Temozolomide

Pregnancy Category: D

Lactation: Not known if excreted in breast milk, do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism Of Action

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 alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.

Pharmacokinetics

Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax ) achieved in a median T max of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median T max increased by 2-fold (from 1-2.25 hours) when temozolomide was administered after a modified high-fat breakfast.

A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m² TEMODAR for injection administered over 90 minutes is bioequivalent to 150 mg/m² TEMODAR oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m², the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m², the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m², the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg·hr/mL and 891 ng·hr/mL, respectively. Following a single oral dose of 150 mg/m², the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg·hr/mL and 864 ng·hr/mL, respectively.

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%.

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.

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/m² . 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/m²/day.

A population pharmacokinetic analysis indicated that age (range: 19-78 years) has no influence on the pharmacokinetics of temozolomide.

A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.

The effect of race on the pharmacokinetics of temozolomide has not been studied.

A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.

A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m² 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/m²). Caution should be exercised when TEMODAR is administered to patients with severe renal impairment [see Use in Special Populations]. TEMODAR has not been studied in patients on dialysis.

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].

Effect of Other Drugs on Temozolomide Pharmacokinetics

In a multiple-dose study, administration of TEMODAR Capsules with ranitidine did not change the Cmax 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].

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.

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/m²). These changes were most commonly seen at doses where mortality was observed.

Clinical Studies

Newly Diagnosed Glioblastoma Multiforme

Five hundred and seventy-three patients were randomized to receive either TEMODAR (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the TEMODAR+RT arm received concomitant TEMODAR (75 mg/m²) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of TEMODAR alone (150 or 200 mg/m²) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2to 3-cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ+RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.

At the time of disease progression, TEMODAR was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the TEMODAR+RT arm.

The addition of concomitant and maintenance TEMODAR 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=0.52-0.75) with a log-rank P < 0.0001 in favor of the TEMODAR arm. The median survival was increased by 2.5 months in the TEMODAR arm.

FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population)

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 (19-76). 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 (4.2-75.4).

TEMODAR Capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m²/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was greater than or equal to 1.5 x 109/L (1500/μL) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 x 109/L (100,000/μL), the TEMODAR dose was increased to 200 mg/m²/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: 16-114 weeks) and the median duration of complete responses was 64 weeks (range: 52-114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%-58%) and progression-free survival at 12 months was 29% (95% CI: 16%-42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%-86%) and 12-month overall survival was 65% (95% CI: 52%-78%). Median overall survival was 15.9 months.

It is not known if temozolomide crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using temozolomide.

• Temozolomide may be taken by mouth as a capsule at home, or you may receive temozolomide by injection into a vein (intravenous). Your doctor will decide the best way for you to take temozolomide.

There are two common dosing schedules for taking temozolomide.

• Some people take temozolomide for 42 days in a row (possibly 49 days depending on side effects) with radiation treatment. This is one cycle of treatment. After this, you may have "maintenance" treatment. Your doctor may prescribe 6 more cycles of temozolomide. For each of these cycles, you take temozolomide one time each day for 5 days in a row and then you stop taking it for the next 23 days. This is a 28-day maintenance treatment cycle.
• Another way to take temozolomide is to take it one time each day for 5 days in a row only, and then you stop taking it for the next 23 days. This is one cycle of treatment (28 days). Your doctor will watch your progress on temozolomide and decide how long you should take it. You might take temozolomide until your tumor gets worse or for possibly up to 2 years.
• Your dose is based on your height and weight, and the number of treatment cycles will depend on how you respond to and tolerate this treatment.
• Your doctor may modify your schedule based on how you tolerate the treatment.
• If your doctor prescribes a treatment regimen that is different from the information provided here, make sure you follow the specific instructions given to you by your doctor.

