Temozolomide Sun

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 5 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 5 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 30.97 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsules, with white opaque cap and body, imprinted in green ink. The cap is imprinted 
with ‘890’. The body is imprinted with ‘5 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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 



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- the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction. 

 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4) 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide SUN 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). 
 



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4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1. 
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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. 
 



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Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN should 
be administered without food. 



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Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ. 
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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). 
 



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4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 
 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 



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System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Uncommon: Agitation, apathy, behaviour 
disorder, depression, 
hallucination 

Hallucination, amnesia 
 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 
neuropathy, paresthesia, speech 
disorder, tremor 

Hemiparesis, aphasia, balance 
impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 
neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 
 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, Stomatitis, diarrhoea, 



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System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

abdominal pain, dyspepsia, 
dysphagia 
 

dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 
Very common: Rash, alopecia Rash, alopecia 
Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, 
photosensitivity reaction, 
pigmentation abnormal 

Erythema, pigmentation 
abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

*A patient who was randomised to the RT arm only, received TMZ + RT. 
 
Laboratory results 
 
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for 
most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse 



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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 Temozolomide SUN. 
 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 

 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 



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Other special populations 
 
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: 
 



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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  

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 
Frequency 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, 
multiorgan 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. 
 
 

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


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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. 



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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 
noncomparative 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. 
 



16 

 

Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 
5.3 Preclinical safety data 
 
Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in 
rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, 
testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and 
dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, 
except for adverse events on the male reproductive system and retinal degeneration. However, because 
the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect 
has been observed in clinical studies, this finding was not considered to have clinical relevance. 
 
TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and 
dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. 
Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A 
variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell 
adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were 
evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the 
occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even 
for an alkylating agent. 
 



17 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Yellow iron oxide (E172) 
Blue #1/Brilliant Blue FCF Aluminium Lake (E133) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  
 
6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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. 
 



18 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/013 (5 capsules in blister) 
EU/1/11/697/014 (20 capsules in blister) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



19 

 

1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 20 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 20 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 18.16 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsule, with white opaque cap and body, imprinted in yellow ink. The cap is imprinted 
with ‘891’. The body is imprinted with ’20 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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: 



20 

 

- 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 



21 

 

- the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction. 

 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4) 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide SUN 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). 
 



22 

 

4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jiroveciipneumonia 
 
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 jiroveciipneumonia (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. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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. 
 



23 

 

Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN should 
be administered without food. 



24 

 

 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ. 
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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 
 
Summary of the safety profile 
 
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, 



25 

 

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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 
 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 

Uncommon: Agitation, apathy, behaviour 
disorder, depression, 
hallucination 

Hallucination, amnesia 
 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness Hemiparesis, aphasia, balance 



26 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 
neuropathy, paresthesia, speech 
disorder, tremor 

impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 
neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 
 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, 

abdominal pain, dyspepsia, 
dysphagia 
 

Stomatitis, diarrhoea, 
dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 



27 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Very common: Rash, alopecia Rash, alopecia 
Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, 
photosensitivity reaction, 
pigmentation abnormal 

Erythema, pigmentation 
abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

*A patient who was randomised to the RT arm only, received TMZ + RT. 
 
Laboratory results 
 
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for 
most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse 
events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 
neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or 
Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the 
patients who received TMZ. 
 
Recurrent or progressive malignant glioma 
 
In clinical trials, the most frequently occurring treatment-related undesirable effects were 
gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were 



28 

 

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 Temozolomide SUN. 
 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 

 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Other special populations 
 
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 % 



29 

 

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  

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 
Frequency 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. 

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


30 

 

 
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, 
multiorgan failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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). 
 



31 

 

 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 
noncomparative 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 



32 

 

similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-
1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. 
Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In 
vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr. 
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 



33 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Yellow iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  
 



34 

 

6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/015 (5 capsules in blister) 
EU/1/11/697/016 (20 capsules in blister) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



35 

 

1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 100 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 100 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 90.801 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsules, with white opaque cap and body, imprinted in pink ink. Thw cap is imprinted 
with ‘892’. The body is imprinted with ‘100 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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: 



36 

 

- 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 



37 

 

- the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction. 

 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4) 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide SUN 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). 
 



38 

 

4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jiroveciipneumonia 
 
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 jiroveciipneumonia (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. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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. 
 



39 

 

Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN should 
be administered without food. 



40 

 

 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ. 
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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 
 
Summary of the safety profile 
 
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, 



41 

 

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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 
 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 

Uncommon: Agitation, apathy, behaviour 
disorder, depression, 
hallucination 

Hallucination, amnesia 
 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness Hemiparesis, aphasia, balance 



42 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 
neuropathy, paresthesia, speech 
disorder, tremor 

impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 
neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, 

abdominal pain, dyspepsia, 
dysphagia 
 

Stomatitis, diarrhoea, 
dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 
Very common: Rash, alopecia Rash, alopecia 



43 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, 
photosensitivity reaction, 
pigmentation abnormal 

Erythema, pigmentation 
abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

*A patient who was randomised to the RT arm only, received TMZ + RT. 
 
Laboratory results 
 
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for 
most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse 
events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 
neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or 
Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the 
patients who received TMZ. 
 
Recurrent or progressive malignant glioma 
 
In clinical trials, the most frequently occurring treatment-related undesirable effects were 
gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were 



44 

 

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 Temozolomide SUN. 
 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 

 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Other special populations 
 
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 % 



45 

 

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  

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 
Frequency 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. 

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


46 

 

 
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, 
multiorgan failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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). 
 



47 

 

 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 
noncomparative 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 



48 

 

similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-
1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. 
Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In 
vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr. 
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 



49 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Red iron oxide (E172) 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 



50 

 

6.4 Special precautions for storage 
 
Do not store above 25°C.  
 
6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/017 (5 capsules in blister) 
EU/1/11/697/018 (20 capsules in blister) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



51 

 

1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 140 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 140 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 127.121 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsules, with white opaque cap and body, imprinted in blue ink. The cap is imprinted 
with ‘929’. The body is imprinted with ‘140 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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: 



52 

 

- 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 



53 

 

- the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction. 

 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4) 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide SUN 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). 
 



54 

 

4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jiroveciipneumonia 
 
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 jiroveciipneumonia (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. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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. 
 



55 

 

Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN should 
be administered without food. 



56 

 

 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ. 
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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 
 
Summary of the safety profile 
 
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, 



57 

 

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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 
 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 

Uncommon: Agitation, apathy, behaviour 
disorder, depression, 
hallucination 

Hallucination, amnesia 
 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness Hemiparesis, aphasia, balance 



58 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 
neuropathy, paresthesia, speech 
disorder, tremor 

impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 
neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, 

abdominal pain, dyspepsia, 
dysphagia 
 

Stomatitis, diarrhoea, 
dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 
Very common: Rash, alopecia Rash, alopecia 



59 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, 
photosensitivity reaction, 
pigmentation abnormal 

Erythema, pigmentation 
abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

*A patient who was randomised to the RT arm only, received TMZ + RT. 
 
Laboratory results 
 
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for 
most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse 
events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 
neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or 
Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the 
patients who received TMZ. 
 
Recurrent or progressive malignant glioma 
 
In clinical trials, the most frequently occurring treatment-related undesirable effects were 
gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were 



60 

 

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 Temozolomide SUN. 
 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Other special populations 
 
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 



61 

 

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  

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 
Frequency 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. 
 

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


62 

 

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, 
multiorgan failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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). 
 



63 

 

 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 
noncomparative 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 



64 

 

similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-
1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. 
Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In 
vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr. 
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 



65 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Titanium dioxide (E171) 
Blue #1/Brilliant Blue FCF Aluminium Lake (E133) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  



66 

 

 
6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/019 (5 capsules in blister) 
EU/1/11/697/020 (20 capsules in blister 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



67 

 

1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 180 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 180 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 163.441 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsules, with white opaque cap and body, imprinted in red ink. The cap is imprinted 
with ‘930’. The body is imprinted with ‘180 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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: 



68 

 

- 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. 
 



69 

 

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 SUN 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). 
 



70 

 

Pneumocystis jiroveciipneumonia 
 
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 jiroveciipneumonia (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. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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 
 



71 

 

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN 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. 
 



72 

 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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). 
 



73 

 

4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 

Uncommon: Agitation, apathy, behaviour Hallucination, amnesia 



74 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

disorder, depression, 
hallucination 

 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 
neuropathy, paresthesia, speech 
disorder, tremor 

Hemiparesis, aphasia, balance 
impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 
neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, 

abdominal pain, dyspepsia, 
dysphagia 
 

Stomatitis, diarrhoea, 
dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 



75 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 
Very common: Rash, alopecia Rash, alopecia 
Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, 
photosensitivity reaction, 
pigmentation abnormal 

Erythema, pigmentation 
abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

*A patient who was randomised to the RT arm only, received TMZ + RT. 
 
Laboratory results 
 
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for 
most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse 
events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 
neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or 
Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the 
patients who received TMZ. 



76 

 

 
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 Temozolomide SUN. 
 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 

 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Other special populations 
 
Gender 
 



77 

 

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  

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 
Frequency not known drug reaction with eosinophilia and systemic 

symptoms (DRESS) 
† Including cases with fatal outcome 
* Frequencies estimated based on relevant clinical trials. 
 



78 

 

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, 
multiorgan failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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). 
 

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


79 

 

 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 
noncomparative 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 



80 

 

similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-
1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. 
Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In 
vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr. 
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 



81 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Red iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  
 



82 

 

6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/021 (5 capsules in blister) 
EU/1/11/697/022 (20 capsules in blister) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



83 

 

1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 250 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 250 mg temozolomide. 
 
Excipient with known effect 
Each hard capsule contains 227.001 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Hard gelatin capsules, with white opaque cap and body, imprinted in black ink. The cap is imprinted 
with ‘893’. The body is imprinted with ‘250 mg’ and two stripes. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide SUN 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 SUN 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 SUN 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: 



84 

 

- 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. 
 



85 

 

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 SUN 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). 
 



86 

 

Pneumocystis jiroveciipneumonia 
 
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 jiroveciipneumonia (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. 
 
Hepatitis B virus 
 
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. 
 
Meningoencephalitis herpetic 
 
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. 
 
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. 
 



87 

 

Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic 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 Lapp lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC). 
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC). 
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide SUN 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. 



88 

 

 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products 
(see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
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 SUN 
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. 
 
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 
 
Summary of the safety profile 
 
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 



89 

 

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. 
 
Tabulated list of adverse reactions 
 
In the tables undesirable effects are classified according to System Organ Class and frequency. 
Frequency groupings are defined according to the following convention: very common (≥ 1/10); 
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very 
rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
Newly-diagnosed glioblastoma multiforme 
 
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma 
multiforme during the concomitant and monotherapy phases of treatment. 
 

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in 
patients with newly-diagnosed glioblastoma multiforme 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

Infections and infestations 
Common: Infection, Herpes simplex, 

wound infection, pharyngitis, 
candidiasis oral 

Infection, candidiasis oral 
 

Uncommon:  Herpes simplex, herpes zoster, 
influenza–like symptoms 

Blood and lymphatic system disorders 
Common: 
 

Neutropenia, thrombocytopenia, 
lymphopenia, leukopenia 

Febrile neutropenia, 
thrombocytopenia, anaemia, 
leukopenia 

Uncommon: Febrile neutropenia, anaemia Lymphopenia, petechiae 
Endocrine disorders 
Uncommon: Cushingoid Cushingoid 
Metabolism and nutrition disorders 
Very common: Anorexia Anorexia 
Common: Hyperglycaemia, weight 

decreased 
Weight decreased 

Uncommon: Hypokalemia, alkaline 
phosphatase increased, weight 
increased 

Hyperglycaemia, weight 
increased 

Psychiatric disorders 
Common: Anxiety, emotional lability, 

insomnia 
Anxiety, depression, emotional 
lability, insomnia 

Uncommon: Agitation, apathy, behaviour 
disorder, depression, 
hallucination 

Hallucination, amnesia 
 

Nervous system disorders 

Very common: Headache Convulsions, headache 
Common: Convulsions, consciousness 

decreased, somnolence, aphasia, 
balance impaired, dizziness, 
confusion, memory impairment, 
concentration impaired, 

Hemiparesis, aphasia, balance 
impaired, somnolence, 
confusion, dizziness, memory 
impairment, concentration 
impaired, dysphasia, 



90 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

neuropathy, paresthesia, speech 
disorder, tremor 

neurological disorder (NOS), 
neuropathy, peripheral 
neuropathy, paresthesia, speech 
disorder, tremor 

Uncommon: Status epilepticus, 
extrapyramidal disorder, 
hemiparesis, ataxia, cognition 
impaired, dysphasia, gait 
abnormal, hyperesthesia, 
hypoesthesia, neurological 
disorder (NOS), peripheral 
neuropathy 

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

Eye disorders 
Common: Vision blurred Visual field defect, vision 

blurred, diplopia 
Uncommon: Hemianopia, visual acuity 

reduced, vision disorder, visual 
field defect, eye pain 

Visual acuity reduced, eye pain, 
eyes dry 
 

Ear and labyrinth disorders 
Common: Hearing impairment Hearing impairment, tinnitus 
Uncommon: Otitis media, tinnitus, 

hyperacusis, earache 
Deafness, vertigo, earache 
 

Cardiac disorders 
 
Uncommon: Palpitation 

 
 

Vascular disorders 
Common: Haemorrhage, oedema, oedema 

leg 
Haemorrhage, deep venous 
thrombosis, oedema leg 

Uncommon: Cerebral haemorrhage, 
hypertension 

Embolism pulmonary, oedema, 
oedema peripheral 

Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, coughing Dyspnoea, coughing 
Uncommon: Pneumonia, upper respiratory 

infection, nasal congestion 
Pneumonia, sinusitis, upper 
respiratory infection, bronchitis 
 

Gastrointestinal disorders 
Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting 
Common: Stomatitis, diarrhoea, 

abdominal pain, dyspepsia, 
dysphagia 
 

Stomatitis, diarrhoea, 
dyspepsia, dysphagia, mouth 
dry 
 

Uncommon:  Abdominal distension, fecal 
incontinence, gastrointestinal 
disorder (NOS), gastroenteritis, 
haemorrhoids 
 

Skin and subcutaneous tissue disorders 
Very common: Rash, alopecia Rash, alopecia 
Common: 
 

Dermatitis, dry skin, erythema, 
pruritus 

Dry skin, pruritus 
 

Uncommon: Skin exfoliation, Erythema, pigmentation 



91 

 

System organ class TMZ + concomitant RT 
n=288* 

TMZ monotherapy 
n=224 

photosensitivity reaction, 
pigmentation abnormal 

abnormal, sweating increased 
 

Musculoskeletal and connective tissue disorders 
Common: Muscle weakness, arthralgia Muscle weakness, arthralgia, 

musculoskeletal pain, myalgia 
 

Uncommon: Myopathy, back pain, 
musculoskeletal pain, myalgia 

Myopathy, back pain 
 

Renal and urinary disorders 
Common: Micturition frequency, urinary 

incontinence 
Urinary incontinence 
 

Uncommon:  Dysuria 
Reproductive system and breast disorders 
 
Uncommon: Impotence Vaginal haemorrhage, 

menorrhagia, amenorrhea, 
vaginitis, breast pain 

General disorders and administration site conditions 
Very common: Fatigue Fatigue 
Common: Allergic reaction, fever, 

radiation injury, face oedema, 
pain, taste perversion 

Allergic reaction, fever, 
radiation injury, pain, taste 
perversion 

Uncommon: Asthenia, flushing, hot flushes, 
condition aggravated, rigors, 
tongue discolouration, 
parosmia, thirst 
 

Asthenia, face oedema, pain, 
condition aggravated, rigors, 
tooth disorder 

Investigations 
Common: 
 

ALT increased ALT increased 

Uncommon: Hepatic enzymes increased, 
Gamma GT increased, AST 
increased 

 

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



92 

 

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant 
glioma and following the marketing of Temozolomide SUN. 

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma 
Infections and infestations 
Rare: Opportunistic infections, including PCP 
Blood and lymphatic system disorders 
Very common: Neutropenia or lymphopenia (grade 3-4), 

thrombocytopenia (grade 3-4) 
Uncommon: Pancytopenia, anaemia (grade 3-4), leukopenia 
Metabolism and nutrition disorders 
Very common: Anorexia 
Common: Weight decrease 
Nervous system disorders 
Very common: Headache 
Common: Somnolence, dizziness, paresthesia 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea 
Gastrointestinal disorders 
Very common: Vomiting, nausea, constipation 
Common: Diarrhoea, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rash, pruritus, alopecia 
Very rare: Erythema multiforme, erythroderma, urticaria, 

exanthema 
General disorders and administration site conditions 
Very common: Fatigue 
Common: Fever, asthenia, rigors, malaise, pain, taste 

perversion 
Very rare: Allergic reactions, including anaphylaxis, 

angioedema 
 
Laboratory results 
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Other special populations 
 
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. 
 



93 

 

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  

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 
Frequency 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 

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


94 

 

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, 
multiorgan failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other alkylating agents, ATC code: L01A X03. 
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at 
the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of 
the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day 
of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 4 
weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis 
jiroveciipneumonia (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). 
 



95 

 

 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 
noncomparative 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 



96 

 

similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-
1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. 
Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In 
vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr. 
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 
 
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC 
of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-
carboxamide (AIC) or unidentified polar metabolites. 
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and 
half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 



97 

 

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 
Lactose 
Sodium starch glycolate (Type B) 
Tartaric acid 
Stearic acid 
  
Capsule shell  
Gelatin 
Titanium dioxide (E171) 
Sodium laurilsulfate 
 
Printing ink 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  
 



98 

 

6.5 Nature and contents of container 
 
Aluminium/aluminium unit dose blisters, consisting of an OPA [Oriented Poly Amide] / Aluminium / 
PVC [Polyvinyl chloride] forming film and peelable Aluminium lidding foil with heat seal laquer. 
Pack size: blisters are packed in cartons containing 5 or 20 hard capsules. 
 
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 Temozolomide SUN 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/697/023 (5 capsules in blister) 
EU/1/11/697/024 (20 capsules in blister) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorization: 13 July 2011 
Date of latest renewal: 21 April 2016 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



99 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



100 

 

 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Sun Pharmaceutical Industries Europe BV 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
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 (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates 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) 
 
Not applicable. 



101 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



102 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



103 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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.  
 
 
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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/013 (5 hard capsules) 
EU/1/11/697/014 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 5 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



105 

 

PC 
SN  
NN  



106 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 5 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



107 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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.  
 
 
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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/015 (5 hard capsules) 
EU/1/11/697/016 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 20 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



109 

 

PC 
SN  
NN  



110 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 20 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



111 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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.  
 
 
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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/017 (5 hard capsules) 
EU/1/11/697/018 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 100 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



113 

 

PC 
SN  
NN  



114 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 100 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



115 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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 
 
 



116 

 

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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/019 (5 hard capsules) 
EU/1/11/697/020 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 140 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



117 

 

PC 
SN  
NN  



118 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 140 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



119 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/021 (5 hard capsules) 
EU/1/11/697/022 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 180 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



121 

 

PC 
SN  
NN  



122 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 180 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



123 

 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON (BLISTER) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide SUN 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 
 
5x1 hard capsule 
20x1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral 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(S), 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 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/697/023 (5 hard capsules) 
EU/1/11/697/024 (20 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide SUN 250 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 



125 

 

PC 
SN  
NN  



126 

 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
Temozolomide SUN 250 mg hard capsules 
temozolomide 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUN Pharma logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
PEEL  



127 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



128 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 5 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



129 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



130 

 

Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



131 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 
Review the dose with your doctor each time you start a new cycle, since it may be different from the 
last cycle. 



132 

 

 
Always take Temozolomide SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred 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 



133 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN 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. 



134 

 

 
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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 5 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, yellow iron oxide (E172), blue #1/Brilliant Blue FCF 

Aluminium Lake (E133). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 5 mg hard capsules have a white opaque body and cap, imprinted in green ink. 
The cap is imprinted with ‘890’. The body is imprinted with ‘5 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 



135 

 

  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 214 403 990 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 
Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  
02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 



136 

 

România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd 
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu/. 
 



137 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 20 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



138 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



139 

 

Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



140 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 



141 

 

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 SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred vision, double vision, hearing 
impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, 



142 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN and medicines like it may have a small risk of 
developing secondary cancers, including leukaemia. 
 



143 

 

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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 20 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, yellow iron oxide (E172). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 20 mg hard capsules have a white opaque body and cap, imprinted in yellow ink. 
The cap is imprinted with ‘891’. The body is imprinted with ’20 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 



144 

 

Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 214 403 990 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 
Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  



145 

 

02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd 
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 
 



146 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 100 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



147 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



148 

 

Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



149 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 



150 

 

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 SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred vision, double vision, hearing 
impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, 



151 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN and medicines like it may have a small risk of 
developing secondary cancers, including leukaemia. 
 



152 

 

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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 100 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, red iron oxide (E172), yellow iron oxide (E172), 

titanium dioxide (E171). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 100 mg hard capsules have a white opaque body and cap, imprinted in pink ink. 
The cap is imprinted with ‘892’. The body is imprinted with ‘100 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 



153 

 

 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 214 403 990 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 



154 

 

Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  
02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd 
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



155 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 140 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



156 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



157 

 

Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



158 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 



159 

 

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 SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred vision, double vision, hearing 
impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, 



160 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN and medicines like it may have a small risk of 
developing secondary cancers, including leukaemia. 
 



161 

 

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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 140 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, titanium dioxide (E171),  blue #1/Brilliant Blue FCF 

Aluminium Lake (E133). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 140 mg hard capsules have a white opaque body and cap, imprinted in blue ink. 
The cap is imprinted with ‘929’. The body is imprinted with ‘140 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 



162 

 

 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 214 403 990 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 



163 

 

Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  
02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd 
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



164 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 180 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



165 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



166 

 

Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



167 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 



168 

 

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 SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred vision, double vision, hearing 
impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, 



169 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN and medicines like it may have a small risk of 
developing secondary cancers, including leukaemia. 
 



170 

 

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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 180 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, red iron oxide (E172). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 180 mg hard capsules have a white opaque body and cap, imprinted in red ink. 
The cap is imprinted with ‘930’. The body is imprinted with ‘180 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 



171 

 

Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
The Netherlands 
  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 214 403 990 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 
Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  



172 

 

02-954 Warszawa  
Polska 
Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd 
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



173 

 

Package Leaflet: Information for the user 
 

Temozolomide SUN 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 SUN is and what it is used for 
2. What you need to know before you take Temozolomide SUN 
3. How to take Temozolomide SUN 
4. Possible side effects 
5. How to store Temozolomide SUN 
6. Contents of the pack and other information 
 
 
1. What Temozolomide SUN is and what it is used for 
 
Temozolomide SUN contains a medicine called temozolomide. This medicine is an antitumour agent. 
 
Temozolomide SUN is used for the treatment of specific forms of brain tumours: 
- in adults with newly-diagnosed glioblastoma multiforme. Temozolomide SUN is at 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 SUN is used in these tumours if they 
return or get worse after standard treatment. 

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

section 6). 
- if you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes called 
 DTIC). Signs of allergic reaction include itchiness, breathlessness or wheezing, or swelling of 
 the face, lips, tongue or throat. 
- if the numbers of certain kinds of blood cells, such as your white blood cells or platelets are 

severely reduced (known as myelosuppression). 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 SUN, 



174 

 

 
- as you should be observed closely for the development of a serious form of chest infection 

called Pneumocystis jirovecii pneumonia (PCP). If you have been newly-diagnosed with 
glioblastoma multiforme you may be receiving Temozolomide SUN 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 
SUN 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 
blood will be tested frequently during treatment to monitor the side effects of Temozolomide 
SUN on your blood cells. 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 SUN.  

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

Temozolomide SUN (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 SUN 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 infection, bruising or 

bleeding. 
- if you have liver or kidney problems, your dose of Temozolomide SUN 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 SUN. 
 
Other medicines and Temozolomide SUN 
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 SUN during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide SUN (see also “Male fertility” below). 
You should stop breast-feeding while receiving treatment with Temozolomide SUN. 
 
Male fertility 
Temozolomide SUN 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 SUN 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). 
 



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Temozolomide SUN contains lactose 
Temozolomide SUN 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 medicine. 
 
 
3. How to take Temozolomide SUN 
 
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 SUN. This is based on your size (height and 
weight) and whether 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 
SUN 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 Temozolomide SUN only (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide SUN at a dose of 75 mg/m2 (usual 
dose). You will take this dose every day for 42 to 49 days in combination with radiotherapy. The 
Temozolomide SUN 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 have no 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 SUN can vary. Your doctor 
will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 
days. The first dose will be 150 mg/m2. You will take your new dose of Temozolomide SUN once 
daily for the first 5 days (“dosing days”) of each cycle. Then you will have 23 days without 
Temozolomide SUN. This adds up to a 28-day treatment cycle. 
After day 28, the next cycle will begin. You will again take Temozolomide SUN once daily for 5 days 
followed by 23 days without Temozolomide SUN. The Temozolomide SUN dose may be 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 SUN only 
 
A treatment cycle with Temozolomide SUN lasts 28 days. 
You will take Temozolomide SUN only 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 SUN 
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 SUN will be 150 mg/m2 once daily for the first 5 
days. Then, you will have 23 days without Temozolomide SUN. This adds up to a 28-day treatment 
cycle. 
 



176 

 

After day 28, the next cycle will begin. You will again receive Temozolomide SUN once daily for 5 
days, followed by 23 days without Temozolomide SUN. 
 
Before each new treatment cycle, your blood will be tested to see if the Temozolomide SUN 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 SUN 
 
Take your prescribed dose of Temozolomide SUN 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 at the same time. You 
may have to take different strengths to make up the dose. The marking on the capsule is different for 
each strength (see table below). 
 

Strength Imprint 
Temozolomide SUN 5 mg hard capsules 890 & 5 mg 
Temozolomide SUN 20 mg hard capsules 891 & 20 mg 
Temozolomide SUN 100 mg hard capsules 892 & 100 mg 
Temozolomide SUN 140 mg hard capsules 929 & 140 mg 
Temozolomide SUN 180 mg hard capsules 930 & 180 mg 
Temozolomide SUN 250 mg hard capsules 893 & 250 mg 
 
You should make sure you fully understand and remember the following: 
- the number of capsules you need to take every dosing day. Ask your doctor or pharmacist to 

write it down (including the marking) 
- which days are your dosing days. 



177 

 

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 SUN exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Making a mistake in how you take this medicine 
may have serious health consequences. 
 
If you take more Temozolomide SUN than you should 
If you accidentally take more Temozolomide SUN capsules than you were told to, contact your doctor, 
pharmacist or nurse immediately. 
 
If you forget to take Temozolomide SUN 
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 SUN 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 SUN dose will be reduced or treatment stopped. 
 
Side effects from clinical studies 
 
Temozolomide SUN in combination treatment with radiotherapy in newly-diagnosed glioblastoma 
 
Patients receiving Temozolomide SUN in combination with radiotherapy may experience different 
side effects from patients taking Temozolomide SUN 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), vomiting, rash, hair loss, tiredness. 
 
Common (may affect up to 1 in 10 people): 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 blurred vision, double vision, hearing 
impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, 



178 

 

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, 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 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 irritation, breast pain, hot flushes, shivering, discolouration 
of your tongue, change in your sense of smell, thirst, tooth disorder.  
 
Temozolomide SUN 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), 
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, 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 SUN. 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 SUN 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 



179 

 

(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 SUN 
 
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. The expiry date 
refers to the last day of that month. 
 
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 SUN contains 
 
- The active substance is temozolomide. Each hard capsule contains 250 mg temozolomide. 
- The other ingredients are: 
 capsule content: lactose, sodium starch glycolate (Type B), tartaric acid, stearic acid (see 

section 2 "Temozolomide SUN contains lactose") 
 capsule shell: gelatin, titanium dioxide (E171), sodium laurilsulfate 
 printing ink: shellac, propylene glycol, black iron oxide (E172). 
 
What Temozolomide SUN looks like and contents of the pack 
 
Temozolomide SUN 250 mg hard capsules have a white opaque body and cap, imprinted in black ink. 
The cap is imprinted with ‘893’. The body is imprinted with ‘250 mg’ and two stripes. 
 
The hard capsules are available in blister packs containing 5 capsules. For the 20 capsules packs, 4 
blisters of 5 capsules will be included in a carton. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 



180 

 

2132 JH Hoofddorp 
The Netherlands 
  
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien/България/Česká republika/ 
Danmark/Eesti/Ελλάδα/Hrvatska/Ireland/Ísland/ 
Κύπρος/Latvija/Lietuva/Luxembourg/Luxemburg/Magyarország/ 
Malta/Nederland/Norge/Österreich/Portugal/ 
Slovenija/Slovenská republika/Suomi/Finland/Sverige 
Sun Pharmaceutical Industries Europe B.V. 
Polarisavenue 87 
2132 JH Hoofddorp 
Nederland/Pays-Bas/Niederlande/Нидерландия/Nizozemsko/ 
Nederlandene/Holland/Ολλανδία/Nizozemska/The Netherlands/Holland/ 
Ολλανδία/Nīderlande/Nyderlandai/Pays-Bas/Niederlande/Hollandia/ 
L-Olanda/Nederland/Nederland/Niederlande/Países Baixos/ 
Nizozemska/Holandsko/Alankomaat/Nederländerna/Nederländerna 
Tel./тел./tlf./τηλ./Sími/τηλ./Tlf./Puh./ 
 +31 (0)23 568 5501 
 
Deutschland 
Sun Pharmaceuticals Germany GmbH 
Hemmelrather Weg 201 
51377 Leverkusen 
Deutschland 
tel. +49 (0) 214 403 99 192 
 
España 
Sun Pharma Laboratorios, S.L.  
Rambla de Catalunya 53-55 
08007 Barcelona 
España 
tel. +34 93 342 78 90 
 
France 
Sun Pharma France 
11-15, Quai de Dion Bouton 
92800 Puteaux 
France 
Tel. +33 1 41 44 44 50 
 
Italia 
Ranbaxy Italia S.p.A. 
Viale Giulio Richard, 1 
20143 Milano 
Italia 
tel. +39 02 33 49 07 93 
 
Polska 
Ranbaxy (Poland) Sp. Z o. o. 
ul. Kubickiego 11  
02-954 Warszawa  
Polska 



181 

 

Tel. +48 22 642 07 75 
 
România 
Terapia S.A. 
Str. Fabricii nr 124 
Cluj-Napoca, Judeţul Cluj 
România 
Tel. +40 (264) 501 500 
 
United Kingdom 
Ranbaxy UK Ltd  
a Sun Pharma Company 
Millington Road 11 
Hyde Park, Hayes 3 
5th Floor 
UB3 4AZ HAYES 
United Kingdom 
tel. +44 (0) 208 848 8688  
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	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
	A. LABELLING
	B. PACKAGE LEAFLET