英文药名: Temodal(Temozolomide hard capsules)

中文药名: 替莫唑胺硬胶囊

生产厂家: 默沙东（英国）公司
药物名称和成分
中文药名: 替莫唑胺胶囊
这个药通常也叫: Temodar 在加拿大等欧洲国家为商品名
成份: 替莫唑胺
性状: 本品为白色胶囊
药品介绍
Temodal/Temodar为治疗脑癌的新型药物用于;
★脑胶质瘤最新产品
★迅速通过血脑屏障20分钟达到血药峰浓度
★影响DNA复制和修复，发挥细胞毒作用
★起效快，中位生存期长，有效降低复发率
★口服方便，疗效好，不良反应轻、依从性高
药理作用
替莫唑胺为咪唑并四嗪类具有抗肿瘤活性的烷化剂。在体循环生理pH状态下，迅速转化为活性产物MTIC（3-甲基-(三嗪-1-)咪唑-4-甲酰胺）。MTIC的细胞毒作用主要表现为DNA分子上鸟嘌呤第6位氧原子上的烷基化以及第7位氮原子的烷基化。通过甲基化加成物的错配修复，发挥细胞毒作用。
药代动力学
临床前数据提示本品能迅速通过血脑屏障，进入脑脊液。成年患者口服本品后，被迅速吸收，最早在服药后20分钟就可达到血药峰浓度（平均时间为0.5-1.5小时）。血浆清除率、分布容积和半衰期都与剂量无关。本品的蛋白结合率低(10-20%)，因此估计不会与蛋白结合率高的药物发生相互作用。口服14C-本品后7天内粪便内排泄的14C为0.8%，表明药物是完全吸收的。口服后，24小时尿内的原形药占剂量的5%-10%左右，其余是以AIC（4-氨基-5-咪唑-盐酸羧酰胺）形式或其他极性代谢物排泄到尿中。
本品药代动力学的群体分析表明本品血浆清除率与年龄、肾功能或吸烟无关。
儿科患者的AUC比成人患者高，但是儿童和成人每周期的最大耐受剂量(MTD) 都是1000mg/m2
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。
用法用量
新诊断的多形性胶质母细胞瘤的成人患者：
同步放化疗期
口服本品，75mg/m2/日，共42天，同时接受放疗。随后接受6个周期的本品辅助治疗。根据患者耐受程度可暂停用药，但无需降低剂量。
辅助治疗期
同步放化疗期结束后4周，进行6个周期的本品单药辅助治疗。
起始剂量：150mg/m2/日，共5天，然后停药23天。一周期为28天。从第2周期开始，根据前1周期不良反应，剂量可增至200 mg/m2/日，或减至100 mg/m2。
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患者：
成人患者
以前曾接受过化疗者的起始剂量是150mg/m2/日，共5天。 成人没有接受过其他化疗者的起始剂量为200mg/m2/日，均连用5天，28天为一个周期。治疗可继续到病变出现进展，最多为2年。
儿童患者
在以前接受过化疗3岁或以上的患儿，每28天周期中本品口服起始剂量是150 mg/m2/日，共5天。如果没有出现毒性，下个周期的剂量增至200mg/m2/日.治疗可继续到病变出现进展，最多为2年。
全部患者
应空腹（进餐前至少一小时）服用本品。服用本品前后可使用止吐药。如果服药后出现呕吐，当天不能服用第2剂。
不能打开或咀嚼本品，应用一杯水整粒吞服。如果胶囊有破损，应避免皮肤或粘膜与胶囊内粉状内容物接触。
FDA妊娠分级
D级: 有明确证据显示，药物对人类胎儿有危害性，但尽管如此，孕妇用药后绝对有益（例如用该药物来挽救孕妇的生命，或治疗用其他较安全的药物无效的严重疾病）。
禁忌
对本药或达卡巴嗪过敏、妊娠期、严重骨髓抑制的患者禁用。
注意事项
对于接受42-49天合并治疗者需要预防卡氏肺囊虫性肺炎发生。男性患者在治疗过程及治疗结束后6个月之内应避孕，在接受该治疗之前应冰冻保存精子。严重肝功能异常或肾功能异常者慎用。本药不应用于哺乳期妇女。目前尚无3岁以下多形性胶质母细胞瘤患儿使用该药的临床经验。
孕妇及哺乳期妇女用药
对妊娠期妇女使用该药尚未进行研究。在用大鼠和兔所进行的临床前研究中，给药150 mg/m2曾有致畸和/或胎儿毒性的报道。因此替莫唑胺不应常规用于妊娠期妇女，如果妊娠期内必须使用该药，应将可能对胎儿造成的潜在风险告知病人。对于可能怀孕的妇女，应劝阻其在接受替莫唑胺治疗或在终止替莫唑胺治疗后6个月内怀孕。
替莫唑胺是否可经母乳分泌尚不可知，因此替莫唑胺胶囊不应用于哺乳期妇女。
儿童用药
尚无3岁以下多形性胶质母细胞瘤患儿使用该药的临床经验；对于3岁以上胶质瘤儿童患者，使用该药的临床经验有限。
老年患者用药
与年轻患者相比，老年患者（>70岁）中性粒细胞减少及血小板减少的可能性较大。
不良反应
轻中度胃肠道功能紊乱，具有自限性，或标准止吐药易于控制。骨髓抑制（一般在开始几个周期的第21-28天），通常在1-2周内迅速恢复。其他不良反应包括 ：口腔念珠菌病、感染，血象异常，体重降低，焦虑、抑郁、情绪不稳定、失眠、头痛、惊厥、头晕等神经系统症状，视力障碍，听力损害、耳鸣，下肢浮肿、出血、深静脉血栓形成，咳嗽、呼吸困难，脱发、皮肤干燥，肌无力，尿失禁，疲乏、发热、疼痛、过敏反应、放射损伤、味觉异常，SGPT升高。
药物相互作用
同时服用丙戊酸，替莫唑胺清除率轻度降低。与其他可导致骨髓抑制的的药物联合应用时，骨髓抑制可能加重。
药物过量
在患者中已进行了剂量为500，750，1000和1250mg/m2 (每治疗周期服药5天的总剂量)的临床评价。剂量限制性毒性为血液学毒性，在任一剂量下均有报道，但在较高剂量时较为严重。1患者5天中每天过量服用2000mg，所报道的不良事件为全血细胞减少症、发热、多器官衰竭及死亡。在服药超过5天（最长达64天）的患者中所发生的不良事件包括骨髓抑制（伴随或不伴随感染），某些严重且持久的病例最终死亡。在药物过量事件中，应进行血液学评价。必要时应采取支持性措施。
注：本品在英国批准上市，采购以咨询为准