Oral:

• Take temozolomide capsules exactly as prescribed.
• Temozolomide capsules come in different strengths. Each strength has a different color cap. Your doctor may prescribe more than one strength of temozolomide capsules for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many capsules you need to take on each day of your treatment, and what strengths to take. This may be different whenever you start a new cycle.
• Talk to your doctor before you take your dose if you are not sure how much to take. This will help to prevent taking too much temozolomide and decrease your chances of getting serious side effects.
• Take each day's dose of temozolomide capsules at one time, with a full glass of water.
• Swallow temozolomide capsules whole. Do not chew, open, or split the capsules.
• If temozolomide capsules are accidentally opened or damaged, be careful not to breathe in (inhale) the powder from the capsules or get the powder on your skin or mucous membranes (for example, in your nose or mouth). If contact with any of these areas happens, flush the area with water.
• If you vomit temozolomide capsules, do not take any more capsules. Wait and take your next planned dose.
• The medicine is used best by your body if you take it at the same time every day in relation to a meal.
• To lessen nausea, try to take temozolomide on an empty stomach or at bedtime. Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to lessen side effects with temozolomide.
• See your doctor regularly to check your progress. Your doctor will check you for side effects that you might not notice.
• If you miss a dose of temozolomide, talk with your doctor for instructions about when to take your next dose of temozolomide.
• Call your doctor right away if you take more than the prescribed amount of temozolomide. It is important that you do not take more than the amount of temozolomide prescribed for you.

Injectable

• You will receive temozolomide as an infusion directly into your vein. Your treatment will take about 90 minutes.
• Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to relieve side effects with temozolomide.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Newly diagnosed glioblastoma multiforme: 75 mg/m² for 42 days along with radiotherapy followed by starting maintenance dose of 150 mg/m² once daily for Days 1–5 of a 28-day cycle of temozolomide for 6 cycles.

Refractory anaplastic astrocytoma: Starting dose of 150 mg/m² once daily for 5 consecutive days per 28-day treatment cycle.

Temozolomide interferes with the development of cancer cells, slowing their growth and spread in the body.

Temozolomide is used together with radiation therapy to treat certain types of brain tumor in adults.

Temozolomide is usually given after other cancer medicines have been tried without success.

Temozolomide may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not take this medicine if you are allergic to temozolomide or to another cancer medication called dacarbazine (DTIC).

To make sure temozolomide is safe for you, tell your doctor if you have:

• liver disease; or

• kidney disease.

Using temozolomide may increase your risk of developing certain types of bone marrow cancer. Ask your doctor about your specific risk.

Do not use temozolomide if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Use birth control to prevent pregnancy while you are receiving temozolomide, whether you are a man or a woman. Temozolomide use by either parent may cause birth defects.

It is not known whether temozolomide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Usual Adult Dose for Anaplastic Astrocytoma:

Oral:
Initial Dose: 150 mg/m2 orally once a day
Maintenance Dose: 200 mg/m2 orally once a day

Duration of Therapy: 5 consecutive days per 28-day treatment cycle

IV:
Initial Dose: 150 mg/m2 IV over 90 minutes once a day
Maintenance Dose: 200 mg/m2 IV over 90 minutes once a day

Duration of Therapy: 5 consecutive days per 28-day treatment cycle

Comments:
-Dose should only be increased to 200 mg/m2 if both the nadir and day of dosing (Day 29, Day 1 of next cycle), the ANC is greater than or equal to 1.5 x 10(9)/L and platelet count is greater than or equal to 100 x 10(9)/L.
-A complete blood count should be obtained on day 22 or within 48 hours of that day of each cycle and weekly until the ANC is above 1.5 x 10(9)/L and the platelet count is above 100 x 10(9)/L.
-The next cycle should not be started until the ANC and platelet count exceed the above levels.
-In clinical trial, treatment could be continued for a maximum of 2 years. Optimum duration of therapy is not known.
-Treatment with this drug may be continued until disease progression.

Use:
-Refractory anaplastic astrocytoma with disease progression on a drug regimen containing nitrosourea and procarbazine.

