutive days of a 28-day treatment cycle.

Subsequent dosage is adjusted based on nadir platelet and ANC during the previous cycle and on ANC and platelet counts on day 29 (i.e., day 1 of the next cycle). A CBC should be obtained prior to treatment on day 1 and on day 22 (i.e., 21 days after the first dose) of the cycle or within 48 hours of that day and weekly until the ANC and platelet counts exceed 1500 and 100,000/mm, respectively. The next cycle should be withheld until these counts are exceeded. If both nadir and day-of-dosing ANC and platelet counts exceed 1500 and 100,000/mm, respectively, then temozolomide dosage may be increased to 200 mg/m daily for 5 consecutive days of the next 28-day cycle. If either the ANC is between 1000-1500/mm or the platelet count is between 50,000-100,000/mm during any cycle, therapy should be postponed until the ANC and platelet counts exceed 1500 and 100,000/mm, respectively, at which time a dosage of 150 mg/m daily for 5 consecutive days should be used. If either the ANC or platelet count declines to less than 1000 or 50,000/mm, respectively, during any cycle, dosage for the next cycle should be reduced by 50 mg/m daily, but not to less than the lowest recommended dosage of 100 mg/m daily.

Temozolomide therapy can be continued until disease progression occurs. Although therapy was continued for up to 2 years in the clinical study establishing efficacy, the optimum duration is not known.

Special Populations

Renal and Hepatic Impairment

Use with caution in patients with severe hepatic or renal impairment. Pharmacokinetics in patients with mild to moderate hepatic impairment is similar to those in patients with normal hepatic function. Drug clearance is not affected by renal function in patients with creatinine clearances of 36-130 mL/minute per m.

Geriatric and Female Patients

Among patients receiving temozolomide for anaplastic astrocytoma, geriatric patients and women had a greater risk of developing myelosuppression, but the manufacturer makes no specific recommendations regarding dosage adjustment other than usual adjustment for ANC and platelet counts.(See Warnings: Hematologic Effects, in Cautions.)

Dosage should be selected with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions

Contraindications

Known hypersensitivity (e.g., urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome) to temozolomide or any ingredient in the formulation. Known hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).

Warnings/Precautions

Warnings

Hematologic Effects

Thrombocytopenia and neutropenia are dose-limiting toxicities for all patients receiving temozolomide. Prolonged pancytopenia, which may result in aplastic anemia and in some cases has been fatal, has been reported. In some cases, assessment has been complicated by exposure to concomitant medications (e.g., carbamazepine, phenytoin, co-trimoxazole) which may be associated with aplastic anemia.

Among patients receiving temozolomide for newly diagnosed glioblastoma multiforme, grade 3 or 4 platelet abnormalities including thrombocytopenia occurred in 14% and grade 3 or 4 neutrophil abnormalities including neutropenia occurred in 8%.

Among patients receiving temozolomide for anaplastic astrocytoma, greater incidence of grade 4 thrombocytopenia and/or neutropenia in women and geriatric patients. Occurs late in the treatment cycle; nadirs occur at a median of 26 days for platelets and 28 days for neutrophils. Usually develops during the first few cycles of temozolomide therapy, resolves within 14 days, and is not cumulative. Hospitalization, blood transfusion, or drug discontinuance for myelosuppression may be required. Pancytopenia, leukopenia, and anemia also reported. Periodic blood cell count monitoring and possible dosage adjustment, schedule interruption, or discontinuance of therapy required.(See Dosage and Administration: General.)

Carcinogenic Effects

Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Temozolomide may be associated with a risk of Pneumocystis jiroveci (formerly known as Pneumocystis carinii) pneumonia (PCP), particularly with longer dosage regimens. All patients (particularly those receiving corticosteroids) should be monitored closely for development of PCP (regardless of regimen). PCP prophylaxis is required for all patients receiving temozolomide in conjunction with radiation therapy for glioblastoma multiforme; prophylaxis in patients who develop lymphocytopenia should be continued until lymphocytopenia resolves (grade 1 or less).(See Dosage and Administration: General.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. No adequate and well-controlled studies to date in humans. Pregnancy should be avoided during therapy. If used during pregnancy, apprise of potential fetal hazard.

Hepatic Effects

Reactivation of hepatitis B resulting in death has been reported in a patient receiving temozolomide for glioblastoma. Hepatitis screening and prophylactic therapy with antiviral agents as clinically indicated should be considered in patients receiving temozolomide.

Sensitivity Reactions

Allergic reactions, including cases of anaphylaxis and erythema multiforme, have been reported.

General Precautions

Dispensing

Patients may need to take combinations of temozolomide capsules of different strengths to receive the correct daily dose.(See Dosage and Administration: Reconstitution and Administration.) To minimize the risk of inappropriate dosing, the clinician or pharmacist should provide written instructions for the dosage schedule.

Specific Populations

Pregnancy

Category D. (See Warnings: Fetal/Neonatal Morbidity and Mortality, in Cautions.)

Lactation

Not known whether temozolomide is distributed in milk; discontinue nursing because of potential risk in nursing infants.

Pediatric Use

Safety and efficacy in pediatric patients have not been established. Efficacy was not demonstrated in open-label studies of children 3-18 years of age receiving temozolomide mostly for CNS tumors. Similar toxicity was observed in pediatric patients and adults.

Geriatric Use

Experience in those 65 years of age and older insufficient to determine whether they respond differently than younger adults. Caution is advised.(See Warnings: Hematologic Effects, in Cautions and also see Special Populations: Geriatric and Female Patients, in Dosage and Administration.)

An increased incidence of grade 4 thrombocytopenia and/or neutropenia has been reported in patients 70 years of age or older compared with younger patients receiving temozolomide for refractory anaplastic astrocytoma.

Similar toxicity in geriatric patients (65 years of age or older) and younger patients receiving temozolomide for newly diagnosed glioblastoma multiforme.

Severe Hepatic or Renal Impairment

Use with caution.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Among patients receiving temozolomide for newly diagnosed glioblastoma multiforme, alopecia, fatigue, nausea, vomiting, anorexia, headache, and constipation were most frequent. About half (49%) of patients experienced at least one severe or life-threatening adverse effect, most commonly fatigue (13%), convulsions (6%), headache (5%), or thrombocytopenia (5%).

Among patients receiving temozolomide for anaplastic astrocytoma, nausea, vomiting, headache, and fatigue most frequent and clearly drug related. Adverse effects usually were mild to moderate in severity and self-limiting, with nausea and vomiting controllable with antiemetics. Nausea and vomiting were severe in 10 and 6%, respectively. Myelosuppression also clearly drug related.(See Warnings: Hematologic Effects, in Warnings/Precautions.)

Among patients receiving temozolomide by IV infusion, adverse reactions probably related to treatment that were not reported in patients receiving oral temozolomide include pain, irritation, pruritus, warmth, swelling, erythema at the injection site, petechiae, and hematoma.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) are only minimally metabolized by CYP isoenzymes. Pharmacokinetic interactions with drugs affecting hepatic microsomal enzymes unlikely.

Carbamazepine

Unlikely to affect temozolomide clearance. Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.

Co-trimoxazole

Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.

Dexamethasone

Unlikely to affect temozolomide clearance.

Histamine H2-receptor Antagonists

Unlikely to affect temozolomide clearance. Ranitidine did not affect maximum plasma concentrations or AUC of temozolomide or MTIC.

Ondansetron

Unlikely to affect temozolomide clearance.

Phenobarbital

Unlikely to affect temozolomide clearance.

Phenytoin

Unlikely to affect temozolomide clearance. Possible additive hematologic toxicity (i.e., aplastic anemia); concomitant administration may complicate assessment of hematologic toxicity.

Prochlorperazine

Unlikely to affect temozolomide clearance.

Valproic Acid

Pharmacokinetic interaction (decreased temozolomide clearance by about 5%). Clinical importance unknown.

Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration, with nearly 100% bioavailability. Peak plasma concentrations usually are attained within 1 hour.

Bioequivalence of temozolomide (with respect to both peak plasma concentration and area under the concentration-time curve (AUC)) administered orally or as an IV infusion over 90 minutes at a dosage of 150 mg/m has been demonstrated.

Food

Food decreases rate and extent of absorption after oral administration. Modified high fat breakfast decreased mean peak plasma temozolomide concentrations (32%) and AUC (9%).

Distribution

Extent

Efficiently crosses the blood brain barrier.

It is not known whether temozolomide is distributed into human milk.

Plasma Protein Binding

Approximately 15%.

Elimination

Metabolism

Temozolomide is a prodrug; undergoes rapid, nonenzymatic hydrolysis at physiologic pH to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and to methylhydrazine.

CYP isoenzymes play only a minor role in metabolism of temozolomide and MTIC.

Elimination Route

About 38% of administered dose is recovered over 7 days, principally in urine with <1% in feces.

Half-life

Approximately 1.8 hours. Apparent half-lives for metabolites MTIC and AIC are 2.1 and 2.6 hours, respectively.

Special Populations

In patients with mild to moderate hepatic impairment, pharmacokinetic profile resembles that in patients with normal hepatic function.

Temozolomide clearance is not affected by renal function in patients with Clcr 36-130 mL/minute per m. Not studied in patients with severe renal impairment (Clcr<36 mL/minute per m) or patients receiving dialysis.

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