Temozolomide Sandoz

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 5 mg hard capsules  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 5 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 168 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
  
The hard capsules have a white coloured body, a green coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ”. The body is imprinted with “5”. 
 
Each capsule is approximately 15.8 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

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-  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. 
 

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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 
 
Temozolomide Sandoz 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). 
 
Meningoencephalitis herpetic 

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In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
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 

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Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 
 

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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). Temozolomide 
Sandoz 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), Not known: frequency cannot be estimated from the 
available data.  

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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, thrombo-
cytopenia, 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 

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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 

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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 TMZ. 
 
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 

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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†, 
meningoencephalitis herpetic†, sepsis† 

Blood and lymphatic system disorders 

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Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
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 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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 

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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. 

 14 



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 contents 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 

 15 



Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Indigo carmine (E132) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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. 
 

 16 



7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/001 
EU/1/10/617/002 
EU/1/10/617/025 
EU/1/10/617/026 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

 17 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 20 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 20 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 14.6 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
The hard capsules have a white coloured body, a yellow coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ”. The body is imprinted with “20”. 
 
Each capsule is approximately 11.4 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

 18 



-  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. 

 19 



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 
 
Temozolomide Sandoz 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). 
 

Meningoencephalitis herpetic 

 20 



In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 

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. 
 

 21 



Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 

 22 



 
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). Temozolomide 
Sandoz 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:  
 

 23 



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)), Not known: frequency cannot be estimated from the 
available data. 
 
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, thrombo-
cytopenia, 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 

 24 



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 

 25 



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 TMZ. 
 
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 

 26 



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†, 
meningoencephalitis herpetic†, sepsis† 

Blood and lymphatic system disorders 

 27 



Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
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 

 28 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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 

 29 



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. 
 

 30 



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 

 31 



Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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. 
 
 

 32 



7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/005 
EU/1/10/617/006 
EU/1/10/617/027 
EU/1/10/617/028 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

 33 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 100 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 100 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 73 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
The hard capsules have a white coloured body, a pink coloured cap, and are imprinted with black ink. 
The cap is imprinted with “TMZ”. The body is imprinted with “100”. 
 
Each capsule is approximately 15.8 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

 34 



-  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. 

 35 



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 
 
Temozolomide Sandoz 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). 
 
Meningoencephalitis herpetic 

 36 



In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
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 

 37 



 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 
 

 38 



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). Temozolomide 
Sandoz 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), Not known: frequency cannot be estimated from the 
available data. 

 39 



 
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, thrombocyto-
penia, 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 

Hemiplegia, ataxia, coordination 
abnormal, gait abnormal, 
hyperesthesia, sensory 
disturbance 

 40 



disorder (NOS), peripheral 
neuropathy 

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 

 41 



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 TMZ. 
 
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 

 42 



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†, 
meningoencephalitis herpetic†, sepsis† 

 43 



Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
Mechanism of action 
 

 44 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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 

 45 



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 

 46 



 
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 

 47 



Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Red iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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.  
 

 48 



Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/009 
EU/1/10/617/010 
EU/1/10/617/029 
EU/1/10/617/030 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

 49 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 140 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 140 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 102.2 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
The hard capsules have a white coloured body, a transparent blue coloured cap, and are imprinted 
with black ink. The cap is imprinted with “TMZ”. The body is imprinted with “140”. 
 
Each capsule is approximately 19.3 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

 50 



-  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. 
 

 51 



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 
 
Temozolomide Sandoz 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). 
 
Meningoencephalitis herpetic 

 52 



In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
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 

 53 



 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 
 

 54 



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). Temozolomide 
Sandoz 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), Not known: frequency cannot be estimated from the 
available data. 

 55 



 
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, thrombocyto-
penia, 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 

 56 



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 

 57 



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 TMZ. 
 
 
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 

 58 



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†, 
meningoencephalitis herpetic†, Sepsis† 

 59 



Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
Mechanism of action 
 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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 

 61 



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 

 62 



 
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 

 63 



Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Indigo carmine (E 132) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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.  
 

 64 



Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/013 
EU/1/10/617/014 
EU/1/10/617/031 
EU/1/10/617/032 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

 65 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 180 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 180 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 131.4 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
The hard capsules have a white coloured body, a maroon coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ”. The body is imprinted with “180”. 
 
Each capsule is approximately 19.3 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

 66 



-  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. 
 

