Temozolomide Accord

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 



1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 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.  
 
The hard capsules are green/white hard gelatin capsules imprinted ‘TMZ’ on cap & ‘5’ on body. 
 
Each capsule is approximately 15 mm in length. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy 
(60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation 
of TMZ administration should be decided weekly according to haematological and non-haematological 
toxicity criteria.  TMZ administration can be continued throughout the 42 day concomitant period (up to 
49 days) if all of the following conditions are met:  

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

nausea and vomiting). 



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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 
interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 



150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not been established. No data are available.  
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients.  
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not 
affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4).  
 
Method of administration 
 
Temozolomide Accord should be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were 
shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis 
against PCP is required for all patients receiving concomitant TMZ and RT for the 42 day regimen (with 
a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the 
prophylaxis until recovery of lymphopenia to grade ≤1.  
 



There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely 
for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been 
reported in patients using TMZ, in particular in combination with dexamethasone or other steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. 
Experts in liver disease should be consulted before treatment is initiated in patients with positive 
hepatitis B serology (including those with active disease). During treatment patients should be monitored 
and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, 
physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal 
hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway 
during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For 
patients with significant liver function abnormalities, physicians should assess the benefit/risk of 
continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with 
temozolomide. 
 
Meningoencephalitis herpetic 
 
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8).  
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ.  
Anti-emetic therapy may be administered prior to or following administration of TMZ.  
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it   
is strongly recommended during the monotherapy phase.  
 
Patients with recurrent or progressive malignant glioma  
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require 
anti-emetic therapy.  
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which 
may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, 
exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, 
phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following 
laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 



platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.    
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.  
 
 
4.5 Interaction with other medicinal products and other forms of interaction 

 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
 
 
 
 
 



4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Accord should 
not be administered to pregnant women. If use during pregnancy must be considered, the patient should 
be apprised of the potential risk to the foetus.  
 
 Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8) . 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 events 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 reactions reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the 
event of an overdose, haematological evaluation is needed. Supportive measures should be provided as 
necessary. 
 
 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active 
monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due 
primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 
position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl 
adduct.  
 
Clinical efficacy and safety 
 
Newly diagnosed glioblastoma multiforme  
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of 



RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150 – 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the 
RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  
 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 10%) 
is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a 
statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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



Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to 
worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The 
median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for 
procarbazine (log rank p = < 0.01 to 0.03).  
 
Recurrent anaplastic astrocytoma  
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment 
of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46%. The median PFS was 
5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer 
assessment, was 35% (13 CR and 43 PR) for the intent-to- treat-population (ITT) n=162. In 43 patients 
stable disease was reported. The 6-month event-free survival for the ITT population was 44% with a 
median event-free survival of 4.6 months, which was similar to the results for the progression-free 
survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological 
objective response or maintaining progression-free status was strongly associated with maintained or 
improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to 
TMZ is similar to adults.  
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-
yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative 
to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo, the t1/2 of 
MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as 
early as 20 minutes post administration (mean times 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 rapidly the blood-brain barrier 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 reactions 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  
 
Capsule shell 
Gelatine 
Water 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 
Indigo carmine (E132) 
 
Printing ink 
Shellac 
 
Propylene glycol 
Black iron oxide (E172) 
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 bottle in order to protect from moisture.  
Keep the bottle tightly closed. 
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 or 
20 capsules 
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin 
or mucous membrane must be avoided. If Temozolomide Accord 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
 
 
 



8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/001 
EU/1/10/615/002 
EU/1/10/615/025 
EU/1/10/615/026 
 
 
9  DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 12 January 2015 

 
 

10  DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  
 



1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 20 mg hard capsules. 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 20 mg temozolomide.  
 
Excipients 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.  
 
The hardcapsules are yellow/ white hard gelatin capsules, imprinted ‘TMZ’ on cap & ‘20’ on body.  
 
Each capsule is approximately 11 mm in length. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy 
(60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation 
of TMZ administration should be decided weekly according to haematological and non-haematological 
toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 
49 days) if all of the following conditions are met:  

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

nausea and vomiting). 
 



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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 
interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 



150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not beenestablished. 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 Accord should be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42 -day schedule were 
shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis 
against PCP is required for all patients receiving concomitant TMZ and RT for the 42 day regimen (with 
a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the 
prophylaxis until recovery of lymphopenia to grade ≤1.  
 



There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely 
for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been 
reported in patients using TMZ, in particular in combination with dexamethasone or other steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. 
Experts in liver disease should be consulted before treatment is initiated in patients with positive 
hepatitis B serology (including those with active disease). During treatment patients should be monitored 
and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, 
physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal 
hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway 
during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For 
patients with significant liver function abnormalities, physicians should assess the benefit/risk of 
continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with 
temozolomide. 
 