Usual Adult Dose for Glioblastoma Multiforme:

Concomitant phase with focal radiotherapy:

Oral:
75 mg/m2 orally once a day

Duration of therapy: 42 days

IV:
75 mg/m2 IV over 90 minutes once a day

Duration of therapy: 42 days

Comments:
-No dose reductions are recommended during the concomitant phase.
-Dose interruptions or discontinuation may occur based on toxicity.
-Therapy should continue throughout the 42-day concomitant phase up to 49 days if all of the following conditions are met: ANC greater than or equal to 1.5 x 10(9)/L, platelet count greater than 100 x 10(9)/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1.
-A complete blood count should be obtained weekly during treatment.
-Pneumocystis pneumonia prophylaxis is required during the concomitant administration of this drug and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery.

Monotherapy Phase:
Cycle 1:

Oral:
150 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

IV:
150 mg/m2 IV over 90 minutes once a day

Duration of therapy: 5 days followed by 23 days without treatment

Cycles 2-6:

Oral:
200 mg/m2 by mouth once a day

Duration of therapy: First 5 days of each cycle

IV:
200 mg/m2 IV over 90 minutes once a day

Duration of therapy: First 5 days of each cycle

Comments:
-At the start of cycle 2, the dose should be escalated to 200 mg/m2 if: CTC nonhematological toxicity for Cycle 1 is grade less than or equal to 2 (except for alopecia, nausea, and vomiting), ANC is greater than or equal to 1.5 x 10(9)/L, and the platelet count is greater than or equal to 100 x 10(9)/L.
-The dose remains at 200 mg/m2 for cycles 2 through 6 unless toxicity occurs.
-If the dose was not escalated at the beginning of cycle 2, escalation should not be done in subsequent cycles.
-Obtain a complete blood count on day 22 or within 48 hours of that day of each cycle and weekly until the ANC is greater than 1.5 x 10(9)/L and the platelet count is greater than 100 x 10(9)/L. The next cycle should not be started until the ANC and platelet levels exceed these numbers.
-Dose reductions should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle.

Use:
-Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

Usual Pediatric Dose for Anaplastic Astrocytoma:

Less than 3 years: Safety and efficacy have not been established

3 years or older:
Previously Untreated with Chemotherapy:

200 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

Previously Treated with Chemotherapy:

Initial Dose: 150 mg/m2 orally once a day

Maintenance Dose: 200 mg/m2 orally once a day

Duration of therapy: First 5 days of each treatment cycle

Comments:
-Dose in cycle 2 for patients previously treated with chemotherapy should be increased if there is no haematological toxicity.
-If the nadir on day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are greater than or equal to 1.5 × 10(9)/L and platelet counts are greater than or equal to 100 × 10(9)/L, the dose may be increased to 200 mg/m2 orally once daily 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 × 10(9)/L and the platelet count exceeds 100 × 10(9)/L. The next cycle should not be started until the ANC and platelet count exceed these levels.
-If the ANC falls to less than 1.0 × 10(9)/L or the platelet count is less than 50 × 10(9)/L during any cycle, the next cycle should be reduced by 50 mg/m2 , but not below 100 mg/m2 , the lowest recommended dose.
-Treatment may be continued until disease progression or a maximum of 2 years.

Use:
-Recurrent or progressive malignant glioblastoma multiforme or anaplastic astrocytoma

Usual Pediatric Dose for Glioblastoma Multiforme:

Less than 3 years: Safety and efficacy have not been established

3 years or older:
Previously Untreated with Chemotherapy:

200 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

Previously Treated with Chemotherapy:

Initial Dose: 150 mg/m2 orally once a day

Maintenance Dose: 200 mg/m2 orally once a day

Duration of therapy: First 5 days of each treatment cycle

Comments:
-Dose in cycle 2 for patients previously treated with chemotherapy should be increased if there is no haematological toxicity.
-If the nadir on day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are greater than or equal to 1.5 × 10(9)/L and platelet counts are greater than or equal to 100 × 10(9)/L, the dose may be increased to 200 mg/m2 orally once daily 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 × 10(9)/L and the platelet count exceeds 100 × 10(9)/L. The next cycle should not be started until the ANC and platelet count exceed these levels.
-If the ANC falls to less than 1.0 × 10(9)/L or the platelet count is less than 50 × 10(9)/L during any cycle, the next cycle should be reduced by 50 mg/m2 , but not below 100 mg/m2 , the lowest recommended dose.
-Treatment may be continued until disease progression or a maximum of 2 years.