 67 



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 
 
Temozolomide Sandoz 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). 
 
Meningoencephalitis herpetic 

 68 



In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
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 

 69 



 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 
 

 70 



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). Temozolomide 
Sandoz 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), Not known: frequency cannot be estimated from the 
available data. 

 71 



 
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, thrombocyto-
penia, 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 

 72 



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 

 73 



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 TMZ. 
 
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 

 74 



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†, 
meningoencephalitis herpetic†, sepsis† 

Blood and lymphatic system disorders 

 75 



Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
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 

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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 

 77 



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. 
 

 78 



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 

 79 



Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Red iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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. 
 

 80 



7. MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/017 
EU/1/10/617/018 
EU/1/10/617/033 
EU/1/10/617/034 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

 81 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 250 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 250 mg temozolomide. 
 
Excipient with known effect:  
Each hard capsule contains 182.5 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
  
The hard capsules have a white coloured body, a white coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ”. The body is imprinted with “250”. 
 
Each capsule is approximately 21.4 mm in length. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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 
 
Temozolomide Sandoz 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:  

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-  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. 
 

 83 



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 
 
Temozolomide Sandoz 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). 
 
Meningoencephalitis herpetic 

 84 



In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
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 

 85 



 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, 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 total 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, Temozolomide Sandoz 
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). 
 

 86 



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). Temozolomide 
Sandoz 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), Not known: frequency cannot be estimated from the 
available data. 

 87 



 
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 

 88 



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 

 89 



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 TMZ. 
 
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 

 90 



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†, 
meningoencephalitis herpetic†, sepsis† 

Blood and lymphatic system disorders 

 91 



Table 6. Summary of events reported with temozolomide in the post-marketing setting 
 
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 
Not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† 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 national reporting system 
listed in Appendix V. 
 
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: L01AX03  
 
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 

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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 

 93 



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. 
 

 94 



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 

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Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch. 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 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 Temozolomid Sandoz 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 

 96 



 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/021 
EU/1/10/617/022 
EU/1/10/617/035 
EU/1/10/617/036 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

  

 97 

http://www.ema.europa.eu/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION  
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 

 98 



A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
  
Salutas Pharma GmbH 
Otto-von-Guericke-Allee 1 
D-39179 Barleben 
Germany 
  
Lek Pharmaceuticals d.d 
Verovskova 57  
SL-1526 Ljubljana  
Slovenia 
  
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports  
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 
for under Article 107c(7) of Directive 2001/83/EC and  published on the European medicines web-
portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of  new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
  

 99 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
  

 100 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  

 101 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 5 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 5 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 102 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/001 
EU/1/10/617/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 5 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number} 
 

 103 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 20 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 20 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 104 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/005 
EU/1/10/617/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 20 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 105 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 100 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 106 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/009 
EU/1/10/617/010 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 100 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 107 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 140 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 140 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 108 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/013 
EU/1/10/617/014 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 140 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 109 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 180 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 180 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 110 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/017 
EU/1/10/617/018 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 180 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number} 
  

 111 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 250 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 250 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules 
20 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH  OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 112 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/021 
EU/1/10/617/022 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 250 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number} 
  

 113 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 5 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 
  

 114 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 20 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 
  

 115 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 100 mg capsules 
emozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 
  

 116 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 140 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 
  

 117 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 180 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 
  

 118 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 250 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 capsules 
20 capsules 
 
 
6. OTHER 
 
 

 119 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 5 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 5 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
 
  

 120 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/025 
EU/1/10/617/026 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 5 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 121 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandozl 20 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 20 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
 
 

 122 



 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/027 
EU/1/10/617/028 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 20 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 123 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 100 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
  

 124 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/029 
EU/1/10/617/030 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 100 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 125 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 140 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 140 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
  

 126 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/031 
EU/1/10/617/032 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 140 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 127 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 180 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 180 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
  

 128 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/033 
EU/1/10/616/034 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 180 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 129 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Sandoz 250 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 250 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 x 1 hard capsule in sachet 
20 x 1 hard capsule in sachet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can 
be lethal for children. 
 
 
7. OTHER SPECIAL WARNING, IF NECESSARY 
 
Cytotoxic 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
 
 
 

 130 



9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/617/035 
EU/1/10/617/036 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Sandoz 250 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  

 131 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 5 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
 
  

 132 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 20 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
  

 133 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 100 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
  

 134 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 140 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
  

 135 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 180 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
  

 136 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Sandoz 250 mg capsules 
temozolomide 
 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 capsule 
 
 
6. OTHER 
  

 137 



 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 138 



Package leaflet: information for the user 
 

Temozolomide Sandoz 5 mg hard capsules 
 

Temozolomide Sandoz 20 mg hard capsules 
 

Temozolomide Sandoz 100 mg hard capsules 
 

Temozolomide Sandoz 140 mg hard capsules 
 

Temozolomide Sandoz 180 mg hard capsules 
 

Temozolomide Sandoz 250 mg hard capsules 
 

temozolomide 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Temozolomide Sandoz is and what it is used for 
2. What you need to know before you take Temozolomide Sandoz 
3. How to take Temozolomide Sandoz 
4. Possible side effects 
5.  How to store Temozolomide Sandoz 
6. Contents of the pack and other information 
 
 
1. What Temozolomide Sandoz is and what it is used for 
 
Temozolomide Sandoz contains a medicine called temozolomide. This medicine is an antitumour 
agent. 
 
Temozolomide Sandoz is used for the treatment of specific forms of brain tumours: 
• in adults with newly-diagnosed glioblastoma multiforme. Temozolomide Sandoz is first used 

together with radiotherapy (concomitant phase of treatment) and after that alone (monotherapy 
phase of treatment). 

• in children 3 years and older and adult patients with malignant glioma , such as glioblastoma 
multiforme or anaplastic astrocytoma. Temozolomide Sandoz is used in these tumours if they 
return or get worse after standard treatment. 

 
 
2.  What you need to know before you  take Temozolomide Sandoz 
 
Do not take Temozolomide Sandoz 
 
• if you are allergic to temozolomide or any of the other ingredients of this medicine (listed in 

section 6). 

 139 



• if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
DTIC). Signs of allergic reaction include feeling itchy, breathlessness or wheezing, swelling of 
the face, lips, tongue or throat. 

• if certain kinds of blood cells are severely reduced (myelosuppression), such as your white 
blood cell count and platelet count. These blood cells are important for fighting infection and 
for proper blood clotting. Your doctor will check your blood to make sure you have enough of 
these cells before you begin treatment.  

 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before taking Temozolomide Sandoz 
 
• as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you are a newly-diagnosed patient 
(glioblastoma multiforme) you may be receiving Temozolomide Sandoz for 42 days in 
combination with radiotherapy. In this case, your doctor will also prescribe medicine to help 
you prevent this type of pneumonia (PCP). 

• if you have ever had or might now have a hepatitis B infection. This is because temozolomide 
could cause hepatitis B to become active again, which can be fatal in some cases. Patients will 
be carefully checked by their doctor for signs of this infection before treatment is started. 

• if you have low counts of red blood cells (anaemia), white blood cells and platelets, or blood 
clotting problems before starting the treatment, or if you develop them during treatment. Your 
doctor may decide to reduce the dose, interrupt, stop or change your treatment. You may also 
need other treatments. In some cases, it may be necessary to stop treatment with Temozolomide 
Sandoz. Your blood will be tested frequently during treatment to monitor the side effects of 
Temozolomide Sandoz on your blood cells. 

• as you may have a small risk of other changes in blood cells, including leukaemia. 
• if you have nausea (feeling sick in your stomach) and/or vomiting which are both very common 

side effects of Temozolomide Sandoz (see section 4), your doctor may prescribe you a 
medicine (an anti-emetic) to help prevent vomiting.  
If you vomit frequently before or during treatment, ask your doctor about the best time to take 
Temozolomide Sandoz until the vomiting is under control. If you vomit after taking your dose, 
do not take a second dose on the same day. 

• if you develop fever or symptoms of an infection, contact your doctor immediately.  
• if you are older than 70 years of age. You might be more prone to infections, bruising or 

bleeding. 
• if you have liver or kidney problems. Your dose of Temozolomide Sandoz may need to be 

adjusted. 
 
Children and adolescents 
 
Do not give this medicine to children under the age of 3 years because it has not been studied. There 
is limited information in patients over 3 years of age who have taken Temozolomide Sandoz. 
 
Other medicines and Temozolomide Sandoz 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine. This is because you must not be treated with 
Temozolomide Sandoz during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide Sandoz (see also “Male fertility” below). 

 140 



You should stop breast-feeding while receiving treatment with Temozolomide Sandoz. 
 
Male fertility 
 
Temozolomide Sandoz may cause permanent infertility. Male patients should use effective 
contraception and not father a child for up to 6 months after stopping treatment. It is recommended to 
seek advice on conservation of sperm prior to treatment. 
 
Driving and using machines 
 
Temozolomide Sandoz may make you feel tired or sleepy. In this case, do not drive or use any tools 
or machines or cycle until you see how this medicine affects you (see section 4).  
 
Temozolomide Sandoz contains lactose  
 
Temozolomide Sandoz contains lactose (a kind of sugar). If you have been told by your doctor that 
you have an intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3.  How to take Temozolomide Sandoz 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Dosage and duration of treatment 
 
Your doctor will work out your dose of Temozolomide Sandoz. This is based on your size (height and 
weight) and if you have a recurrent tumour and have had chemotherapy treatment in the past. 
 
You may be given other medicines (anti-emetics) to take before and/or after taking Temozolomide 
Sandoz to prevent or control nausea and vomiting. 
 
Patients with newly-diagnosed glioblastoma multiforme 
 
If you are a newly-diagnosed patient, treatment will occur in two phases: 
• treatment together with radiotherapy (concomitant phase) first 
• followed by treatment with only Temozolomide Sandoz (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide Sandoz at a dose of 75 mg/m2 
(usual dose).You will take this dose every day for 42 days (up to 49 days) in combination with 
radiotherapy. The Temozolomide Sandoz dose may be delayed or stopped, depending on your blood 
counts and how you tolerate your medicine during the concomitant phase. 
 
Once the radiotherapy is completed, you will interrupt treatment for 4 weeks. This will give your 
body a chance to recover. 
 
Then, you will start the monotherapy phase.  
 
During the monotherapy phase, the dose and way you take Temozolomide Sandoz will be different. 
Your doctor will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one 
lasts 28 days. You will take your new dose of Temozolomide Sandoz alone once daily for the first 
5 days (“dosing days”) of each cycle. The first dose will be 150 mg/m2. Then you will have 23 days 
without Temozolomide Sandoz. This adds up to a 28-day treatment cycle.  
 
After Day 28, the next cycle will begin. You will again take Temozolomide Sandoz once daily for 
5 days followed by 23 days without Temozolomide Sandoz. The Temozolomide Sandoz dose may be 

 141 



adjusted, delayed or stopped depending on your blood counts and how you tolerate your medicine 
during each treatment cycle. 
 
Patients with tumours that have returned or worsened (malignant glioma, such as glioblastoma 
multiforme or anaplastic astrocytoma) taking Temozolomide Sandoz only 
 
A treatment cycle with Temozolomide Sandoz lasts 28 days.  
You will take Temozolomide Sandoz alone once daily for the first 5 days. This daily dose depends on 
whether or not you have received chemotherapy before. 
 
If you have not been previously treated with chemotherapy, your first dose of Temozolomide Sandoz 
will be 200 mg/m2 once daily for the first 5 days. If you have been previously treated with 
chemotherapy, your first dose of Temozolomide Sandoz will be 150 mg/m2 once daily for the first 
5 days. 
 
Then, you will have 23 days without Temozolomide Sandoz. This adds up to a 28-day treatment 
cycle. 
 
After Day 28, the next cycle will begin. You will again receive Temozolomide Sandoz once daily for 
5 days, followed by 23 days without Temozolomide Sandoz. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide dose needs to 
be adjusted. Depending on your blood test results, your doctor may adjust your dose for the next 
cycle. 
 
How to take Temozolomide Sandoz 
 
Take your prescribed dose of Temozolomide Sandoz once a day, preferably at the same time each 
day. 
 
Take the capsules on an empty stomach; for example, at least one hour before you plan to eat 
breakfast. Swallow the capsule(s) whole with a glass of water. Do not open, crush or chew the 
capsules. If a capsule is damaged, avoid contact of the powder with your skin, eyes or nose. If you 
accidentally get some in your eyes or nose, flush the area with water. 
  
Depending on the prescribed dose, you may have to take more than one capsule together, eventually 
with different strengths (content of active substance, in mg). The colour of the capsule cap is different 
for each strength (see in the table below). 
 

Strength Colour of the cap 

Temozolomide Sandoz     5 mg hard capsules green 

Temozolomide Sandoz   20 mg hard capsules  yellow 

Temozolomide Sandoz 100 mg hard capsules  pink 

Temozolomide Sandoz 140 mg hard capsules  blue 

Temozolomide Sandoz 180 mg hard capsules  maroon 

Temozolomide Sandoz 250 mg hard capsules  white 
 
You should make sure you fully understand and remember the following: 
• how many capsules you need to take every dosing day. Ask your doctor or pharmacist to write 

it down (including the colour). 
• which days are your dosing days. 
 

 142 



Review the dose with your doctor each time you start a new cycle, since it may be different from the 
last cycle. 
 
Always take Temozolomide Sandoz exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Errors in how you take this medicine may have 
serious health consequences. 
 
If you take more Temozolomide Sandoz than you should 
If you accidentally take more Temozolomide Sandoz capsules than you were told to, contact your 
doctor, pharmacist or nurse immediately. 
 
If you forget to take Temozolomide Sandoz  
Take the missed dose as soon as possible during the same day. If a full day has gone by, check with 
your doctor. Do not take a double dose to make up for a forgotten dose, unless your doctor tells you to 
do so. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Contact your doctor immediately if you have any of the following: 
• a severe allergic (hypersensitive) reaction (hives, wheezing or other breathing difficulty),  
• uncontrolled bleeding,  
• seizures (convulsions), 
• fever, 
• chills 
• severe headache that does not go away. 
 
Temozolomide Sandoz treatment can cause a reduction in certain kinds of blood cells. This may cause 
you to have increased bruising or bleeding, anaemia (a shortage of red blood cells), fever, and reduced 
resistance to infections. The reduction in blood cell counts is usually short-lived. In some cases, it 
may be prolonged and may lead to a very severe form of anaemia (aplastic anaemia). Your doctor will 
monitor your blood regularly for any changes, and will decide if any specific treatment is needed. In 
some cases, your Temozolomide Sandoz dose will be reduced or treatment stopped. 
 
Side effects from clinical studies: 
 
Temozolomide in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving temozolomide in combination with radiotherapy may experience different side 
effects than patients taking temozolomide alone. The following side effects may occur, and may 
require medical attention. 
 
Very common (may affect more than 1 in 10 people):  
• loss of appetite  
• headache  
• constipation (difficulty passing stools)  
• nausea (feeling sick in your stomach)  
• vomiting 
• rash  
• hair loss  
• tiredness. 
 
Common (may affect up to 1 in 10 people):  

 143 



• oral infections  
• wound infection  
• reduced number of blood cells (neutropenia, thrombocytopenia, lymphopenia, leukopenia)  
• increased sugar in the blood  
• loss of weight  
• change in mental status or alertness  
• anxiety/depression  
• sleepiness  
• difficulty speaking  
• impaired balance  
• dizziness  
• confusion  
• forgetfulness  
• difficulty concentrating  
• inability to fall asleep or stay asleep  
• tingling sensation  
• bruising, shaking  
• abnormal or blurry vision  
• double vision  
• hearing impairment  
• shortness of breath  
• cough 
• blood clot in the legs  
• fluid retention  
• swollen legs  
• diarrhoea  
• stomach or abdominal pain  
• heartburn  
• upset stomach  
• difficulty swallowing  
• dry mouth  
• skin irritation or redness  
• dry skin  
• itching  
• muscle weakness  
• painful joints  
• muscle aches and pains  
• frequent urination  
• difficulty with holding your urine  
• allergic reaction  
• fever  
• radiation injury  
• face swelling  
• pain  
• abnormal taste  
• abnormal liver function tests. 
 
Uncommon (may affect up to 1 in 100 people):  
• flu-like symptoms  
• red spots under the skin  
• low potassium level in the blood  
• weight gain  
• mood swings  
• hallucination and memory impairment  
• partial paralysis  
• impaired coordination   
• impaired sensations 

 144 



• partial loss of vision  
• dry or painful eyes  
• deafness  
• infection of the middle ear  
• ringing in the ears  
• earache  
• palpitations (when you can feel your heart beat)  
• blood clot in the lung  
• high blood pressure  
• pneumonia  
• inflammation of your sinuses  
• bronchitis  
• a cold or the flu  
• swollen stomach   
• difficulty controlling your bowel movements  
• haemorrhoids  
• peeling skin  
• increased skin sensitivity to sunlight  
• change in skin colour  
• increased sweating  
• muscle damage  
• back pain  
• difficulty in urinating  
• vaginal bleeding  
• sexual impotence  
• absent or heavy menstrual periods, 
• vaginal irriation  
• breast pain  
• hot flushes  
• shivering  
• discolouration of your tongue  
• change in your sense of smell  
• thirst  
• tooth disorder. 
 