Meningoencephalitis herpetic 
 
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8).  
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ.  
Anti-emetic therapy may be administered prior to or following administration of TMZ.  
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it   
is strongly recommended during the monotherapy phase.  
 
Patients with recurrent or progressive malignant glioma  
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require 
anti-emetic therapy.  
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which 
may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, 
exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, 
phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following 
laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 



platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.  
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of child bearing should be advised to use effective contraception to avoid pregnancy while they 
are receiving TMZ.  



 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). TMZ should not be 
administered to pregnant women. If use during pregnancy must be considered, the patient should be 
apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 reactions reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the 
event of an overdose, haematological evaluation is needed. Supportive measures should be provided as 
necessary. 
 
 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active 
monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due 
primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 
position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl 
adduct.  
 
Clinical efficacy and safety 
 
Newly diagnosed glioblastoma multiforme  
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of 
RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150 – 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 



TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the 
RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  
 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 10%) 
is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a 
statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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

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



assessment, was 35% (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients 
stable disease was reported. The 6-month event-free survival for the ITT population was 44% with a 
median event-free survival of 4.6 months, which was similar to the results for the progression-free 
survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological 
objective response or maintaining progression-free status was strongly associated with maintained or 
improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to 
TMZ is similar to adults.  
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-
yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative 
to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo, the t1/2 of 
MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as 
early as 20 minutes post administration (mean times 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 rapidly the blood-brain barrier 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 reactions 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  
 
Capsule shell: 
Gelatine  
Water  
Titanium dioxide (E171)  
Iron oxide yellow (E172) 
 
Printing ink 
 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
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 bottle in order to protect from moisture. 



Keep the bottle tightly closed.  
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 or 
20 capsules.  
The carton contains one bottle. 
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions fordisposable and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin 
or mucous membrane must be avoided. If Temozolomide Accord 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/005 
EU/1/10/615/006 
EU/1/10/615/027 
EU/1/10/615/028 

 
 

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 12 January 2015 
 
 
 
 
 



10 DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 



 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 100 mg hard capsules. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 100 mg temozolomide. 
 
Excipients 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.  
 
The hard capsules are pink/white hard gelatin capsules, imprinted ‘TMZ’ on cap & ‘100’ on body. 
 
Each capsule is approximately 15 mm in length. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy 
(60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation 
of TMZ administration should be decided weekly according to haematological and non-haematological 
toxicity criteria.  TMZ administration can be continued throughout the 42 day concomitant period (up to 
49 days) if all of the following conditions are met:  

- absolute neutrophil count (ANC) ≥ 1.5 x 109/l  
- thrombocyte count ≥ 100 x 109/l  



- common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, 
nausea and vomiting). 

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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 
interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 



150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not been established. No data are available.  
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients.  
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not 
affected by age. However, elderly patients (>70  years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4).  
 
Method of administration 
 
Temozolomide Accordshould be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were 
shown to be at particular risk for developing Pneumocystis jirovrcci  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. 
 
Meningoencephalitis herpetic 
 
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8).  
 
Anti-emetic therapy 
 
Nausea and vomiting are very commonly associated with TMZ.  
Anti-emetic therapy may be administered prior to or following administration of TMZ.  
 
Adult patients with newly-diagnosed glioblastoma multiforme: 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it   
is strongly recommended during the monotherapy phase.  
 
Patients with recurrent or progressive malignant glioma  
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require 
anti-emetic therapy.  
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which 
may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, 
exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, 
phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following 
laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 



platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.  
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 



 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Accord should 
not be administered to pregnant women. If use during pregnancy must be considered, the patient should 
be apprised of the potential risk to the foetus.  
Breast-feeding 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment. because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influences 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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 reaction reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the 
event of an overdose, haematological evaluation is needed. Supportive measures should be provided as 
necessary. 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active 
monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due 
primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 
position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl 
adduct.  
 
Clinical efficacy and safety 
 
Newly diagnosed glioblastoma multiforme  
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of 
RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150 – 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the 
RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  



 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 10%) 
is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a 
statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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

 
The results from the trial were not consistent in the subgroup of patients with a poor performance status 
(WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, 
no unacceptable risks appear to be present in this patient group.  
 
Recurrent or progressive malignant glioma 
Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] 
≥70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. 
One was a non-comparative trial in 138 patients (29% received prior chemotherapy), and the other was a 
randomised active-controlled trial of TMZ vs. procarbazine in a total of 225 patients (67% received prior 
treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-
free survival (PFS) defined by MRI scans or neurological worsening. In the non-comparative trial, the 
PFS at 6 months was 19%, the median progression-free survival was 2.1 months, and the median overall 
survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8%.  
 
In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for 
procarbazine (21% vs. 8%, respectively – chi-square p = 0.008) with median PFS of 2.89 and 
1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ 
and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was 
significantly higher in the TMZ arm (60%) compared with the procarbazine arm (44%) (chi-square p = 
0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS ≥ 80.  
 
Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to 
worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The 
median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for 
procarbazine (log rank p = < 0.01 to 0.03).  
 
Recurrent anaplastic astrocytoma 
 
In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment 
of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46%. The median PFS was 
5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer 
assessment, was 35% (13 CR and 43 PR) for the intent-to-treat-population (ITT) n=162. In 43 patients 
stable disease was reported. The 6-month event-free survival for the ITT population was 44% with a 



median event-free survival of 4.6 months, which was similar to the results for the progression-free 
survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological 
objective response or maintaining progression-free status was strongly associated with maintained or 
improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to 
TMZ is similar to adults.  
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-
yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative 
to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo, the t1/2 of 
MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as 
early as 20 minutes post administration (mean times 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 rapidly the blood-brain barrier 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 reactions 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  
 
Capsule shell: 
Gelatine  
Water  
Titanium dioxide (E171)  
Iron oxide red (E172) 
 
Printing ink 
 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
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 bottle in order to protect from moisture. 
Keep the bottle tightly closed.  



 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 or 
20 capsules.  
The carton contains one bottle.  
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of  5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin 
or mucous membrane must be avoided. If Temozolomide Accord 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 thesight 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/009 
EU/1/10/615/010 
EU/1/10/615/029 
EU/1/10/615/030 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:15 March 2010 
Date of latest renewal: 12 January 2015 
 
 
10 DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu. 



 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 140 mg hard capsules. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 140 mg temozolomide. 
 
Excipients 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.  
 
The  hard capsules are transparent blue/white hard gelatin capsules, imprinted ‘TMZ’ on cap & ‘140’ on 
body. 
 
Each capsule is approximately 19 mm in length. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy 
(60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation 
of TMZ administration should be decided weekly according to haematological and non-haematological 
toxicity criteria.  TMZ administration can be continued throughout the 42 day concomitant period (up to 
49 days) if all of the following conditions are met:  

- absolute neutrophil count (ANC) ≥ 1.5 x 109/l  



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

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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
 



A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 
interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 
150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not been established. No data are available.  
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients.  
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not 
affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4).  
 
Method of administration 
 
Temozolomide Accord should be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42 day schedule were 
shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis 
against PCP is required for all patients receiving concomitant TMZ and RT for the 42 day regimen (with 



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



laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 
platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.  
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 



 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Accord should 
not be administered to pregnant women. If use during pregnancy must be considered, the patient should 
be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 events 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 reactions reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the 
event of an overdose, haematological evaluation is needed. Supportive measures should be provided as 
necessary. 
 
 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active 
monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due 
primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 
position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl 
adduct.  
 
Clinical efficacy and safety 
 
Newly diagnosed glioblastoma multiforme  
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of 
RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150 – 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis  jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 



TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the 
RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  
 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 10%) 
is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a 
statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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

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



5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer 
assessment, was 35% (13 CR and 43 PR) for the intent-to-treat-population (ITT) n=162. In 43 patients 
stable disease was reported. The 6-month event-free survival for the ITT population was 44% with a 
median event-free survival of 4.6 months, which was similar to the results for the progression-free 
survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological 
objective response or maintaining progression-free status was strongly associated with maintained or 
improved quality of life. 
 
Paediatric population 
 
Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or 
recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to 
TMZ is similar to adults.  
 
5.2 Pharmacokinetic properties 
 
TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-
yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-
carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to 
methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is 
thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine. Relative 
to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo, the t1/2 of 
MTIC was similar to that of TMZ, 1.8 hr.  
 
Absorption 
 
After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as 
early as 20 minutes post administration (mean times 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 rapidly the blood-brain barrier 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 reactions 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  
 
Capsule shell: 
Gelatine  
Water  
Titanium dioxide (E171)  
Indigo carmine (E132). 
 
Printing ink 
 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
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 bottle in order to protect from moisture.  
Keep the bottle tightly closed.  
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 or 
20 capsules.  
The carton contains one bottle.  
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of  5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin 
or mucous membrane must be avoided. If Temozolomide Accord 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 medicincal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7 MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/013 
EU/1/10/615/014 
EU/1/10/615/031 
EU/1/10/615/032 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:15 March 2010 



Date of latest renewal: 12 January 2015 
 
 
10 DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 



 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 180 mg hard capsules. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 180 mg temozolomide. 
 
Excipients with known effect:  
Each hardcapsule contains 131.4 mg of anhydrous lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule.  
 
The hard capsules are maroon/white, hard gelatin capsules, imprinted with ‘TMZ’ on cap & ‘180’ on 
body. 
 
Each capsule is approximately 19 mm in length.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord 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 temozolomide administration should be decided weekly according to haematological and non-
haematological toxicity criteria.  TMZ administration can be continued throughout the 42 day 
concomitant period (up to 49 days) if all of the following conditions are met:  

- absolute neutrophil count (ANC) ≥ 1.5 x 109/l  



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

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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
 
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
 



A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 
interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 
150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not been established. No data are available.  
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients.  
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not 
affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4).  
 