Use:
-Recurrent or progressive malignant glioblastoma multiforme or anaplastic astrocytoma

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mechanism of Action

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 alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.

Pharmacokinetics

Absorption:

Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of Temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1 to 2.25 hours) when Temozolomide was administered after a modified high-fat breakfast.
 
Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for Temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single oral dose of 150 mg/m2, 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/m2. 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/m2/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/m2 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/m2). Caution should be exercised when Temozolomide is administered to patients with severe renal impairment [see Use in Specific 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 Cmax 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, H2-receptor antagonists, or phenobarbital on the clearance of orally administered Temozolomide.

1. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
2. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm.  2006; 63:1172–1193.
3. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.[3]
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology.

Safe Handling and Disposal

Care should be exercised in the handling and preparation of Temozolomide capsules. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the contents to avoid inhalation or contact with the skin or mucous membranes. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the capsules. Procedures for proper handling and disposal of anticancer drugs should be considered1 to 4. Several guidelines on this subject have been published.

How Supplied

Temozolomide capsules are supplied in amber glass bottles with child-resistant caps or child-resistant blister packs containing the following capsule strengths:

5 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “5 mg” on body and “890” on cap in green ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….………..NDC 47335-890-80

Bottles of 14’s with Child Resistant Cap………….... NDC 47335-890-21

Bottles of 20’s with Child Resistant Cap………….. NDC 47335-890-87

Unit-dose blister pack of 5 (1 × 5)... …….……….…NDC 47335-890-74

Unit-dose blister pack of 20 (4 × 5)... …….……..…NDC 47335-890-75

20 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “20 mg” on body and “891” on cap in golden ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….………...NDC 47335-891-80

Bottles of 14’s with Child Resistant Cap………….....  NDC 47335-891-21

Bottles of 20’s with Child Resistant Cap…………… NDC 47335-891-87

Unit-dose blister pack of 5 (1 × 5)... …….…………. NDC 47335-891-74

Unit-dose blister pack of 20 (4 × 5)... …….………... NDC 47335-891-75

100 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “100 mg” on body and “892” on cap in pink ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….………..NDC 47335-892-80

Bottles of 14’s with Child Resistant Cap………….... NDC 47335-892-21

Bottles of 20’s with Child Resistant Cap………….. NDC 47335-892-87

Unit-dose blister pack of 5 (1 × 5)... …….……….…NDC 47335-892-74

Unit-dose blister pack of 20 (4 × 5)... …….………...NDC 47335-892-75

140 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “140 mg” on body and “929” on cap in blue ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….………...NDC 47335-929-80

Bottles of 14’s with Child Resistant Cap…………….. NDC 47335-929-21

Bottles of 20’s with Child Resistant Cap…………… NDC 47335-929-87

Unit-dose blister pack of 5 (1 × 5)... …….…………..NDC 47335-929-74

Unit-dose blister pack of 20 (4 × 5)... …….…………NDC 47335-929-75

180 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “180 mg” on body and “930” on cap in brown ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….…….…..NDC 47335-930-80

Bottles of 14’s with Child Resistant Cap……….…..... NDC 47335-930-21

Bottles of 20’s with Child Resistant Cap…………… NDC 47335-930-87

Unit-dose blister pack of 5 (1 × 5)... …….…………..NDC 47335-930-74

Unit-dose blister pack of 20 (4 × 5)... …….…………NDC 47335-930-75

250 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “250 mg” on body and “893” on cap in black ink, containing white to light tan/light pink powder and are supplied as:

Bottles of 5’s with Child Resistant Cap…….………...NDC 47335-893-80

Bottles of 14’s with Child Resistant Cap…………..... NDC 47335-893-21

Bottles of 20’s with Child Resistant Cap…………… NDC 47335-893-87

Unit-dose blister pack of 5 (1 × 5)…….………..…….NDC 47335-893-74

Unit-dose blister pack of 20 (4 × 5)…………..………NDC 47335-893-75

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant containers as defined in USP/NF or retain in original bottle.

