FDA新近批准了Temodar（(temozolomide)的一种新适应症。目前与放疗并用以及作为放疗后维持疗法的Temodar可用于延长新近被诊断为多形性胶质母细胞瘤的成人患者的存活期。

1999年，Temodar被指定为治疗使用亚硝基脲和甲基苄肼化疗后病症复发的成人间变性星形细胞瘤的快通道审批产品。该药由先灵葆雅公司推出

【制造商】先灵葆雅 ( Schering-Plough ) 
【成份】Temozolomide
【适应症】
本品用于治疗 :新诊断的多形性胶质母细胞瘤，开始先与放疗联合治疗，随后作为辅助治疗 ；常规治疗后复发或进展的多形性胶质母细胞瘤或间变性星形细胞瘤.

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 PVC infusion bag.2 Compatibility studies with non-PVC bags have not been conducted. 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.

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.

Revised: 07/2010Schering Corporation 

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

Important Safety Information for TEMODAR®

TEMODAR® is contraindicated in patients who have a history of hypersensitivity (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components, or to DTIC.

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. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have also been observed.

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.

TEMODAR® can cause fetal harm when administered to a pregnant woman. In nursing women, a decision should be made whether to discontinue nursing or to discontinue TEMODAR®, taking into account the importance of the drug to the mother. The safety and effectiveness of TEMODAR® in children have not been established.

As bioequivalence between TEMODAR® Capsules and TEMODAR® for Injection 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.

TEMODAR® Capsules should not be opened or chewed. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.

Caution should be exercised when administered to those with severe hepatic or renal impairment.

The adverse event profile was similar in patients <65 years of age and those ≥65 years.

The most common adverse reactions in clinical studies in the Concomitant Phase (Radiotherapy + TEMODAR®) and the Maintenance Phase (TEMODAR® alone), respectively, were alopecia 69%, 55%; fatigue 54%, 61%; nausea 36%, 49%; vomiting 20%, 29%; anorexia 19%, 27%; headache 19%, 23%; rash 19%, 13%; constipation 18%, 22%; with the following important adverse events also reported: convulsions 6%, 11% and thrombocytopenia 4%, 8%.

Of these adverse events, those grade ≥3 in clinical studies in the Concomitant Phase (Radiotherapy + TEMODAR®) and the Maintenance Phase (TEMODAR® alone), respectively, were fatigue 7%, 9%; nausea 1%, 1%; vomiting <1%, 2%; anorexia 1%, 1%; headache 2%, 4%; constipation 1%, 0%; convulsions 3%, 3%; thrombocytopenia 3%, 4%.

When laboratory abnormalities and adverse events were combined, Grade 3 or 4 neutropenia occurred in 8% and Grade 3 or 4 platelet abnormalities, including thrombocytopenic events, occurred in 14% of patients treated with temozolomide.

Adverse reactions reported from intravenous formulation studies that were not reported in TEMODAR® Capsule studies were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.

Please see full Prescribing Information for details about TEMODAR®

商標名
TEMODAL Infusion 100mg
一般名
テモゾロミド（JAN）
Temozolomide（JAN）

化学名
3-Methyl-4-oxo-3,4-dihydroimidazo［5,1-d］［1,2,3,5］ tetrazine-8-carboxamide

構造式

原处方附件：http://www.info.pmda.go.jp/go/pack/4219404D1027_1_06/
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原产地英文商品名:
TEMODAR injection 100mg/vial
原产地英文药品名:
TEMOZOLOMIDE
中文参考商品译名:
TEMODAR注射剂 100毫克/瓶
中文参考药品译名:
替莫唑胺
生产厂家中文参考译名:
先灵
生产厂家英文名:
SCHERING