TEMOZOLOMIDE BIOPHRM

Refractory anaplastic astrocytoma (WHO grade III) and Glioblastoma multiforme (WHO grade Intravenous) are primary malignant brain tumours with poor prognosis and limited treatment options.

Despite considerable genetic heterogeneity, these tumours often have impaired DNA repair systems, rendering them initially sensitive to alkylating agents, although they invariably develop resistance to these agents over time. 9, 11, 17 Temozolomide is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; these properties allow for both oral and intravenous administration. 10, 13, 16, 17 Following initial hydrolysis, further reactions liberate a highly reactive methyl diazonium cation capable of methylating various residues on adenosine and guanine bases leading to DNA lesions and eventual apoptosis. 10, 16 Temozomolide as an adjunct to radiotherapy followed by maintenance dosing remains the standard of care for both Glioblastoma and refractory anaplastic astrocytoma.

Temozolomide was granted FDA approval on

August 11, 1999, as an oral capsule and subsequently on February 27, 2009, as an intravenous injection.

It is currently marketed under the trademark TEMODAR® by Merck.

Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter.

It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma.

Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death.

Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients.

Patients must have an

ANC of ≥1.5 x 10 9 /L and a platelet count of ≥100 x 10 9 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery.

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration.

Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages.

Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose.

Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively.

Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH.

Therefore, temozolomide may be administered both Oral and Intravenous with a median T max of one hour.

Following a single oral dose of 150 mg/m 2, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μghr/mL and 864 nghr/mL, respectively.

Similarly, following a single 90-minute Intravenous infusion of 150 mg/m 2, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μghr/mL and 891 nghr/mL, respectively.

Temozolomide kinetics are linear over the range of 75-250 mg/m 2 /day. The median T max is 1 hour 17 Oral temozolomide absorption is affected by food.

Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 hours).

Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg.

After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. 10, 13, 16 MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. 10, 13, 16 The cytochrome P450 system plays only a minor role in temozolomide metabolism.

Relative to the

AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.

Hover over products below to view reaction partners Temozolomide Temozolomide carboxylic acid metabolite (TMA) 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) 5-aminoimidazole-4-carboxamide (AIC) + Methyl diazonium.

Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces.

The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%).

Only 6% of the recovered dose represents unchanged temozolomide.

Temozolomide has a mean elimination half-life of 1.8 hours.

Temozolomide has a clearance of approximately 5.5 L/hr/m 2.

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The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses.

Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death.

One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death.

Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary.

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.

History of serious hypersensitivity to temozolomide or any other ingredients in TEMODAR and dacarbazine.

Administer either orally or intravenously.

Glioblastoma: 75 mg/m 2 once daily for to 49 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days to 5 of each 28-day cycle for 6 cycles.

May increase maintenance dose to 200 mg/m for Cycles to 6 based on toxicity.

Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less.

Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma: Beginning 4 weeks after the end of radiotherapy, administer TEMODAR orally in a single dose on days 1-5 of a 28-day cycle for 12 cycles.

The recommended dosage for

Cycle is 150 mg/m 2 per day and for Cycles to 12 is 200 mg/m 2 if patient experienced no or minimal toxicity in Cycle 1.

Initial dose of 150 mg/m 2 once daily on Days to 5 of each 28-day cycle. 2.1 Monitoring to Inform Dosage and Administration Prior to dosing, withhold TEMODAR until patients have an absolute neutrophil count (ANC) of 1.5 x 10 9 /L or greater and a platelet count of 100 x 10 9 /L or greater.

For concomitant radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment.

For the 28-day treatment cycles, obtain a complete blood count prior to treatment on Day and on Day of each cycle.

Perform complete blood counts weekly until recovery if the ANC falls below 1.5 x 10 9 /L and the platelet count falls below 100 x 10 9 /L. For concomitant use with focal radiotherapy, obtain a complete blood count weekly and as clinically indicated. 2.2 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer TEMODAR either orally or intravenously once daily for to 49 consecutive days during the concomitant use phase with focal radiotherapy, and then once daily on Days to 5 of each 28-day cycle for 6 cycles during the maintenance use phase.

Pneumocystis pneumonia (PCP) prophylaxis during the concomitant use phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less.

The recommended dosage of TEMODAR is 75 mg/m 2 either orally or intravenously once daily for to 49 days in combination with focal radiotherapy.

Focal radiotherapy includes the tumor bed or resection site with a 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.

TABLE 1: Dosage Modifications Due to Adverse Reactions During Concomitant Use Phase Adverse Reaction Interruption Discontinuation Absolute Neutrophil Count Withhold TEMODAR if ANC is greater than or equal to 0.5 × 10 9 /L and less than 1.5 × 10 9 /L. Discontinue TEMODAR if ANC is less than 0.5 × 10 9 /L. Resume TEMODAR at the same dose when ANC is greater than or equal to 1.5 × 10 9 /L. Platelet Count Withhold TEMODAR if platelet count is greater than or equal to 10 × 10 9 /L and less than 100 × 10 9 /L. Discontinue TEMODAR if platelet count is less than 10 × 10 9 /L. Resume TEMODAR at the same dose when platelet count is greater than or equal to 100 × 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold TEMODAR if Grade 2 adverse reaction occurs.

Discontinue TEMODAR if

Grade 3 or 4 adverse reaction occurs.

Resume TEMODAR at the same dose when resolution to Grade 1 or less.

Beginning 4 weeks after concomitant use phase completion, administer TEMODAR either orally or intravenously once daily on Days to 5 of each 28-day cycle for 6 cycles.

The recommended dosage of TEMODAR in the maintenance use phase is: Cycle 1: 150 mg/m 2 per day on days to 5.

Cycles to 6: May increase to 200 mg/m 2 per day on days to 5 before starting Cycle 2 if no dosage interruptions or discontinuations are required (Table 1).

If the dose is not escalated at the onset of Cycle 2, do not increase the dose for Cycles to 6.

Obtain a complete blood count on Day and then weekly until the ANC is above 1.5 × 10 9 /L and the platelet count is above 100 × 10 9 /L. 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 Adverse Reactions Interruption and Dose Reduction Discontinuation Absolute Neutrophil Count Withhold TEMODAR if ANC less than 1 × 10 9 /L. Discontinue TEMODAR if unable to tolerate a dose of 100 mg/m 2 per day. When ANC is above 1.5 × 10 9 /L, resume TEMODAR at reduced dose for the next cycle.

TEMODAR if platelet less than 50 × 10 9 /L. Discontinue TEMODAR if unable to tolerate a dose of 100 mg/m 2 per day. When platelet count is above 100 × 10 9 /L, resume TEMODAR at reduced dose for the next cycle.

Reactions (except for alopecia, nausea, vomiting) Withhold TEMODAR if Grade 3 adverse reaction occurs.

Discontinue TEMODAR if recurrent

Grade 3 adverse reaction occurs after dose reduction, if Grade 4 adverse reaction occurs, or if unable to tolerate a dose of 100 mg/m 2 per day. When resolved to Grade 1 or less, resume TEMODAR at reduced dose for the next cycle. 2.3 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 to 5 of a 28-day cycle for 12 cycles.

The recommended dosage of TEMODAR is

Cycle 1: 150 mg/m 2 per day on days to 5.

Cycles to 12: 200 mg/m 2 per day on days 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 to 6.

The recommended complete blood count testing and dosage modifications due to adverse reactions during adjuvant treatment are provided above and in Table 2.

Refractory Anaplastic Astrocytoma The recommended initial dosage of TEMODAR is 150 mg/m 2 once daily on Days to 5 of each 28-day cycle.

Increase the

TEMODAR dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day of the next cycle: ANC is greater than or equal to 1.5 × 10 9 /L, and Platelet count is greater than or equal to 100 × 10 9 /L. Continue TEMODAR until disease progression or unacceptable toxicity.

Obtain a complete blood count on Day and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels.

If the

ANC is less than 1 × 10 9 /L or the platelet count is less than 50 × 10 9 /L during any cycle, reduce the TEMODAR 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. 2.4 Preparation and Administration TEMODAR is a hazardous drug.

Follow applicable special handling and disposal procedures.

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.

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.

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 [77°F]).

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.

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.

is a hazardous drug.

Follow applicable special handling and disposal procedures.

TEMODAR capsules

TEMODAR capsules are supplied in child-resistant sachets containing the following capsule strengths: 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”.

They are supplied as follows: 5-count – NDC 0085-3004-03 14-count – NDC 0085-3004-04 20 mg: opaque white bodies with yellow caps.

They are supplied as follows: 5-count – NDC 0085-1519-03 14-count – NDC 0085-1519-04 100 mg: opaque white bodies with pink caps.

They are supplied as follows: 5-count – NDC 0085-1366-03 14-count – NDC 0085-1366-04 140 mg: opaque white bodies with blue caps.

They are supplied as follows: 5-count – NDC 0085-1425-03 14-count – NDC 0085-1425-04 180 mg: opaque white bodies with orange caps.

They are supplied as follows: 5-count – NDC 0085-1430-03 14-count – NDC 0085-1430-04 250 mg: opaque white bodies with white caps.

They are supplied as follows: 5-count – NDC 0085-1417-02 Store TEMODAR Capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

TEMODAR for injection

TEMODAR for injection is supplied in single-dose glass vials containing 100 mg temozolomide.

The lyophilized powder is white to light tan or light pink.

NDC 0085-1381-01 Store TEMODAR for injection refrigerated at 2°C to 8°C (36°F to 46°F).

Capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

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.

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.

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

Safety and effectiveness of

TEMODAR have not been established in pediatric patients.

TEMODAR capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 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.

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.

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.

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.