Temodal 5mg, 20mg, 100mg, 140mg, 180mg, or 250mg hard capsules
1. Name of the medicinal product
Temodal 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg hard capsules
2. Qualitative and quantitative composition
Each hard capsule contains 5 mg, 20 mg, 100 mg, 140, 180 mg or 250 mg temozolomide.
Excipient with known effect:
Each 5 mg hard capsule contains 132.8 mg of anhydrous lactose.
Each 20 mg hard capsule contains 182.2 mg of anhydrous lactose.
Each 100 mg hard capsule contains 175.7 mg of anhydrous lactose
Each 140 mg hard capsule contains 246 mg of anhydrous lactose.
Each 180 mg hard capsule contains 316.3 mg of anhydrous lactose.
Each 250 mg hard capsule contains 154.3 mg of anhydrous lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule (capsule).
The 5 mg hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “5 mg”, the Schering-Plough logo and two stripes.
The 20 mg hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “20 mg”, the Schering-Plough logo and two stripes.
The 100 mg hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “100 mg”, the Schering-Plough logo and two stripes.
The 140 mg hard capsules have an opaque white body, a blue cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “140 mg”, the Schering-Plough logo and two stripes.
The 180 mg hard capsules have an opaque white body, an opaque orange cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “180 mg”, the Schering-Plough logo and two stripes.
The 250 mg hard capsules have an opaque white body and cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “250 mg”, the Schering-Plough logo and two stripes.
4. Clinical particulars
4.1 Therapeutic indications
Temodal is indicated for the treatment of:
- adult patients with newly-diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy treatment.
- children from the age of three years, adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy.
4.2 Posology and method of administration
Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.
Anti-emetic therapy may be administered (see section 4.4).
Posology
Adult patients with newly-diagnosed glioblastoma multiforme
Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).
Concomitant phase
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:
- absolute neutrophil count (ANC) ≥ 1.5 x 109/l
- thrombocyte count ≥ 100 x 109/l
- common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).
During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.
Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ

Toxicity	TMZ interruptiona	TMZ discontinuation
Absolute neutrophil count	≥ 0.5 and < 1.5 x 109/l	< 0.5 x 109/l
Thrombocyte count	≥ 10 and < 100 x 109/l	< 10 x 109/l
CTC non-haematological toxicity (except for alopecia, nausea, vomiting)	CTC Grade 2	CTC Grade 3 or 4

a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count ≥ 1.5 x 109/l; thrombocyte count ≥ 100 x 109/l; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting).
Monotherapy phase
Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy 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 TMZ). The dose should be reduced or administration discontinued according to Table 3.
Table 2. TMZ dose levels for monotherapy treatment

Dose level	TMZ 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. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity	Reduce TMZ by 1 dose levela	Discontinue TMZ
Absolute neutrophil count	< 1.0 x 109/l	See footnote b
Thrombocyte count	< 50 x 109/l	See footnote b
CTC non-haematological Toxicity (except for alopecia, nausea, vomiting)	CTC Grade 3	CTC Grade 4b

a: TMZ dose levels are listed in Table 2.
b: TMZ is to be discontinued if:
• dose level -1 (100 mg/m2) still results in unacceptable toxicity
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see section 4.4)
Special populations
Paediatric population
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.
Patients with hepatic or renal impairment
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.
Elderly patients
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).
Method of administration
Temodal hard capsules should be administered in the fasting state.
The capsules must be swallowed whole with a glass of water and must not be opened or chewed.
If vomiting occurs after the dose is administered, a second dose should not be administered that day.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypersensitivity to dacarbazine (DTIC).
Severe myelosuppression (see section 4.4).
4.4 Special warnings and precautions for use
Opportunistic infections and reactivation of infections
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).
Pneumocystis jirovecii pneumonia
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.
HBV
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.
Hepatotoxicity
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.
Malignancies
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).
Anti-emetic therapy
Nausea and vomiting are very commonly associated with TMZ.
Anti-emetic therapy may be administered prior to or following administration of TMZ.
Adult patients with newly-diagnosed glioblastoma multiforme
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.
Patients with recurrent or progressive malignant glioma
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.
Laboratory parameters
Patients treated with TMZ 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 medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count ≥ 100 x 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 ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose is 100 mg/m2.
Paediatric population
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).
Elderly patients (> 70 years of age)
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.
Male patients
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under the curve (AUC).
As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.
Breast-feeding
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.
Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.
Male fertility
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.
4.7 Effects on ability to drive and use machines
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).
4.8 Undesirable effects
Clinical trial experience
In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory findings is presented after each table.
In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Newly-diagnosed glioblastoma multiforme
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.
Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly-diagnosed glioblastoma multiforme

System organ class	TMZ + concomitant RT n=288*	TMZ monotherapy n=224
Infections and infestations
Common:	Infection, Herpes simplex, wound infection, pharyngitis, candidiasis oral	Infection, candidiasis oral
Uncommon:		Herpes simplex, herpes zoster, influenza–like symptoms
Blood and lymphatic system disorders
Common:	Neutropenia, thrombocytopenia, lymphopenia, leukopenia	Febrile neutropenia, thrombocytopenia, anaemia, leukopenia
Uncommon:	Febrile neutropenia, anaemia	Lymphopenia, petechiae
Endocrine disorders
Uncommon:	Cushingoid	Cushingoid
Metabolism and nutrition disorders
Very common:	Anorexia	Anorexia
Common:	Hyperglycaemia, weight decreased	Weight decreased
Uncommon:	Hypokalemia, alkaline phosphatase increased, weight increased	Hyperglycaemia, weight increased
Psychiatric disorders
Common:	Anxiety, emotional lability, insomnia	Anxiety, depression, emotional lability, insomnia
Uncommon:	Agitation, apathy, behaviour disorder, depression, hallucination	Hallucination, amnesia
Nervous system disorders
Very common:	Headache	Convulsions, headache
Common:	Convulsions, consciousness decreased, somnolence, aphasia, balance impaired, dizziness, confusion, memory impairment, concentration impaired, neuropathy, paresthesia, speech disorder, tremor	Hemiparesis, aphasia, balance impaired, somnolence, confusion, dizziness, memory impairment, concentration impaired, dysphasia, neurological disorder (NOS), neuropathy, peripheral neuropathy, paresthesia, speech disorder, tremor
Uncommon:	Status epilepticus, extrapyramidal disorder, hemiparesis, ataxia, cognition impaired, dysphasia, gait abnormal, hyperesthesia, hypoesthesia, neurological disorder (NOS), peripheral neuropathy	Hemiplegia, ataxia, coordination abnormal, gait abnormal, hyperesthesia, sensory disturbance
Eye disorders
Common:	Vision blurred	Visual field defect, vision blurred, diplopia
Uncommon:	Hemianopia, visual acuity reduced, vision disorder, visual field defect, eye pain	Visual acuity reduced, eye pain, eyes dry
Ear and labyrinth disorders
Common:	Hearing impairment	Hearing impairment, tinnitus
Uncommon:	Otitis media, tinnitus, hyperacusis, earache	Deafness, vertigo, earache
Cardiac disorders
Uncommon:	Palpitation
Vascular disorders
Common:	Haemorrhage, oedema, oedema leg	Haemorrhage, deep venous thrombosis, oedema leg
Uncommon:	Cerebral haemorrhage, hypertension	Embolism pulmonary, oedema, oedema peripheral
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea, coughing	Dyspnoea, coughing
Uncommon:	Pneumonia, upper respiratory infection, nasal congestion	Pneumonia, sinusitis, upper respiratory infection, bronchitis
Gastrointestinal disorders
Very common:	Constipation, nausea, vomiting	Constipation, nausea, vomiting
Common:	Stomatitis, diarrhoea, abdominal pain, dyspepsia, dysphagia	Stomatitis, diarrhoea, dyspepsia, dysphagia, mouth dry
Uncommon:		Abdominal distension, fecal incontinence, gastrointestinal disorder (NOS), gastroenteritis, haemorrhoids
Skin and subcutaneous tissue disorders
Very common:	Rash, alopecia	Rash, alopecia
Common:	Dermatitis, dry skin, erythema, pruritus	Dry skin, pruritus
Uncommon:	Skin exfoliation, photosensitivity reaction, pigmentation abnormal	Erythema, pigmentation abnormal, sweating increased
Musculoskeletal and connective tissue disorders
Common:	Muscle weakness, arthralgia	Muscle weakness, arthralgia, musculoskeletal pain, myalgia
Uncommon:	Myopathy, back pain, musculoskeletal pain, myalgia	Myopathy, back pain
Renal and urinary disorders
Common:	Micturition frequency, urinary incontinence	Urinary incontinence
Uncommon:		Dysuria
Reproductive system and breast disorders
Uncommon:	Impotence	Vaginal haemorrhage,menorrhagia, amenorrhea, vaginitis, breast pain
General disorders and administration site conditions
Very common:	Fatigue	Fatigue
Common:	Allergic reaction, fever, radiation injury, face oedema, pain, taste perversion	Allergic reaction, fever, radiation injury, pain, taste perversion
Uncommon:	Asthenia, flushing, hot flushes, condition aggravated, rigors, tongue discolouration, parosmia, thirst	Asthenia, face oedema, pain, condition aggravated, rigors, tooth disorder
Investigations
Common:	ALT increased	ALT increased
Uncommon:	Hepatic enzymes increased, Gamma GT increased, AST increased

A patient who was randomised to the RT arm only, received TMZ + RT.
Laboratory results
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients who received TMZ.
Recurrent or progressive malignant glioma
In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.
Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.
Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations
Rare:	Opportunistic infections, including PCP
Blood and lymphatic system disorders
Very common:	Neutropenia or lymphopenia (grade 3-4), thrombocytopenia (grade 3-4)
Uncommon:	Pancytopenia, anaemia (grade 3-4), leukopenia
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Weight decrease
Nervous system disorders
Very common:	Headache
Common:	Somnolence, dizziness, paresthesia
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea
Gastrointestinal disorders
Very common:	Vomiting, nausea, constipation
Common:	Diarrhoea, abdominal pain, dyspepsia
Skin and subcutaneous tissue disorders
Common:	Rash, pruritus, alopecia
Very rare:	Erythema multiforme, erythroderma, urticaria, exanthema
General disorders and administration site conditions
Very common:	Fatigue
Common:	Fever, asthenia, rigors, malaise, pain, taste perversion
Very rare:	Allergic reactions, including anaphylaxis, angioedema

Laboratory results
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.
Gender
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.
Paediatric population
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.
Post-Marketing Experience
The following additional serious adverse reactions have been identified during post-marketing exposure:
Table 6. Summary of events reported with temozolomide in the post-marketing setting

Infections and infestations*
Uncommon:	cytomegalovirus infection, infection reactivation such as cytomegalovirus, hepatitis B virus†
Blood and lymphatic system disorders
Very rare:	prolonged pancytopenia, aplastic anaemia†
Neoplasm benign, malignant and unspecified
Very rare:	myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia
Endocrine disorders*
Uncommon:	diabetes insipidus
Respiratory, thoracic and mediastinal disorders
Very rare:	interstitial pneumonitis/pneumonitis, pulmonary fibrosis, respiratory failure†
Hepatobiliary disorders*
Common:	liver enzymes elevations
Uncommon:	hyperbilirubinemia, cholestasis, hepatitis, hepatic injury, hepatic failure†
Skin and subcutaneous tissue disorders
Very rare:	toxic epidermal necrolysis, Stevens-Johnson syndrome

Including cases with fatal outcome
* Frequencies estimated based on relevant clinical trials.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03
Mechanism of action
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.
Clinical efficacy and safety
Newly-diagnosed glioblastoma multiforme
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (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 monotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm.
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)
The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.
Recurrent or progressive malignant glioma
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS ≥ 80.
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).
Recurrent anaplastic astrocytoma
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.
Paediatric population
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.
5.2 Pharmacokinetic properties
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.
Absorption
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.
Distribution
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.
Elimination
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.
Special populations
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.
5.3 Preclinical safety data
Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.
TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.
Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content:
anhydrous lactose,
colloidal anhydrous silica,
sodium starch glycolate type A,
tartaric acid,
stearic acid.
Capsule shell:
5 mg:
gelatin,
titanium dioxide (E 171),
sodium laurilsulfate,
yellow iron oxide (E 172),
indigo carmine (E 132),
20 mg:
gelatin,
titanium dioxide (E 171),
sodium lauril sulfate,
yellow iron oxide (E 172)
100 mg:
gelatin,
titanium dioxide (E 171),
sodium lauril sulfate,
red iron oxide (E172).
140 mg:
gelatin,
titanium dioxide (E 171),
sodium lauril sulfate ,
indigo carmine (E 132),
180 mg:
gelatin,
titanium dioxide (E 171),
sodium lauril sulfate,
yellow iron oxide (E 172),
red iron oxide (E 172)
250 mg:
gelatin,
titanium dioxide (E 171),
sodium lauril sulfate
Printing ink:
shellac,
propylene glycol,
purified water,
ammonium hydroxide,
potassium hydroxide,
black iron oxide (E 172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Bottle presentation
Do not store above 30 °C.
Store in the original bottle in order to protect from moisture.
Keep the bottle tightly closed.
Sachet presentation
Do not store above 30 °C.
6.5 Nature and contents of container
Bottle presentation
Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.
The carton contains one bottle.
Sachet presentation
Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.
Each sachet contains 1 hard capsule and is dispensed in a cardboard carton.
The carton contains 5 or 20 hard capsules, individually sealed in sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.
Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8. Marketing authorisation number(s)
Temodal 5 mg Capsules:      EU/1/98/096/001-2, 024-025
Temodal 20 mg Capsules:    EU/1/98/096/003-4, 013-014
Temodal 100 mg Capsules:  EU/1/98/096/005-6, 015-016
Temodal 140 mg Capsules:  EU/1/98/096/009-10, 017-018
Temodal 180 mg Capsules:  EU/1/98/096/011-12, 019-020
Temodal 250 mg Capsules:  EU/1/98/096/007-8, 021-022
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 26 January 1999
Date of latest renewal: 26 January 2009
10. Date of revision of the text
27 May 2015