(te moe ZOE loe mide)

• SCH 52365
• TMZ

• Antineoplastic Agent, Alkylating Agent (Triazene)

Temozolomide is a prodrug which is rapidly and nonenzymatically converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]; this conversion is spontaneous, nonenzymatic, and occurs under physiologic conditions in all tissues to which it distributes. The cytotoxic effects of MTIC are manifested through alkylation (methylation) of DNA at the O6, N7 guanine positions which lead to DNA double strand breaks and apoptosis. Non-cell cycle specific.

Absorption

Oral: Rapid and complete

Distribution

Vd: Parent drug: 0.4 L/kg; penetrates blood-brain barrier; CSF levels are ~35% to 39% of plasma levels (Yung 1999)

Metabolism

Prodrug, hydrolyzed to the active form, MTIC; MTIC is eventually eliminated as CO2 and 5-aminoimidazole-4-carboxamide (AIC), a natural constituent in urine; CYP isoenzymes play only a minor role in metabolism (of temozolomide and MTIC)

Excretion

Urine (~38%; parent drug 6%); feces <1%

5.5 L/hour/m2; women have a ∼5% lower clearance than men (adjusted for body surface area); children 3-17 years have similar temozolomide clearance as adults

Time to Peak

Oral: Empty stomach: 1 hour; with food (high-fat meal): 2.25 hours

Half-Life Elimination

Mean: Parent drug: Children: 1.7 hours; Adults: 1.6-1.8 hours

Protein Binding

15%

A 10 mg/mL temozolomide oral suspension may be compounded in a vertical flow hood. Mix the contents of ten 100 mg capsules and 500 mg of povidone K-30 powder in a glass mortar; add 25 mg anhydrous citric acid dissolved in 1.5 mL purified water and mix to a uniform paste; mix while adding 50 mL Ora-Plus in incremental proportions. Transfer to an amber plastic bottle, rinse mortar 4 times with small portions of either Ora-Sweet or Ora-Sweet SF, and add quantity of Ora-Sweet or Ora-Sweet SF sufficient to make 100 mL. Store in plastic amber prescription bottles; label "shake well" and "refrigerate"; include the beyond-use date. Stable for 7 days at room temperature or 60 days refrigerated (preferred).

Temozolomide is associated with a moderate emetic potential (Dupuis 2011; Roila 2010); antiemetics are recommended to prevent nausea and vomiting.

Oral: Swallow capsules whole with a glass of water. Absorption is affected by food; therefore, administer consistently either with food or without food (was administered in studies under fasting and nonfasting conditions). May administer on an empty stomach and/or at bedtime to reduce nausea and vomiting. Do not repeat dose if vomiting occurs after dose is administered; wait until the next scheduled dose. Do not open or chew capsules; avoid contact with skin or mucous membranes if capsules are accidentally opened or damaged.

IV: Infuse over 90 minutes. Flush line before and after administration. May be administered through the same IV line as sodium chloride 0.9%; do not administer other medications through the same IV line.

The incidence of nausea/vomiting is decreased when taken on an empty stomach. Take capsules consistently either with food or without food (absorption is affected by food).

CBC with differential and platelets (prior to each cycle; weekly during glioma concomitant phase treatment; at or within 48 hours of day 22 and weekly until ANC >1,500/mm3 and platelets >100,000/mm3 for glioma maintenance and astrocytoma treatment). Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose.