Temodar

temozolomide

Dosage Form: capsule
FULL PRESCRIBING INFORMATION

Indications and Usage for Temodar

Newly Diagnosed Glioblastoma Multiforme

Temodar® (temozolomide) is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

Refractory Anaplastic Astrocytoma

Temodar is indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

Temodar Dosage and Administration

Recommended Dosing and Dose Modification Guidelines

The recommended dose for Temodar as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when Temodar for Injection was given over 90 minutes [see Clinical Pharmacology (12.3)]. Dosage of Temodar must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For Temodar dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6.

Patients with Newly Diagnosed High Grade Glioma:

Concomitant Phase:

Temodar is administered at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance Temodar for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The Temodar dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count ≥1.5 × 109 /L, platelet count ≥100 × 109/L, common toxicity criteria (CTC) nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. PCP prophylaxis is required during the concomitant administration of Temodar and radiotherapy and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade ≤1).

TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide

Toxicity	TMZ Interruption*	TMZ Discontinuation
TMZ=temozolomide; CTC=Common Toxicity Criteria.
* Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count ≥1.5 × 109/L; platelet count ≥100 × 109/L; CTC nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, vomiting).
Absolute Neutrophil Count	≥0.5 and <1.5 × 109/L	<0.5 × 109/L
Platelet Count	≥10 and <100 × 109/L	<10 × 109/L
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting)	CTC Grade 2	CTC Grade 3 or 4

Maintenance Phase:

Cycle 1:

Four weeks after completing the Temodar+RT phase, Temodar is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment.

Cycles 2–6:

At the start of Cycle 2, the dose can be escalated to 200 mg/m2, if the CTC nonhematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is ≥1.5 × 109/L, and the platelet count is ≥100 × 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.

Dose Reduction or Discontinuation During Maintenance:

Dose reductions during the maintenance phase should be applied according to Tables 2 and 3.

During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of Temodar) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L (1500/µL) and the platelet count exceeds 100 × 109/L (100,000/µL). The next cycle of Temodar should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3.

TABLE 2: Temozolomide Dose Levels for Maintenance Treatment

Dose Level	Dose (mg/m2/day)	Remarks
−1	100	Reduction for prior toxicity
0	150	Dose during Cycle 1
1	200	Dose during Cycles 2–6 in absence of toxicity

TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment

Toxicity	Reduce TMZ by 1 Dose Level*	Discontinue TMZ
TMZ=temozolomide; CTC=Common Toxicity Criteria.
* TMZ dose levels are listed in Table 2. † TMZ is to be discontinued if dose reduction to <100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.
Absolute Neutrophil Count	<1.0 × 109/L	See footnote †
Platelet Count	<50 × 109/L	See footnote †
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting)	CTC Grade 3	CTC Grade 4†

Patients with Refractory Anaplastic Astrocytoma:

For adults the initial dose is 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are ≥1.5 × 109/L (1500/µL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are ≥100 × 109/L (100,000/µL), the Temodar dose may be increased to 200 mg/m2/day 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 × 109/L (1500/µL) and the platelet count exceeds 100 × 109/L (100,000/µL). The next cycle of Temodar should not be started until the ANC and platelet count exceed these levels. If the ANC falls to <1.0 × 109/L (1000/µL) or the platelet count is <50 × 109/L (50,000/µL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 4). Temodar therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.

TABLE 4: Dosing Modification Table

TABLE 5: Daily Dose Calculations by Body Surface Area (BSA)

Total BSA (m2)	75 mg/m2 (mg daily)	150 mg/m2 (mg daily)	200 mg/m2 (mg daily)
1.0	75	150	200
1.1	82.5	165	220
1.2	90	180	240
1.3	97.5	195	260
1.4	105	210	280
1.5	112.5	225	300
1.6	120	240	320
1.7	127.5	255	340
1.8	135	270	360
1.9	142.5	285	380
2.0	150	300	400
2.1	157.5	315	420
2.2	165	330	440
2.3	172.5	345	460
2.4	180	360	480
2.5	187.5	375	500

TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults

Number of Daily Capsules by Strength (mg)
Total Daily Dose (mg)	250 mg	180 mg	140 mg	100 mg	20 mg	5 mg
75	0	0	0	0	3	3
82.5	0	0	0	0	4	0
90	0	0	0	0	4	2
97.5	0	0	0	1	0	0
105	0	0	0	1	0	1
112.5	0	0	0	1	0	2
120	0	0	0	1	1	0
127.5	0	0	0	1	1	1
135	0	0	0	1	1	3
142.5	0	0	1	0	0	0
150	0	0	1	0	0	2
157.5	0	0	1	0	1	0
165	0	0	1	0	1	1
172.5	0	0	1	0	1	2
180	0	1	0	0	0	0
187.5	0	1	0	0	0	1
195	0	1	0	0	0	3
200	0	1	0	0	1	0
210	0	0	0	2	0	2
220	0	0	0	2	1	0
225	0	0	0	2	1	1
240	0	0	1	1	0	0
255	1	0	0	0	0	1
260	1	0	0	0	0	2
270	1	0	0	0	1	0
280	0	0	2	0	0	0
285	0	0	2	0	0	1
300	0	0	0	3	0	0
315	0	0	0	3	0	3
320	0	1	1	0	0	0
330	0	1	1	0	0	2
340	0	1	1	0	1	0
345	0	1	1	0	1	1
360	0	2	0	0	0	0
375	0	2	0	0	0	3
380	0	1	0	2	0	0
400	0	0	0	4	0	0
420	0	0	3	0	0	0
440	0	0	3	0	1	0
460	0	2	0	1	0	0
480	0	1	0	3	0	0
500	2	0	0	0	0	0

Preparation and Administration

Temodar Capsules:

In clinical trials, Temodar was administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12)], and consistency of administration with respect to food is recommended. There are no dietary restrictions with Temodar. To reduce nausea and vomiting, Temodar should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of Temodar.

Temodar (temozolomide) Capsules should not be opened or chewed. They should be swallowed whole with a glass of water.

If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1)].

Temodar for Injection:

Each vial of Temodar for Injection contains sterile and pyrogen-free temozolomide lyophilized powder. When reconstituted with 41 mL Sterile Water for Injection, the resulting solution will contain 2.5 mg/mL temozolomide. Bring the vial to room temperature prior to reconstitution with Sterile Water for Injection. The vials should be gently swirled and not shaken. Vials should be inspected, and any vial containing visible particulate matter should not be used. Do not further dilute the reconstituted solution. After reconstitution, store at room temperature (25°C [77°F]). Reconstituted product must be used within 14 hours, including infusion time.

 Using aseptic technique, withdraw up to 40 mL from each vial to make up the total dose based on Table 5 above and transfer into an empty 250 mL infusion bag.2 Temodar for Injection should be infused intravenously using a pump over a period of 90 minutes. Temodar for Injection should be administered only by intravenous infusion. Flush the lines before and after each Temodar 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, other medications should not be infused simultaneously through the same intravenous line.

Dosage Forms and Strengths

• Temodar (temozolomide) Capsules for oral administration
  

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  5-mg capsules have 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."

  
  

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  20-mg capsules have opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "Temodar."

  
  

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  100-mg capsules have opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "Temodar."

  
  

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  140-mg capsules have opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "Temodar."

  
  

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  180-mg capsules have opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "Temodar."

  
  

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  250-mg capsules have opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "Temodar."

  
  



• Temodar (temozolomide) is available as 100-mg/vial powder for injection. The lyophilized powder is white to light tan/light pink.

Contraindications

Hypersensitivity

Temodar (temozolomide) is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. Temodar is also contraindicated in patients who have a history of hypersensitivity to DTIC, since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).

Warnings and Precautions

Myelosuppression

Patients treated with Temodar may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, patients must have an absolute neutrophil count (ANC) ≥1.5 × 109/L and a platelet count ≥100 × 109/L. 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 × 109/L and platelet count exceeds 100 × 109/L. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.

Myelodysplastic Syndrome

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

Pneumocystis carinii Pneumonia

For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis carinii pneumonia is required for all patients receiving concomitant Temodar and radiotherapy for the 42-day regimen.

There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

Laboratory Tests

For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.

For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 × 109/L and the platelet count falls below 100 × 109/L [see Recommended Dosing and Dose Modification Guidelines (2.1)].

Use in Pregnancy

Temodar can cause fetal harm when administered to a pregnant woman. Administration of Temodar to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m2), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species [see Use in Specific Populations (8.1)].

Infusion Time

As bioequivalence has been established only when Temodar for Injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion-related adverse reactions cannot be ruled out.

Adverse Reactions

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 Multiforme:

During the concomitant phase (Temodar+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the Temodar+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative Temodar experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see Table 7). Forty-nine percent (49%) of patients treated with Temodar reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of Temodar.

TABLE 7: Number (%) of Patients with Adverse Reactions: All and Severe/Life Threatening (Incidence of 5% or Greater)

	Concomitant Phase RT Alone (n=285)				Concomitant Phase RT+TMZ (n=288)*				Maintenance Phase TMZ (n=224)
	All		Grade ≥3		All		Grade ≥3		All		Grade ≥3
RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified.
Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column.
* One patient who was randomized to RT only arm received RT+temozolomide.
Subjects Reporting any Adverse Reaction	258	(91)	74	(26)	266	(92)	80	(28)	206	(92)	82	(37)
Body as a Whole - General Disorders
Anorexia	25	(9)	1	(<1)	56	(19)	2	(1)	61	(27)	3	(1)
Dizziness	10	(4)	0		12	(4)	2	(1)	12	(5)	0
Fatigue	139	(49)	15	(5)	156	(54)	19	(7)	137	(61)	20	(9)
Headache	49	(17)	11	(4)	56	(19)	5	(2)	51	(23)	9	(4)
Weakness	9	(3)	3	(1)	10	(3)	5	(2)	16	(7)	4	(2)
Central and Peripheral Nervous System Disorders
Confusion	12	(4)	6	(2)	11	(4)	4	(1)	12	(5)	4	(2)
Convulsions	20	(7)	9	(3)	17	(6)	10	(3)	25	(11)	7	(3)
Memory Impairment	12	(4)	1	(<1)	8	(3)	1	(<1)	16	(7)	2	(1)
Disorders of the Eye
Vision Blurred	25	(9)	4	(1)	26	(9)	2	(1)	17	(8)	0
Disorders of the Immune System
Allergic Reaction	7	(2)	1	(<1)	13	(5)	0		6	(3)	0
Gastrointestinal System Disorders
Abdominal Pain	2	(1)	0		7	(2)	1	(<1)	11	(5)	1	(<1)
Constipation	18	(6)	0		53	(18)	3	(1)	49	(22)	0
Diarrhea	9	(3)	0		18	(6)	0		23	(10)	2	(1)
Nausea	45	(16)	1	(<1)	105	(36)	2	(1)