Temozolomide monotherapy in recurrent or progressive glioma 
 
The following side effects may occur, and may require medical attention. 
 
Very common (may affect more than 1 in 10 people):  
• reduced number of blood cells (neutropenia or lymphopenia, thrombocytopenia)  
• loss of appetite  
• headache  
• vomiting  
• nausea (feeling sick in your stomach)  
• constipation (difficulty passing stools) 
• tiredness. 
 
Common (may affect up to 1 in 10 people):  
• loss of weight  
• sleepiness  
• dizziness  
• tingling sensation  
• shortness of breath  
• diarrhoea  
• abdominal pain  
• upset stomach  

 145 



• rash  
• itching  
• hair loss  
• fever  
• weakness  
• shivering  
• feeling unwell  
• pain  
• change in taste. 
 
Uncommon (may affect up to 1 in 100 people):  
•  reduced blood cell counts (pancytopenia, anaemia, leukopenia). 
 
Rare (may affect up to 1 in 1,000 people):  
• cough  
• infections including pneumonia. 
 
Very rare (may affect up to 1 in 10,000 people):  
• Skin redness  
• urticaria (hives)  
• skin eruption  
• allergic reactions. 
 
Other side effects: 
 
Cases of elevations of liver enzymes have been commonly reported. Cases of increased bilirubin, 
problems with bile flow (cholestasis), hepatitis and injury to the liver, including fatal liver failure, 
have been uncommonly reported. 
 
Very rare cases of severe rash with skin swelling, including on the palms of the hands and soles of the 
feet, or painful reddening of the skin and/or blisters on the body or in the mouth have been observed.  
Tell your doctor immediately if this occurs 
 
Very rare cases of lung side effects have been observed with temozolomide. Patients usually present 
with shortness of breath and cough. Tell your doctor if you notice any of these symptoms. 
 
In very rare cases, patients taking temozolomide and medicines like it may have a small risk of 
developing secondary cancers, including leukaemia. 
 
New or reactivated (recurring) cytomegalovirus infections and reactivated hepatitis B virus infections 
have been uncommonly reported. Cases of brain infections caused by herpes virus 
(meningoencephalitis herpetic), including fatal cases, have been uncommonly reported. Cases of 
sepsis (when bacteria and their toxins circulate in the blood and start to damage the organs) have been 
uncommonly reported. 
 
Cases of diabetes insipidus have been uncommonly reported. Symptoms of diabetes insipidus include 
passing a lot of urine and feeling thirsty. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Temozolomide Sandoz 
 

 146 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


Keep this medicine out of the sight and reach of children, preferably in a locked cupboard. Accidental 
ingestion can be lethal for children. 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Bottle 
Do not store above 25°C 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25°C 
 
Tell your pharmacist if you notice any change in the appearance of the capsules. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Temozolomide Sandoz contains 
 
• The active substance is temozolomide.  
 

Temozolomide Sandoz 5 mg hard capsules 
Each capsule contains 5 mg temozolomide. 
 
Temozolomide Sandoz 20 mg hard capsules 
Each capsule contains 20 mg temozolomide. 
 
Temozolomide Sandoz 100 mg hard capsules 
Each capsule contains 100 mg temozolomide. 
 
Temozolomide Sandoz 140 mg hard capsules 
Each capsule contains 140 mg temozolomide. 
 
Temozolomide Sandoz 180 mg hard capsules 
Each capsule contains 180 mg temozolomide. 
 
Temozolomide Sandoz 250 mg hard capsules 
Each capsule contains 250 mg temozolomide. 

 
• The other ingredients of the capsule are  
 

Temozolomide Sandoz 5 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), yellow iron oxide (E 172), indigo 

carmine (E 132), water. 
-  Printing ink: shellac, black iron oxide (E 172), potassium hydroxide. 

 
Temozolomide Sandoz 20 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), yellow iron oxide (E 172), water. 
-  Printing ink: shellac, black iron oxide (E 172), potassium hydroxide. 

 

 147 



Temozolomide Sandoz 100 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), red iron oxide (E 172), water. 
-  Printing ink: shellac, black iron oxide (E 172), potassium hydroxide. 

 
Temozolomide Sandoz 140 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), indigo carmine (E 132), water. 
-  Printing ink: shellac, black iron oxide (E 172), potassium hydroxide. 

 
Temozolomide Sandoz 180 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), yellow iron oxide (E 172), red iron 

oxide (E 172), water. 
-  Printing ink: shellac, black iron oxide (E 172), potassium hydroxide. 

 
Temozolomide Sandoz 250 mg hard capsules 
-  Capsule content: anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate 

type A, tartaric acid, stearic acid.  
-  Capsule shell: gelatine, titanium dioxide (E 171), water. 
-  Printing ink: contains shellac, black iron oxide (E 172), potassium hydroxide. 

 
What Temozolomide Sandoz looks like and contents of the pack 
 
Bottle 
The hard capsules are dispensed in amber glass bottles (Type 3 glass) with polypropylene child-
resistant closures. Each bottle contains either 5 or 20 capsules. The bottles also contain a desiccant 
pouch. Keep the desiccant pouch in the bottle. Do not swallow it. 
 
Sachet 
Each hard capsule (capsule) is individually packed in a sachet. Each carton contains 5 or 20 hard 
capsules. 
 
Not all pack sizes may be marketed. 
 
Temozolomide Sandoz 5 mg hard capsules 
The hard capsules have a white coloured body, a green coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “5”. 
Each capsule is approximately 15.8 mm in length. 
 
Temozolomide Sandoz 20 mg hard capsules 
The hard capsules have a white coloured body, a yellow coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “20”. 
Each capsule is approximately 11.4 mm in length. 
 
Temozolomide Sandoz 100 mg hard capsules 
The hard capsules have a white coloured body, a pink coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “100”. 
Each capsule is approximately 15.8 mm in length. 
 
Temozolomide Sandoz 140 mg hard capsules 
The hard capsules have a white coloured body, a transparent blue coloured cap, and are imprinted 
with black ink. The cap is imprinted with “TMZ” and the body is imprinted with “140”. 
Each capsule is approximately 19.3 mm in length. 

 148 



Temozolomide Sandoz 180 mg hard capsules 
The hard capsules have a white coloured body, a maroon coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “180”. 
Each capsule is approximately 19.3 mm in length. 
 
Temozolomide Sandoz 250 mg hard capsules 
The hard capsules have a white coloured body, a white coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “250”. 
Each capsule is approximately 21.4 mm in length. 
 
Marketing Authorisation Holder 
Sandoz GmbH 
Biochemiestraße 10 
A-6250 Kundl 
Austria 
 
Manufacturer 
Salutas Pharma GmbH 
Otto-von-Guericke-Allee 1 
D-39179 Barleben 
Germany 
 
Lek Pharmaceuticals d.d 
Verovskova 57 
SL-1526 Ljubljana 
Slovenia 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder:  
 
België/Belgique/Belgien 
Sandoz N.V. 
Telecom Gardens 
Medialaan 40 
B-1800 Vilvoorde 
Tél/Tel: +32 2 738 78 37 
 

Lietuva 
Sandoz Pharmaceuticals d.d  
Branch Office Lithuania 
Seimyniskiu 3A 
LT – 09312 Vilnius 
Tel: +370 5 2636 037 
 

България 
Sandoz Bulgaria Branch Office 
55 Nikola Vaptzarov blvd. 
Building 4, floor 4 
1407-Sofia 
Teл.: '+359 2 970 47 54 
 

Luxembourg/Luxemburg 
HEXAL AG 
Industriestraße 25 
D-83607 Holzkirchen 
Tél/Tel: +49 39205 42-1305 
dra.co_de@hexal.com  

Česká republika 
Sandoz s.r.o. 
Na Pankráci 1724/129 
CZ-140 00, Praha 4  
Tel: +420 225 755 111 
CZ.Sandoz.Regulatory_ORG_GX_cz@dl.mgd.no
vartis.com 

Magyarország 
Sandoz Hungaria Kft. 
Bartók Béla út 43-47 
H-1114 Budapest 
Tel: +36 1 430 2890 
registration.hungary@sandoz.com  

 149 



Danmark 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
 
+45 6395 1000 
variations.nordic@sandoz.com 
 

Malta 
V J Salomone Pharma Limited 
Upper Cross Road,  
Marsa MRS 1542 
Tel: +356 22983 143 
regvjsp@vjsalomone.com 

Deutschland 
Hexal AG 
Industriestr. 25 
D-83607 Holzkirchen 
Tel: +49 39205 42-1305 
dra.co_de@hexal.com 

Nederland 
Sandoz B.V. 
Veluwezoom 22 
NL-1327 AH Almere 
Tel: +31 (0)36 5241600 
nl.registration@sandoz.com  

 
Eesti 
Sandoz d.d. Eesti filiaal 
Pärnu mnt 105 
EE – 11312 Tallinn 
Tel: +372 6652405 
 

 
Norge 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
+45 6395 1000 
variations.nordic@sandoz.com 
 

Ελλάδα 
Novartis (Hellas) S.A.C.I 
18, Kifisias Ave. & Gyzi,  
151 25 Marousi, Athens 
Τηλ: +30 216 6005011 
regulatory.greece@sandoz.com 

Österreich 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Tel: +43(0)1 86659-0 
registration.vienna@sandoz.com 
 

 
España 
Sandoz Farmacéutica, S.A  
Centro Empresarial Parque Norte 
C/ Serrano Galvache Nº 56, Edificio Roble  
E-28033 Madrid 
Tel: +34 91 602 30 62 
registros.spain@sandoz.com 
 

 
Polska 
Sandoz Polska Sp. z o.o. 
ul. Domaniewska 50 C 
PL – 02 672 Warszawa 
Tel.: +48 22 209 6828 
maintenance.pl@sandoz.com 
 
 

France 
Sandoz SAS 
49, avenue Georges Pompidou 
F-92593 Levallois-Perret Cedex 
Tél: +33 1 49 64 48 43 
regaff.france@sandoz.com 
 
 

Portugal 
Sandoz Farmacêutica Lda. 
Avenida Professor Doutor Cavaco Silva, n.º 10E 
Taguspark 
P-2740−255 Porto Salvo 
Tel: +351 21 196 40 42 
regaff.portugal@sandoz.com 
 

Hrvatska 
Sandoz d.o.o. 
Maksimirska 120 
HR – 10 000 Zagreb 
Tel : +385 1 235 3111 

România 
SC Sandoz S.R.L. 
Strada Livezeni 7a 
540472 Targu Mures 
Tel: +40 21 407 51 60 
RegAffairs.ro@sandoz.com 
 
 
 

 
 

 
 

 150 



Ireland 
Rowex Ltd 
IE-Bantry Co. Cork 
Tel: +353 27 50077 

Slovenija 
Lek Pharmaceuticals d.d. 
Verovškova 57 
SI-1526 Ljubljana 
Tel: +386 1 580 3059 
si.regaffairs@sandoz.com 
 

Ísland 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
+45 6395 1000 
variations.nordic@sandoz.com  

Slovenská republika 
Sandoz d.d. -  organizačná zložka 
Žižkova 22B,  
811 02 BratislavaTel: 
+421250706111sk.regulatory@sandoz.com 
 

Italia 
Sandoz S.p.A. 
Largo Umberto Boccioni, 1 
I-21040 Origgio / VA 
Tel: +39 02 96 54 3494 
regaff.italy@sandoz.com 
 

Suomi/Finland 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 Kööpenhamina S/Köpenhamn S 
+45 6395 1000 
variations.nordic@sandoz.com 
 

Κύπρος 
P.T.Hadjigeorgiou Co Ltd  
31 Yildiz Street, 3042 Limassol  
Τηλ: 00357 – 25372425 
info.pth@cytanet.com.cy 
 

Sverige 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 Köpenhamn S 
+45 6395 1000 
variations.nordic@sandoz.com 
 

Latvija 
Sandoz d.d. Latvia brunch  
K.Valdemāra 33 – 30 
LV-1010 Rīga 
Tel: +371 67892006 
balt.regaffairs@sandoz.com 

United Kingdom 
Sandoz Ltd 
Frimley Business Park 
Frimley, Camberley  
Surrey GU16 7SR - UK 
Tel: +44 1276 69 8020 
uk.regaffairs@sandoz.com 

 
 
This leaflet was last revised in <{MM/YYYY}>. 
 
Other sources of information 
 
Detailed information on this medicine is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 
 
 
 

 151 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET