Temozolomide Hexal

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal 
radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or 
discontinuation of TMZ administration should be decided weekly according to haematological and 
non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day 
concomitant period (up to 49 days) if all of the following conditions are met:  



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-  absolute neutrophil count (ANC) ≥ 1.5 x 109/l  
-  thrombocyte count ≥ 100 x 109/l  
-  common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, 

nausea and vomiting).  
 
During treatment a complete blood count should be obtained weekly. TMZ administration should be 
temporarily interrupted or permanently discontinued during the concomitant phase according to the 
haematological and non-haematological toxicity criteria as noted in Table 1. 

 
Table 1.TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ 
 

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil 
count ≥ 1.5 x 109/l; thrombocyte count ≥ 100 x 109/l; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, 
nausea, vomiting). 

 
Monotherapy phase 
 
Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 
6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 
5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 
200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, 
nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is 
≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent 
cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent 
cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase 
should be applied according to Tables 2 and 3. 
 
During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of 
TMZ). The dose should be reduced or administration discontinued according to Table 3. 

 
Table 2. TMZ dose levels for monotherapy treatment 

 
Dose level TMZ Dose 

(mg/m2/day) 
Remarks 

- 1 100 Reduction for prior toxicity 
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 

 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 

Toxicity Reduce TMZ by 1 dose 
levela 

Discontinue TMZ 

Absolute neutrophil count < 1.0 x 109/l See footnote b 
Thrombocyte count < 50 x 109/l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, 
vomiting) 

CTC Grade 3 CTC Grade 4b 

a:  TMZ dose levels are listed in Table 2. 
b:  TMZ is to be discontinued if: 
•  dose level -1 (100 mg/m2) still results in unacceptable toxicity 
•  the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) 

recurs after dose reduction. 



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Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4). 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Meningoencephalitis herpetic 



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In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 



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Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, including 
carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to 
dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count 
≥ 100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or 
within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If 
ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should 
be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 
200 mg/m2. The lowest recommended dose is 100 mg/m2. 
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in 
older children and adolescents is very limited (see sections 4.2 and 5.1). 
 
Elderly patients (> 70 years of age) 
 
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly 
patients. 
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
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 Hexal 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. 
 



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No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal 
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of grade 3-4 laboratory findings is 
presented after  table 4. 
 
For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 



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Tabulated list of adverse reactions 
Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention:  
 
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known: frequency cannot be estimated from 
the available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 
 

 
Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritisb 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 



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Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 
Common: Ataxia, balance impaired, cognition impaired, 

concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 



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Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 
exanthema, dermatitis, sweating increased, pigmentation 
abnormal 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 
 
Newly-diagnosed glioblastoma multiforme 

Laboratory results  
 



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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 
 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 

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


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the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 



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Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population) 
 
The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 
 
Recurrent or progressive malignant glioma 
 
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 



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central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 
 
Distribution 
 
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with 
highly protein-bound substances. 



 15 

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly 
and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on 
AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data. 
 
Elimination 
 
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. 
Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the 
urine over 24 hours, and the remainder excreted as temozolomide acid, 
5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.  
 
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution 
and half-life are independent of dose. 
 
Special populations 
 
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was 
independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma 
pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those 
observed in patients with normal hepatic function. 
 
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose 
(MTD) was 1,000 mg/m2 per cycle both in children and in adults. 
 
5.3  Preclinical safety data 
 
Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in 
rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, 
testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and 
dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, 
except for adverse events on the male reproductive system and retinal degeneration. However, 
because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable 
effect has been observed in clinical studies, this finding was not considered to have clinical relevance. 
 
TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and 
dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. 
Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A 
variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell 
adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were 
evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the 
occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even 
for an alkylating agent. 
 
Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome 
aberration tests showed a positive mutagenicity response. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 



 16 

Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Indigo carmine (E 132) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet  
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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.  



 17 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/001 
EU/1/10/616/002 
EU/1/10/616/025 
EU/1/10/616/026 
EU/1/10/616/037 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

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


 18 

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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal 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:  



 19 

-  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. 
 



 20 

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 Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Meningoencephalitis herpetic 



 21 

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids.  
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 



 22 

 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, including 
carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to 
dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count 
≥ 100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or 
within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If 
ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should 
be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 
200 mg/m2. The lowest recommended dose is 100 mg/m2. 
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in 
older children and adolescents is very limited (see sections 4.2 and 5.1). 
 
Elderly patients (> 70 years of age) 
 
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly 
patients. 
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
 
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 Hexal 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. 
 



 23 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal  
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus.  
 
Breast-feeding 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
Summary of the safety profile 

Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is 
presented after Table 4. 
 
For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 
 
Tabulated list of adverse reactions 



 24 

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention:  
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known: frequency cannot be estimated from 
the available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 

Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritisb 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 

Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 



 25 

Common: Ataxia, balance impaired, cognition impaired, 
concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 
exanthema, dermatitis, sweating increased, pigmentation 
abnormal 



 26 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 
 
Newly-diagnosed glioblastoma multiforme 
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. 
 



 27 

Recurrent or progressive malignant glioma 
 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  

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


 28 

 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 

 
Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population) 
 
The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 
 
Recurrent or progressive malignant glioma 
 



 29 

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 
central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 



 30 

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



 31 

Capsule content 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 



 32 

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/005 
EU/1/10/616/006 
EU/1/10/616/027 
EU/1/10/616/028 
EU/1/10/616/038 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 

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


 33 

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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal 
radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or 
discontinuation of TMZ administration should be decided weekly according to haematological and 
non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day 
concomitant period (up to 49 days) if all of the following conditions are met:  



 34 

-  absolute neutrophil count (ANC) ≥ 1.5 x 109/l  
-  thrombocyte count ≥ 100 x 109/l  
-  common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, 

nausea and vomiting).  
 
During treatment a complete blood count should be obtained weekly. TMZ administration should be 
temporarily interrupted or permanently discontinued during the concomitant phase according to the 
haematological and non-haematological toxicity criteria as noted in Table 1. 

 
Table 1.TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ 
 

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil 
count ≥ 1.5 x 109/l; thrombocyte count ≥ 100 x 109/l; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, 
nausea, vomiting). 

 
Monotherapy phase 
 
Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 
6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 
5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 
200 mg/m2 if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, 
nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/l, and the thrombocyte count is 
≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent 
cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent 
cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase 
should be applied according to Tables 2 and 3. 
 
During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of 
TMZ). The dose should be reduced or administration discontinued according to Table 3. 

 
Table 2. TMZ dose levels for monotherapy treatment 
 

Dose level TMZ Dose 
(mg/m2/day) 

Remarks 

- 1 100 Reduction for prior toxicity 
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 

 
Table 3.  TMZ dose reduction or discontinuation during monotherapy treatment 
 

Toxicity Reduce TMZ by 1 dose 
levela 

Discontinue TMZ 

Absolute neutrophil count < 1.0 x 109/l See footnote b 
Thrombocyte count < 50 x 109/l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, 
vomiting) 

CTC Grade 3 CTC Grade 4b 

a:  TMZ dose levels are listed in Table 2. 
b:  TMZ is to be discontinued if: 
•  dose level -1 (100 mg/m2) still results in unacceptable toxicity 
•  the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) 

recurs after dose reduction. 



 35 

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma 
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day 
treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial 
dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days 
if there is no haematological toxicity (see section 4.4). 
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant 
glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy 
of TMZ in children under the age of 3 years have not been established. No data are available. 
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients. 
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is 
not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4). 
 
Method of administration 
 
Temozolomide Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 

Meningoencephalitis herpetic 



 36 

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

 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 



 37 

Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, including 
carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to 
dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count 
≥ 100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or 
within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If 
ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should 
be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 
200 mg/m2. The lowest recommended dose is 100 mg/m2. 
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in 
older children and adolescents is very limited (see sections 4.2 and 5.1). 
 
Elderly patients (> 70 years of age) 
 
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly 
patients. 
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
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 Hexal 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. 
 



 38 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal 
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is 
presented after Table 4. 

. 



 39 

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 

Tabulated list of adverse reactions 
Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention:  
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known: frequency cannot be estimated from the 
available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 

Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritis b 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 

Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 



 40 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 
Common: Ataxia, balance impaired, cognition impaired, 

concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 



 41 

exanthema, dermatitis, sweating increased, pigmentation 
abnormal 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 
 
Newly-diagnosed glioblastoma multiforme 
 
 
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 



 42 

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 
 
 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 

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


 43 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 

 
Figure 1 Kaplan-Meier curves for overall survival ( intent-to-treat population) 
 



 44 

The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 
 
Recurrent or progressive malignant glioma 
 
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 
central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 



 45 

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



 46 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Red iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 



 47 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/009 
EU/1/10/616/010 
EU/1/10/616/029 
EU/1/10/616/030 
EU/1/10/616/039 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

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


 48 

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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal 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:  



 49 

-  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 duringconcomitant 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. 



 50 

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 Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Meningoencephalitis herpetic 



 51 

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 



 52 

 
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 totallactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
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 Hexal 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. 
 



 53 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal 
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
Summary of the safety profile 

Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is 
presented after Table 4. 

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 

Tabulated list of adverse reactions 



 54 

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention:  
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥1/10,000 to <1/1,000); Very rare (<1/10,000), Not known: frequency cannot be estimated from the 
available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 

Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritisb 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 

Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 



 55 

Common: Ataxia, balance impaired, cognition impaired, 
concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 
exanthema, dermatitis, sweating increased, pigmentation 
abnormal 



 56 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 
 
Newly-diagnosed glioblastoma multiforme 
 
 
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 



 57 

or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of 
the patients who received TMZ. 
 
Recurrent or progressive malignant glioma 
 
 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 

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


 58 

 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 

 
Figure 1 Kaplan-Meier curves for overall survival ( intent-to-treat population) 
 



 59 

The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 
 
Recurrent or progressive malignant glioma 
 
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 
central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 



 60 

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



 61 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Indigo carmine (E 132) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 



 62 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/013 
EU/1/10/616/014 
EU/1/10/616/031 
EU/1/10/616/032 
EU/1/10/616/040 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

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


 63 

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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal 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:  



 64 

-  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. 



 65 

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 Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Meningoencephalitis herpetic 



 66 

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 



 67 

 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, including 
carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to 
dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count 
≥ 100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or 
within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If 
ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should 
be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 
200 mg/m2. The lowest recommended dose is 100 mg/m2. 
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in 
older children and adolescents is very limited (see sections 4.2 and 5.1). 
 
Elderly patients (> 70 years of age) 
 
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly 
patients. 
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
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 Hexal 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. 
 



 68 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal 
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus. 
 
Breast-feeding 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is 
presented after Table 4. 

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 

Tabulated list of adverse reactions 



 69 

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention:  
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥1/10,000 to <1/1,000); Very rare (<1/10,000), Not known: frequency cannot be estimated from the 
available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 
 

Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritisb 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 

Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 



 70 

Common: Ataxia, balance impaired, cognition impaired, 
concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 
exanthema, dermatitis, sweating increased, pigmentation 
abnormal 



 71 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 

 
 

Newly-diagnosed glioblastoma multiformeLaboratory 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. 



 72 

 
Recurrent or progressive malignant glioma 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  

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


 73 

 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 

 
Figure 1 Kaplan-Meier curves for overall survival ( intent-to-treat population) 
 
The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 
 
Recurrent or progressive malignant glioma 
 



 74 

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 
central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly with peak concentrations reached 
as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral 
administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % 
indicating complete absorption. 



 75 

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



 76 

Capsule content 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Yellow iron oxide (E 172) 
Red iron oxide (E 172) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years.  
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 



 77 

 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/017 
EU/1/10/616/018 
EU/1/10/616/033 
EU/1/10/616/034 
EU/1/10/616/041 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

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


 78 

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

 
4.1 Therapeutic indications 
 
Temozolomide Hexal 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 Hexal 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 Hexal 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:  



 79 

-  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. 



 80 

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 Hexal hard capsules should be administered in the fasting state. 
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
 
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections 
(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Meningoencephalitis herpetic 



 81 

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule 
were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, 
prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day 
regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they 
are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.  
 
There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed 
closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have 
been reported in patients using TMZ, in particular in combination with dexamethasone or other 
steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been 
reported. Experts in liver disease should be consulted before treatment is initiated in patients with 
positive hepatitis B serology (including those with active disease). During treatment patients should 
be monitored and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If 
abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the 
potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should 
be repeated midway during this cycle. For all patients, liver function tests should be checked after 
each treatment cycle. For patients with significant liver function abnormalities, physicians should 
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after 
the last treatment with temozolomide. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8). 
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ. 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is 
strongly recommended during the monotherapy phase. 
 
Patients with recurrent or progressive malignant glioma 
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may 
require anti-emetic therapy. 
 
Laboratory parameters 



 82 

 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, 
which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some 
cases, exposure to concomitant medicinal products associated with aplastic anaemia, including 
carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to 
dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count 
≥ 100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or 
within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If 
ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should 
be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 
200 mg/m2. The lowest recommended dose is 100 mg/m2. 
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in 
older children and adolescents is very limited (see sections 4.2 and 5.1). 
 
Elderly patients (> 70 years of age) 
 
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly 
patients. 
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
 
Lactose 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose 
intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this 
medicine. 
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
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 Hexal 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. 
 



 83 

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits 
low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal 
products (see section 5.2). 
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Hexal 
should not be administered to pregnant women. If use during pregnancy must be considered, the 
patient should be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ. 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father 
a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm 
prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
Summary of the safety profile 

Clinical trial experience 
 
In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, 
vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic 
adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is 
presented after Table 4. 

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) 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 %. 

Tabulated list of adverse reactions 



 84 

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed 
in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency 
groupings are defined according to the following convention 
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare 
(≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known: frequency cannot be estimated from 
the available data.  
 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 

Table 4. Adverse reactions in patients treated with temozolomide 

Infections and infestations 

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral 

Uncommon: Opportunistic infection (including PCP), sepsis†, 
meningoencephalitis herpetic†, CMV infection, CMV 
reactivation, hepatitis B virus†, herpes simplex, infection 
reactivation, wound infection, gastroenteritisb 

Neoplasm benign, malignant, and unspecified 

Uncommon: Myelodysplastic syndrome (MDS), secondary 
malignancies, including myeloid leukaemia 

Blood and lymphatic system disorders 

Common: Febrile neutropenia, neutropenia, thrombocytopenia, 
lymphopenia, leukopenia, anaemia 

Uncommon: Prolonged pancytopenia, aplastic anaemia†, 
pancytopenia, petechiae 

Immune system disorders 

Common: Allergic reaction 

Uncommon: Anaphylaxis 

Endocrine disorders 

Common: Cushingoidc 
Uncommon: Diabetes insipidus 

Metabolism and nutrition disorders 

Very common: Anorexia 
Common: Hyperglycaemia 

Uncommon: Hypokalaemia, alkaline phosphatase increased 

Psychiatric disorders 

Common: Agitation, amnesia, depression, anxiety, confusion, 
insomnia 

Uncommon: Behaviour disorder, emotional lability, hallucination, 
apathy 

Nervous system disorders 

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache 



 85 

Common: Ataxia, balance impaired, cognition impaired, 
concentration impaired, consciousness decreased, 
dizziness, hypoesthesia, memory impaired, neurologic 
disorder, neuropathyd, paraesthesia, somnolence, speech 
disorder, taste perversion, tremor 

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, 
parosmia, gait abnormality, hyperaesthesia, sensory 
disturbance, coordination abnormal 

Eye disorders 

Common: Hemianopia, vision blurred, vision disordere, visual field 
defect, diplopia, eye pain 

Uncommon: Visual acuity reduced, eyes dry 

Ear and labyrinth disorders 

Common: Deafnessf, vertigo, tinnitus, earacheg 

Uncommon: Hearing impairment, hyperacusis, otitis media 

Cardiac disorders 

Uncommon: Palpitation 

Vascular disorders 

Common: Haemorrhage, embolism pulmonary, deep vein 
thrombosis, hypertension  

Uncommon: Cerebral haemorrhage, flushing, hot flushes 

Respiratory, thoracic and mediastinal disorders 

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, 
upper respiratory infection 

Uncommon: Respiratory failure†, interstitial  
pneumonitis/pneumonitis, pulmonary fibrosis, nasal 
congestion 

Gastrointestinal disorders 

Very common: Diarrhoea, constipation, nausea, vomiting 

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia  

Uncommon: Abdominal distension, faecal incontinence, 
gastrointestinal disorder, haemorrhoids, mouth dry 

Hepatobiliary disorders 

Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, 
hyperbilirubinemia 

Skin and subcutaneous tissue disorders 

Very Common: Rash, alopecia 

Common: Erythema, dry skin, pruritus 

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, 
angioedema, erythema multiforme, erythroderma, skin  
exfoliation, photosensitivity reaction, urticaria, 
exanthema, dermatitis, sweating increased, pigmentation 
abnormal 



 86 

Not known: Drug reaction with eosinophilia and systemic symptoms  
(DRESS) 

Musculoskeletal and connective tissue disorders 

Common: Myopathy, muscle weakness, arthralgia, back pain, 
musculoskeletal pain, myalgia  

Renal and urinary disorders 

Common: Micturition frequency, urinary incontinence  

Uncommon: Dysuria 

Reproductive system and breast disorders 

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, 
vaginitis, breast pain, impotence 

General disorders and administration site conditions 

Very common: Fatigue 

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, 
oedema, oedema peripherali 

Uncommon:  Condition aggravated, rigors, face oedema, tongue 
discolouration, thirst, tooth disorder 

Investigations 

Common: Liver enzymes elevationj, weight decreased, weight 
increased 

Uncommon: Gamma-glutamyltransferase increased 

Injury, poisoning and procedural complications  

Common: Radiation injuryk 
aIncludes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal  
b Includes gastroenteritis, gastroenteritis viral 
cIncludes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
eIncludes visual impairment, eye disorder 
fIncludes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
gIncludes earache, ear discomfort 
hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
iIncludes oedema peripheral, peripheral swelling 
jIncludes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase 
increased, hepatic enzymes increased 
k Includes radiation injury, radiation skin injury 
† Including cases with fatal outcome 
 
Newly-diagnosed glioblastoma multiforme 
 
 
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 



 87 

or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of 
the patients who received TMZ. 
 
Recurrent or progressive malignant glioma 
 
Laboratory results  
 
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients 
treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 
4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the 
nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of 
cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk 
of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection. 
 
Gender 
 
In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 
169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male 
subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 
neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, in 
women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 
neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % 
of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with 
newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of 
male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first 
cycle of therapy. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although 
the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in 
children under the age of 3 years has not been established. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated 
clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is 
expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, 
over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, 
multi-organ failure and death. There are reports of patients who have taken the recommended dose for 
more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In 
the event of an overdose, haematological evaluation is needed. Supportive measures should be 
provided as necessary. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 

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 88 

5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01AX03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the 
active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to 
be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring 
at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair 
of the methyl adduct. 
Clinical efficacy and safety 
 
Newly-diagnosed glioblastoma multiforme 
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first 
day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150-200 mg/m2) on Days 1-5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy. 
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in 
the RT alone arm, and 62 patients of the 277 (22 %) in the TMZ + RT arm. 
 
The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33-1.91) with a log-rank 
p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % 
vs 10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by 
TMZ monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme 
demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone 
(Figure 1). 

 
Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population) 
 
The results from the trial were not consistent in the subgroup of patients with a poor performance 
status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. 
However, no unacceptable risks appear to be present in this patient group. 



 89 

 
Recurrent or progressive malignant glioma 
 
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status 
[KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral 
TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the 
other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67 % 
received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint 
was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the 
non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 
2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on 
MRI scans was 8 %. 
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than 
for procarbazine (21 % vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for 
TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving 
patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %) 
(chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a 
KPS ≥ 80. 
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time 
to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). 
The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ 
than for procarbazine (log rank p = < 0.01 to 0.03). 
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the 
treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The 
median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the 
central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) 
n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT 
population was 44 % with a median event-free survival of 4.6 months, which was similar to the results 
for the progression-free survival. For the eligible histology population, the efficacy results were 
similar. Achieving a radiological objective response or maintaining progression-free status was 
strongly associated with maintained or improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance 
to TMZ is similar to adults. 
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 
3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 
5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid 
biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and 
N7 positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 
23 %, respectively. In vivo, the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 



 90 

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



 91 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
Anhydrous lactose 
Colloidal anhydrous silica 
Sodium starch glycolate type A 
Tartaric acid 
Stearic acid 
Capsule shell 
Gelatin 
Titanium dioxide (E 171) 
Water 
 
Printing ink 
Shellac 
Black iron oxide (E 172) 
Potassium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Bottle 
Do not store above 25 °C. 
Store in the original package. 
Keep the bottles tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottle with polypropylene child-resistant closure containing 5 or 20 hard 
capsules.  
The bottles contain a desiccant pouch.  
The carton contains one bottle. 
 
Multipack (Bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in a type III amber glass bottle 
with polypropylene child-resistant closure. The bottles contain a desiccant pouch.) 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule. 
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed. 
 



 92 

6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomid Hexal 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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/021 
EU/1/10/616/022 
EU/1/10/616/035 
EU/1/10/616/036 
EU/1/10/616/042 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 19 November 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD/MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency (EMA) http://www.ema.europa.eu/ 
 

  

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


 93 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



 94 

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

AUTHORISATION  
 
• Periodic safety update reports  (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  
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) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of  new information 

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

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



 95 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
  



 96 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



 97 

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

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



 98 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/001 
EU/1/10/616/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 5 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 99 

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

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



 100 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/005 
EU/1/10/616/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 20 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 101 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 102 

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

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



 103 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/009 
EU/1/10/616/010 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 100 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 104 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 105 

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

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



 106 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/013 
EU/1/10/616/014 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 140 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 107 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 108 

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

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



 109 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/017 
EU/1/10/616/018 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 180 mg  
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 110 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 111 

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

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



 112 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/021 
EU/1/10/616/022 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 250 mg 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 113 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
  



 114 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 115 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/037 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 5 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 116 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
  



 117 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 118 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/038 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 20 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



 119 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
 
  



 120 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 121 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/039 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 100 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 122 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
 
  



 123 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 124 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/040 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 140 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 125 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
 
  



 126 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 127 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/041 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 180 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 128 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
  



 129 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES - WITH 
THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 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 
 
Multipack: 20 (4 packs of 5) hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 130 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/042 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 250 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 131 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
 
 
  



 132 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 5 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 5 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 133 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/037  20 (4 packs of 5) 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 Hexal 5 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number 
  



 134 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 20 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 20 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 135 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/038  20 (4 packs of 5) 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 Hexal 20 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 136 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 100 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 137 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/039  20 (4 packs of 5) 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 Hexal 100 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 



 138 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 140 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 140 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 139 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/040  20 (4 packs of 5) 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 Hexal 140 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 140 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 180 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 180 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 141 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/041  20 (4 packs of 5) 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 Hexal 180 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 142 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON FOR MULTIPACKS OF 20 (4 PACKS OF 5) HARD CAPSULES 
- WITHOUT THE BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Hexal 250 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 250 mg temozolomide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 hard capsules. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



 143 

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

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/042  20 (4 packs of 5) 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 Hexal 250 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 144 

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



 145 

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



 146 

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



 147 

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



 148 

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



 149 

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



 150 

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

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



 151 

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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/025 
EU/1/10/616/026 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 5 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 152 

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

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



 153 

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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/027 
EU/1/10/616/028 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 20 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 154 

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

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



 155 

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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/029 
EU/1/10/616/030 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 100 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 156 

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

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



 157 

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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/031 
EU/1/10/616/032 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 140 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 158 

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

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



 159 

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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/033 
EU/1/10/616/034 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 180 mg  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number}  



 160 

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

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



 161 

 
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 
 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/616/035 
EU/1/10/616/036 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide Hexal 250 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC {number}  
SN {number}  
NN {number} 
  



 162 

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



 163 

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



 164 

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



 165 

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



 166 

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



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



 168 

 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

B. PACKAGE LEAFLET 



 169 

Package leaflet: information for the user 
 

Temozolomide Hexal 5 mg hard capsules 
 

Temozolomide Hexal 20 mg hard capsules 
 

Temozolomide Hexal 100 mg hard capsules 
 

Temozolomide Hexal 140 mg hard capsules 
 

Temozolomide Hexal 180 mg hard capsules 
 

Temozolomide Hexal 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 Hexal is and what it is used for 
2. What you need to know before you take Temozolomide Hexal 
3. How to take Temozolomide Hexal 
4. Possible side effects 
5.  How to store Temozolomide Hexal 
6. Contents of the pack and other information 
 
 
1. What Temozolomide Hexal is and what it is used for 
 
Temozolomide Hexal contains a medicine called temozolomide. This medicine is an antitumour 
agent. 
 
Temozolomide Hexal is used for the treatment of specific forms of brain tumours: 
• in adults with newly-diagnosed glioblastoma multiforme. Temozolomide Hexal is first used 

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

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

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

section 6). 



 170 

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

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

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

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

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

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

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

effects of Temozolomide Hexal (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 Hexal until the vomiting is under control. If you vomit after taking your dose, 
do not take a second dose on the same day. 

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

bleeding. 
• if you have liver or kidney problems. Your dose of Temozolomide Hexal 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 Hexal. 
 
Other medicines and Temozolomide Hexal 
 
Tell your doctor or pharmacist if you are taking or 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 Hexal during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide Hexal (see also “Male fertility” below). 



 171 

You should stop breast-feeding while receiving treatment with Temozolomide Hexal. 
 
Male fertility 
 
Temozolomide Hexal 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 Hexal may make you feel tired or sleepy. In this case, do not drive or use any tools or 
machines or cycle until you see how this medicine affects you (see section 4). 
 
Temozolomide Hexal contains lactose and sodium 
 
Temozolomide Hexal contains lactose (a kind of sugar). If you have been told by your doctor that you 
have an intolerance to some sugars, contact your doctor before taking this medicinal product.  
 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
3.  How to take Temozolomide Hexal 
 
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 Hexal. This is based on your size (height and 
weight) and if you have a recurrent tumour and have had chemotherapy treatment in the past. 
 
You may be given other medicines (anti-emetics) to take before and/or after taking Temozolomide 
Hexal to prevent or control nausea and vomiting. 
 
Patients with newly-diagnosed glioblastoma multiforme 
 
If you are a newly-diagnosed patient, treatment will occur in two phases: 
• treatment together with radiotherapy (concomitant phase) first 
• followed by treatment with only Temozolomide Hexal (monotherapy phase). 
 
During the concomitant phase, your doctor will start Temozolomide Hexal at a dose of 75 mg/m2 
(usual dose). You will take this dose every day for 42 days (up to 49 days) in combination with 
radiotherapy. The Temozolomide Hexal dose may be delayed or stopped, depending on your blood 
counts and how you tolerate your medicine during the concomitant phase. 
 
Once the radiotherapy is completed, you will interrupt treatment for 4 weeks. This will give your 
body a chance to recover. 
 
Then, you will start the monotherapy phase.  
 
During the monotherapy phase, the dose and way you take Temozolomide Hexal will be different. 
Your doctor will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one 
lasts 28 days. You will take your new dose of Temozolomide Hexal alone once daily for the first 
5 days (“dosing days”) of each cycle. The first dose will be 150 mg/m2. Then you will have 23 days 
without Temozolomide Hexal. This adds up to a 28-day treatment cycle.  
 



 172 

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

Strength Colour of the cap 

Temozolomide Hexal     5 mg hard capsules green 

Temozolomide Hexal   20 mg hard capsules  yellow 

Temozolomide Hexal 100 mg hard capsules  pink 

Temozolomide Hexal 140 mg hard capsules  blue 

Temozolomide Hexal 180 mg hard capsules  maroon 

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

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



 173 

 
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 Hexal exactly as your doctor has told you. It is very important to check 
with your doctor or pharmacist if you are not sure. Errors in how you take this medicine may have 
serious health consequences. 
 
If you take more Temozolomide Hexal than you should 
If you accidentally take more Temozolomide Hexal capsules than you were told to, contact your 
doctor or pharmacist or nurse immediately . 
 
If you forget to take Temozolomide Hexal  
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 Hexal 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 Hexal dose will be reduced or treatment stopped. 
 
Other side effects that have been reported are listed below: 
 
Very common (may affect more than 1 in 10 people ):  
• loss of appetite, difficulty speaking,headache  
•  
• vomiting, nausea, diarrhoea, constipation 
• rash, hair loss,  
• tiredness. 
 



 174 

Common (may affect up to 1 in 10 people ):  
• infections, oral infections, wound infection  
• reduced number of blood cells (neutropenia, thrombocytopenia, lymphopenia)  
• allergic reaction  
• increased blood sugar  
• memory impairment, depression, anxiety, confusion, inability to fall asleep or stay asleep 
• impaired coordination and balance  
• difficulty concentrating, change in mental status or alertness, forgetfulness  
• dizziness, impaired sensations, tingling sensation, shaking, abnormal taste 
• partial loss of vision, abnormal vision,  double vision, dry or painful eyes  
• deafness, ringing in the ears, earache 
• blood clot in lung or legs, high blood pressure 
• pneumonia, shortness of breath, bronchitis, cough, inflammation of your sinuses 
• stomach or abdominal pain, upset stomach/heartburn, difficulty swallowing 
• dry skin, itching 
• muscle damage, muscle weakness, muscle aches and pain 
• painful joint, back pain 
• frequent urination, difficulty withholding your urine 
• fever, flu-like symptoms, pain, feeling unwell, a cold or the flu 
• fluid retention, swollen legs 
• liver enzyme elevations 
• loss of weight, weight gain 
• radiation injury 
•  
 
Uncommon (may affect up to 1 in 100 people):  
• brain infections (meningoencephalitis herpetic) including fatal cases 
• new or reactivated cytomegalovirus infections 
• reactivated hepatitis B virus infections 
• secondary cancers including leukaemia 
• reduced blood cell counts (pancytopenia, anaemia, leukopenia) 
• red spots under the skin 
• diabetes insipidus (symptoms include increased urination and feeling thirsty), low potassium 

level in the blood 
• mood swings, hallucination 
• partial paralysis, change in your sense of smell 
• hearing impairment, infection of the middle ear 
• palpitations (when you can feel your heart beat), hot flushes 
• swollen stomach, difficulty controlling your bowel movements, haemorrhoids, dry mouth 
• hepatitis and injury to the liver (including fatal liver failure), cholestasis, increased bilirubin 
• blisters on body or in mouth, skin peeling, skin eruption, painful reddening of the skin, severe 

rash with skin swelling (including palms and soles) 
• increased sensitivity to sunlight, urticaria (hives), increased sweating, change in skin colour 
• difficulty in urinating 
• vaginal bleeding, vaginal irritation, absent or heavy menstrual periods, breast pain, sexual 

impotence 
• shivering, face swelling, discolouration of the tongue, thirst, tooth disorder 
 
 
 
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. 
 
 

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 175 

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

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

 
• The other ingredients of the capsule are  
 

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

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

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

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

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



 176 

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

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

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

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

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

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

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

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

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

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

 
What Temozolomide Hexal looks like and contents of the pack 
 
Bottle 
The hard capsules are dispensed in amber glass bottles (Type 3 glass) with polypropylene child-
resistant closures. Each bottle contains either 5 or 20 capsules. The bottles also contain a desiccant 
pouch. Keep the desiccant pouch in the bottle. Do not swallow it. 
 
Multipack (bottles) 
Multipack containing 20 hard capsules (4 packs of 5 hard capsules in an amber glass bottle [Type 3 
glass] with polypropylene child-resistant closure. The bottles contain a desiccant pouch. Keep the 
desiccant pouch in the bottle. Do not swallow it.) 
 
Sachet 
Each hard capsule (capsule) is individually packed in a sachet. Each carton contains 5 or 20 hard 
capsules. 
 
Not all pack sizes may be marketed. 
 
Temozolomide Hexal 5 mg hard capsules 
The hard capsules have a white coloured body, a green coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “5”. 
Each capsule is approximately 15.8 mm in length. 
 
Temozolomide Hexal 20 mg hard capsules 
The hard capsules have a white coloured body, a yellow coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “20”. 
Each capsule is approximately 11.4 mm in length. 
 
Temozolomide Hexal 100 mg hard capsules 



 177 

The hard capsules have a white coloured body, a pink coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “100”. 
Each capsule is approximately 15.8 mm in length. 
Temozolomide Hexal 140 mg hard capsules 
The hard capsules have a white coloured body, a transparent blue coloured cap, and are imprinted 
with black ink. The cap is imprinted with “TMZ” and the body is imprinted with “140”. 
Each capsule is approximately 19.3 mm in length. 
 
Temozolomide Hexal 180 mg hard capsules 
The hard capsules have a white coloured body, a maroon coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “180”. 
Each capsule is approximately 19.3 mm in length. 
 
Temozolomide Hexal 250 mg hard capsules 
The hard capsules have a white coloured body, a white coloured cap, and are imprinted with black 
ink. The cap is imprinted with “TMZ” and the body is imprinted with “250”. 
Each capsule is approximately 21.4 mm in length. 
 
Marketing Authorisation Holder 
Hexal AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
 
Manufacturer 
Salutas Pharma GmbH 
Otto-von-Guericke-Allee 1 
D-39179 Barleben 
Germany 
 
Lek Pharmaceuticals d.d 
Verovskova 57 
SL-1526 Ljubljana 
Slovenia 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder:  
 
België/Belgique/Belgien 
Sandoz N.V. 
Telecom Gardens 
Medialaan 40 
B-1800 Vilvoorde 
Tél/Tel: +32 (0)2 722 97 97 
 

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

България 
КЧТ Сандоз България 
Бул.“Никола Вапцаров“ No. 55 
сгр. 4, ет. 4 
1407 София 
Teл.: '+359 2 970 47 47 
regaffairs.bg@sandoz.com 

 

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

mailto:regaffairs.bg@sandoz.com


 178 

Česká republika 
Sandoz s.r.o. 
Na Pankráci 1724/129 
CZ-140 00, Praha 4  
Tel: +420 225 775 111 
office.cz@ sandoz.com 

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

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

Malta 
V J Salomone Pharma Limited 
Upper Cross Road,  
Marsa MRS 1542 
Tel: +356 22983 143 /+ 356 99045928 
regvjsp@vjsalomone.com 

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

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

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

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

Ελλάδα 
Novartis (Hellas) A.E.B.E. / Sandoz Division 
Lamias National Rd (12th km) 
144 51 Metamorfosi, Athens 
Τηλ: +30 210 2811712 
regulatory.greece@sandoz.com 

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

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

 
Polska 
Sandoz Polska Sp. z o.o. 
ul. Domaniewska 50 C 
PL – 02 672 Warszawa 
Tel.: +48 22 209 7000 
maintenance.pl@sandoz.com 
 

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

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

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

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



 179 

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

Slovenija 
Lek Pharmaceuticals d.d. 
Verovškova 57 
SI-1526 Ljubljana 
Tel: +386 1 580 21 11 
Info.lek@sandoz.com 
 

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

Slovenská republika 
Sandoz d.d. -  organizačná zložka 
Žižkova 22B,  
811 02 Bratislava 
Tel: +421 2 48 200 600 
sk.regulatory@sandoz.com 

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

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

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

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

Latvija 
Sandoz d.d. Latvia filiāle   
K.Valdemāra 33 – 29 
LV-1010 Rīga 
Tel: +371 67892006 
 

United Kingdom 
Sandoz Limited 
Park View, Riverside Way 
Watchmoor Park 
Camberley, Surrey  
GU15 3YL 
United Kingdom 
Tel: +44 1276 69 8101 
Sandozgb@EU.propharmagroup.com 

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

mailto:Sandozgb@EU.propharmagroup.com
http://www.ema.europa.eu/

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