Method of administration 
 
Temozolomide Accord should be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecci 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. 
 
Meningoencephalitis herpetic 
 
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8).  
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ.  
Anti-emetic therapy may be administered prior to or following administration of TMZ.  
 
Adult patients with newly-diagnosed glioblastoma multiforme: 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it  
is strongly recommended during the monotherapy phase.  
 
Patients with recurrent or progressive malignant glioma  
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require 
anti-emetic therapy.  
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which 
may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, 
exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, 
phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following 



laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 
platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.  
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 



 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 
 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Accord should 
not be administered to pregnant women. If use during pregnancy must be considered, the patient should 
be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 

 
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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 events 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 reactions reported including bone marrow 
suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the 
event of an overdose, haematological evaluation is needed. Supportive measures should be provided as 
necessary. 
 
 
5 PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03  
 
Mechanism of action 
 
Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active 
monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due 
primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 
position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl 
adduct.  
 
Clinical efficacy and safety 
 
Newly diagnosed glioblastoma multiforme  
 
A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). 
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of 
RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 
monotherapy TMZ (150 – 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 
4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 



TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the 
RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  
 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 10%) 
is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a 
statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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

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



5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer 
assessment, was 35% (13 CR and 43 PR) for the intent-to-treat-population (ITT) population 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 times 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  rapidly the blood-brain barrier 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 reactions 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  
 
Capsule shell: 
Gelatine  
Water  
Titanium dioxide (E171)  
Iron oxide yellow (E172)  
Iron oxide red (E172) 
 
Printing ink 
 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
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 bottle in order to protect from moisture.  
Keep the bottle tightly closed.  
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 or 
20 capsules. 
The carton contains one bottle.  
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin 
or mucous membrane must be avoided. If Temozolomide Accord 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/017 
EU/1/10/615/018 
EU/1/10/615/033 
EU/1/10/615/034 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of the latest renewal: 12 January 2015 



 
 
10 DATE OF REVISION OF THE TEXT 

 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  
 
 



 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 250 mg hard capsules. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 250 mg temozolomide. 
 
Excipients 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.  
 
The hard capsules are white/white, hard gelatin capsules imprinted with ‘TMZ’ on cap & ‘250’ on body. 
 
Each capsule is approximately 21 mm in length. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Temozolomide Accord 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 Accord 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 Accord is administered in combination with focal radiotherapy (concomitant phase) 
followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase). 
 
Concomitant phase 
TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy 
(60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation 
of TMZ administration should be decided weekly according to haematological and non-haematological 
toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 
49 days) if all of the following conditions are met:  

- absolute neutrophil count (ANC) ≥ 1.5 x 109/l  
- thrombocyte count ≥ 100 x 109/l  



- common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, 
nausea and vomiting). 

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

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

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

 
CTC Grade 2 

 
CTC Grade 3 or 4 

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

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

/day) 
Remarks 

–1 100 Reduction for prior toxicity  
0 150 Dose during Cycle 1 
1 200 Dose during Cycles 2-6 in absence of toxicity 
 
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment 
 
Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ 
Absolute neutrophil count < 1.0 x 109 /l See footnote b 
Thrombocyte count < 50 x 109 /l See footnote b 
CTC non-haematological Toxicity 
(except for alopecia, nausea, vomiting) 

CTC Grade 3 CTC Grade 4b 

a : TMZ dose levels are listed in Table 2. 
b : TMZ is to be discontinued if: 
• dose level -1 (100 mg/m2 ) still results in unacceptable toxicity 
• the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs 
after dose reduction.   
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:  
 
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is 
administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment 



interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 
150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is 
no haematological toxicity (see section 4.4)  
 
Special populations 
 
Paediatric population 
 
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. 
Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in 
children under the age of 3 years have not been established. No data are available.  
 
Patients with hepatic or renal impairment 
 
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those 
with mild or moderate hepatic impairment. No data are available on the administration of TMZ in 
patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the 
pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with 
severe hepatic impairment or any degree of renal impairment. However, caution should be exercised 
when TMZ is administered in these patients.  
 
Elderly patients 
 
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not 
affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of 
neutropenia and thrombocytopenia (see section 4.4).  
 
Method of administration 
 
Temozolomide Accord should be administered in the fasting state.  
 
The capsules must be swallowed whole with a glass of water and must not be opened or chewed. 
  
If vomiting occurs after the dose is administered, a second dose should not be administered that day. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to dacarbazine (DTIC). 
 
Severe myelosuppression (see section 4.4).  
 
4.4 Special warnings and precautions for use 
 
Opportunistic infections and reactivation of infections 
 
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such 
as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8). 
 
Pneumocystis jirovecii pneumonia 
 
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were 
shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis 
against PCP is required for all patients receiving concomitant TMZ and RT for the 42 day regimen (with 
a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the 
prophylaxis until recovery of lymphopenia to grade ≤1.  
 



There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. 
However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely 
for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been 
reported in patients using TMZ, in particular in combination with dexamethasone or other steroids. 
 
HBV 
 
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. 
Experts in liver disease should be consulted before treatment is initiated in patients with positive 
hepatitis B serology (including those with active disease). During treatment patients should be monitored 
and managed appropriately. 
 
Hepatotoxicity 
 
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see 
section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If abnormal, 
physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal 
hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway 
during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For 
patients with significant liver function abnormalities, physicians should assess the benefit/risk of 
continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with 
temozolomide. 
 
Meningoencephalitis herpetic 
 
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in 
patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids 
administration. 
 
Malignancies 
 
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have 
also been reported very rarely (see section 4.8).  
 
Anti-emetic therapy  
 
Nausea and vomiting are very commonly associated with TMZ.  
Anti-emetic therapy may be administered prior to or following administration of TMZ.  
 
Adult patients with newly-diagnosed glioblastoma multiforme 
 
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it   
is strongly recommended during the monotherapy phase.  
 
Patients with recurrent or progressive malignant glioma  
 
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require 
anti-emetic therapy.  
 
Laboratory parameters 
 
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which 
may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, 
exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, 
phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following 
laboratory parameters must be met: ANC ≥1.5 x 109/l and platelet count ≥ 100 x 109/l. A complete blood 
count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and 
weekly until ANC > 1.5 x 109/l and platelet count > 100 x 109/l. If ANC falls to < 1.0 x 109/l or the 



platelet count is < 50 x109/l during any cycle, the next cycle should be reduced one dose level (see 
section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose 
is 100 mg/m2.  
 
Paediatric population 
 
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older 
children and adolescents is very limited (see sections 4.2 and 5.1).  
 
Elderly patients (> 70 years of age) 
 
Elderly patients  appear to be at increased risk of neutropenia and thrombocytopenia, compared with 
younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.  
 
Male patients 
 
Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the 
last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6). 
  
Lactose  
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the 
extent of absorption of temozolomide or the exposure to its active metabolite monomethyl 
triazenoimidazole carboxamide (MTIC).  
 
Administration of TMZ with food resulted in a 33 % decrease in Cmax and a 9 % decrease in area under 
the curve (AUC).  
As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Accord should 
be administered without food.  
 
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or 
phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated 
with a small but statistically significant decrease in clearance of TMZ.  
 
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of 
other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low 
protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see 
section 5.2).  
 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of 
myelosuppression. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy 
while they are receiving TMZ. 



 
Pregnancy 
 
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2, 
teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Accord should 
not be administered to pregnant women. If use during pregnancy must be considered, the patient should 
be apprised of the potential risk to the foetus.  
 
Breast-feeding 
 
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued 
while receiving treatment with TMZ.  
 
 
Male fertility  
 
TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a 
child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior 
to treatment, because of the possibility of irreversible infertility due to therapy with TMZ. 
 
4.7 Effects on ability to drive and use machines 
 
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see 
section 4.8). 
 
4.8 Undesirable effects 
Summary of the safety profile 

 
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 

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 (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
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



 

Table 4. Adverse reactions in patients treated with temozolomide 
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 

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 



84

 

Table 4. Adverse reactions in patients treated with temozolomide 
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
a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal 
b Includes gastroenteritis, gastroenteritis viral 
c Includes cushingoid, Cushing syndrome 
d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, 
peripheral motor neuropathy 
e Includes visual impairment, eye disorder 
f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral 
g Includes earache, ear discomfort 
h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort 
i Includes oedema peripheral, peripheral swelling 
j Includes 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.  
 
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 



85

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



86

4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii 
pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.  
 
TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in 
the RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.  
 
The hazard ratio (HR) for overall survival was 1.59 (95% CI for HR=1.33 -1.91) with a log-rank p < 
0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26% vs 
10%) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ 
monotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated 
a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).  
 

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



87

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-populations (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 times 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 rapidly, the blood-brain barrier 
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.  
 



88

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 reactions 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  
 
Capsule shell: 
Gelatine  
Water  
Titanium dioxide (E171) 
 
Printing ink 
 
Shellac 
Propylene glycol 
Black iron oxide (E172) 
Potassium hydroxide 
 
 



89

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 bottle in order to protect from moisture.  
Keep the bottle tightly closed. 
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Bottle 
Type III amber glass bottles with polypropylene child-resistant closures and a desiccant, containing 5 
or 20 capsules.  
The carton contains one bottle.  
 
Sachet 
Polyester/aluminium/polyethylene (PET/alu/PE) sachet.  
Each sachet contains 1 hard capsule.  
Pack-size of 5 or 20 hard capsules individually sealed in sachets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling 
 
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with 
skin or mucous membrane must be avoided. If Temozolomide Accord 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 medicincal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7 MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
8 MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/615/021 



90

EU/1/10/615/022 
EU/1/10/615/035 
EU/1/10/615/036 
 
 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 12 January 2015 
 
 
10 DATE OF REVISION OF THE TEXT 

 
Detailed information on this medicincal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

 
 
 



91

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 



92

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Accord Healthcare Limited 
Sage House, 319 Pinner Road, 
North Harrow, 
Middlesex, HA1 4HF, 
United Kingdom 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, Section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 

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

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

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

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



93

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



94

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING  



95

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 5 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 5 mg of 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 
 
Read the package leaflet before use . 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 
Store in the original bottle.  
Keep the bottle tightly closed in order to protect from moisture. 
 



96

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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/001 
EU/1/10/615/002 
 
 
13. BATCH NUMBER 
 
Batch 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 5mg 

 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 
 
 
 
 
 



97

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 20 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 20 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 



98

Store in the original bottle.  
Keep the bottle 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/005 
EU/1/10/615/006 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 20mg 

 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 



99

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 100 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 



100

Store in the original bottle.  
Keep the bottle 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/009 
EU/1/10/615/010 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 100mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



101

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 140 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 140 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 



102

Store in the original bottle.  
Keep the bottle 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/013 
EU/1/10/615/014 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 140mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



103

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 180 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 180 mg of 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 
 
Read the package leaflet before used. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 
Store in the original bottle.  



104

Keep the bottle 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/017 
EU/1/10/615/018 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 180mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 



105

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

OF THE SIGHT AND OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 



106

Store in the original bottle.  
Keep the bottle 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/021 
EU/1/10/615/022 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 250mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



107

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 5 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
4. BATCH NUMBER 
 
Batch: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



108

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 20 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
4. BATCH NUMBER 
 
Batch: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



109

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 100 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
4. BATCH NUMBER 
 
Batch: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



110

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 140 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



111

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 180 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



112

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
BOTTLE LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 250 mg hard capsules 
temozolomide 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Batch: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 hard capsules 
20 hard capsules 
 
 
6. OTHER 
 
 
 
 
 
 
 
 



113

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
SACHET CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 5 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 5 mg of 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 
 
Read the package leaflet before use . 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture 
 



114

 
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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/025 
EU/1/10/615/026 
 
 
13. BATCH NUMBER 
 
Batch 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 5mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 
 



115

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
SACHET CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 20 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 20 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 



116

Store in the original package 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/027 
EU/1/10/615/028 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 20mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 



117

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
SACHET CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 100 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 



118

Store in the original package 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/029 
EU/1/10/615/030 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 100mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 

 



119

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
SACHET CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 140 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 140 mg of 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 
 
Read the package leaflet before use.  
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture 



120

 
 
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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/031 
EU/1/10/615/032 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 140mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



121

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
SACHET CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Temozolomide Accord 180 mg hard capsules 
temozolomide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 180 mg of 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 
 
Read the package leaflet before used. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture 



122

 
 
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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/033 
EU/1/10/615/034 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 180mg 
 

 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



123

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

OF THE SIGHT AND OF CHILDREN 
 
Keep out of the sight and reach of children, preferably in a locked cupboard. Ingestion can be lethal.  
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
Do not open, crush or chew the capsules, swallow whole. If a capsule is damaged, avoid contact with 
your skin, eyes or nose.  
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25 °C. 



124

Store in the original package 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 
 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  
Spain 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/615/035 
EU/1/10/615/036 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Temozolomide 250mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 
 



125

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



126

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



127

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



128

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



129

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



130

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET  LABEL 
 

 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Temozolomide Accord 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 
 
1 hard capsule 
 
 
6. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



131

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 



132

Package leaflet: Information for the user 
 

Temozolomide Accord 5 mg hard capsules 
Temozolomide Accord 20 mg hard capsules 
Temozolomide Accord 100 mg hard capsules 
Temozolomide Accord 140 mg hard capsules 
Temozolomide Accord 180 mg hard capsules 
Temozolomide Accord 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 Accord is and what it is used for 
2. What you need to know before you take Temozolomide Accord 
3. How to take Temozolomide Accord 
4. Possible side effects 
5. How to store Temozolomide Accord 
6. Contents of the pack and other information 
 
 
1. What Temozolomide Accord is and what it is used for 
 
Temozolomide is an anti-cancer medicine. 
 
Temozolomide Accord capsules are taken to treat specific forms of brain tumours: 
- adults with newly diagnosed specific form of brain tumour (glioblastoma multiforme). 

Temozolomide is first used together with radiotherapy (concomitant phase of treatment) and 
after that alone (monotherapy phase of treatment).  

- children 3 years and older and adult patients with specific forms of brain tumour (e.g. 
glioblastoma multiforme or anaplastic. astrocytoma) that has returned or where the cancer has 
spread after standard therapy. 

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

section 6). 
- if you have had an allergic reaction to another anti-cancer medicine called dacarbazine. Signs of 

allergic reaction include feeling itchy, breathlessness or wheezing, swelling of the face, lips, 
tongue or throat. 

- if you have a reduced number of blood cells, 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 Accord,  
 



133

- as you should be observed closely for the development of a serious form of chest infectioncalled 
Pneumocystis jirovecii pneumonia (PCP). If you are a newly-diagnosed patient (glioblastoma 
multiforme) you may be receiving temozolomide  for 42 days in combination with radiotherapy. 
In this case, your doctor will also prescribe medicine to help you prevent this typeof pneumonia 
(PCP). 
 

- if you have ever had or might now have a hepatitis B infection. This is because Temozolomide 
Accord 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. 
 

- if you have anaemia, low blood count (such as white blood cell count and platelet count), or 
blood clotting problems before treatment, or develop them during treatment. Your doctor may 
need to reduce the dose of your medicine or interrupt your treatment, or you may need other 
treatment. Your doctor will decide whether any change in your treatment is needed. In some 
cases, it may be necessary to stop treatment with temozolomide. Your blood will be tested 
regularly to monitor your condition.  If you develop fever or symptoms of an infection contact 
your doctor immediately. 

 
- you may have a small risk of other changes in blood cells, including leukaemia. 
 
- if you feel sick or vomit, which are very common side effects of Temozolomide (see section 4). 

If you vomit frequently before or during treatment, ask your doctor about medicines to help 
prevent vomiting or control the vomiting and the best time to take temozolomide until the 
vomiting is under control. If you vomit after 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.  Older patients are more prone to infections, increased 

bruising or bleeding.   
 
- if you have liver or kidney problems as your dose of temozolomide 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 Accord. 
 
Other medicines and Temozolomide Accord 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy,breast-feeding and fertility 
If you are pregnant or, 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 Accord during pregnancy unless clearly indicated by your doctor. 
 
Effective contraceptive precautions must be taken by both male and female patients who are taking 
Temozolomide Accord (see also “Male fertility” below). 
 
You must not breast-feed whilst you are being treated with Temozolomide Accord. 
 
Male fertility 
Temozolomide Accord 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. 
  
Ask your doctor for advice before taking any medicine.    



134

 
Driving and using machines 
When you take temozolomide you may 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 Accord contains lactose 
The capsules contain lactose (a kind of sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Temozolomide Accord  
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
How to open sachet  
Open the sachet by folding and tearing along the fold line with the notch in the corner of the sachet. 
 
Temozolomide should only be prescribed by specialists experienced in brain tumours. 
 
Dosage and duration of treatment  
 
Your doctor will decide the correct dose of temozolomide for you to take, based on your size (height 
and weight) and whether you have had chemotherapy treatment. You may be given other medicines to 
take before and/or after temozolomide to avoid or control vomiting. 
 
Take your prescribed dose of Temozolomide Accord once a day. Take the dose 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. Avoid inhaling the 
powder. If you accidentally get some in your eyes or nose, flush the area with water.  
 
If you are taking Temozolomide Accord in combination with radiotherapy (newly diagnosed 
patients): 
 
While the radiotherapy is ongoing your doctor will start temozolomide at a dose of 75 mg/m² and the 
actual daily dose you take will depend on your height and weight. You will take this dose every day 
for 42 days (up to 49 days) in combination with radiotherapy. Based on your blood counts and how 
you tolerate temozolomide, the dose may be delayed or stopped. 
 
Once the radiotherapy is completed, you will interrupt treatment for 4 weeks to give your body a 
chance to recover. 
 
Then there may be up to 6 treatment cycles, and each one lasts 28 days. You will take your new dose 
of temozolomide capsules initially at 150 mg/m² once daily for the first five days (“dosing days”) of 
each cycle, followed by 23 days without temozolomide; this adds up to a 28 day treatment cycle.  
 
After day 28, the next cycle will begin, in which you will again take this medicine once daily for five 
days followed by 23 days without temozolomide. Based on your blood counts and how you tolerate 
temozolomide during each treatment cycle, the dose may be adjusted, delayed or stopped. 
 
If you are taking Temozolomide Accord capsules alone (without radiotherapy): 
 
A treatment cycle with Temozolomide Accord comprises 28 days. You will take the capsules once 
daily for the first five days (“dosing days”) followed by 23 days without temozolomide, adding up to 
the 28 day treatment cycle.  



135

 
After day 28, the next cycle will begin, in which you will again take this medicine once daily for five 
days followed by 23 days without temozolomide. Before each new treatment cycle, your blood will be 
tested to see if the temozolomide dose needs to be adjusted. 
 
If you have not been treated before with chemotherapy, you will take your first dose of temozolomide 
at 200 mg/m² once daily for the first five days (“dosing days”) followed by 23 days without 
temozolomide. If you have been treated before with chemotherapy, you will take your first dose of 
temozolomide at 150 mg/m² once daily for the first five days (“dosing days”) followed by 23 days 
without temozolomide. 
 
Depending on your blood test results, your doctor may adjust your dose for the next cycle. 
Each time you start a new treatment cycle, be sure you understand exactly how many capsules of each 
strength you need to take each day and how many days you will receive this dose. 
 
All patients 
 
Temozolomide comes in different strength capsules (shown on the outer label in mg). Each strength 
has a different colour cap. Depending on the dose of temozolomide that your doctor prescribes, you 
may have to take several capsules on each dosing day of the treatment cycle. 
- Be sure you understand exactly how many capsules you need to take of each strength. Ask your 

doctor or pharmacist to write down the number of each strength (including colour) that you need 
to take each dosing day. 

- Be sure you know exactly which days are your dosing days. 
- Be sure you review the dose with your health care provider each time you start a new cycle. 

Sometimes the dose or the mix of capsules you need to take will be different from the last cycle. 
- Once you take the medicine home, if you are confused or unsure about how to take your dose, 

call for re-instruction before beginning the treatment cycle. Errors in how you take this 
medicine may have serious health consequences. 

 
If you take more Temozolomide Accord than you should 
If you accidentally take more capsules than you were told to, contact your doctor, pharmacist or nurse 
immediately. 
 
If you forget to take Temozolomide Accord 
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 double the next 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. 
 
Patients taking temozolomide in combination with radiation therapy may experience different side 
effects than patients taking temozolomide alone. 
 
Contact your doctor immediately if you have any of the following: 
-  a severe allergic reaction (hypersensitive) (hives, wheezing or other breathing difficulty),  
- uncontrolled bleeding, 
- Seizures (convulsions),  
- fever,  
- chills, 
- severe headache that does not go away. 
 



136

Temozolomide 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/or a reduced 
resistance to infections. The reduction of blood cells is usually temporary, but in some cases may be 
for longer 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 dose will be reduced or discontinued. 
 
Other side effects that have been reported are listed below: 

Very common side effects (may affect more than 1 in 10 people):  
 

- loss of appetite, difficulty speaking, headache 
- vomiting, nausea, diarrhoea, constipation 
- rash, hair loss 
- tiredness 

 
Common side effects (may affect up to 1 in 10 people):  
 
 infections, oral infections, wound infections 
 reduced number of blood cells (neutropenia, lymphopenia, thrombocytopenia) 
 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 sensations, 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 side-effects (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 



137

- 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. 
 
 
5. How to store Temozolomide Accord 
 
Keep this medicine out of the sight and reach of children, preferably in a locked cupboard. 
Accidentally ingestion can be lethal for children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date 
refers to the last day of that month. 
 
Bottle 
Do not store above 25°C.  
Store in the original bottle.  
Keep the bottle tightly closed in order to protect from moisture. 
 
Sachet 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
 
 
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 Accord contains 
 
 
- The active substance is temozolomide.  

Temozolomide Accord 5 mg hard capsules: Each capsule contains 5 mg temozolomide.  
Temozolomide Accord 20 mg hard capsules: Each capsule contains 20 mg temozolomide.  
Temozolomide Accord 100 mg hard capsules: Each capsule contains 100 mg temozolomide.  



138

Temozolomide Accord 140 mg hard capsules: Each capsule contains 140 mg temozolomide. 
Temozolomide Accord 180 mg hard capsules: Each capsule contains 180 mg temozolomide.  
Temozolomide Accord 250 mg hard capsules: Each capsule contains 250 mg temozolomide. 

- The other ingredients are:  
capsule content:  
anhydrous lactose, colloidal anhydrous silica, sodium starch glycolate type A, tartaric acid, 
stearic acid.  
capsule shell: 
Temozolomide Accord 5 mg hard capsules: gelatine, titanium dioxide (E 171), yellow iron 
oxide (E 172), indigo carmine (E 132), water. 
Temozolomide Accord 20 mg hard capsules: gelatine, titanium dioxide (E 171), yellow iron 
oxide (E 172), water. 
Temozolomide Accord 100 mg hard capsules: gelatine, titanium dioxide (E 171), red iron oxide 
(E 172), water. 
Temozolomide Accord 140 mg hard capsules: gelatine, titanium dioxide (E 171), indigo 
carmine (E 132), water. 
Temozolomide Accord 180 mg hard capsules: gelatine, titanium dioxide (E 171), yellow iron 
oxide (E 172), red iron oxide (E 172), water. 
Temozolomide Accord 250 mg hard capsules: gelatine, titanium dioxide (E 171), water. 
printing ink: 
shellac, propylene glycol, black iron oxide (E172) and potassium hydroxide. 

 
What Temozolomide Accord looks like and contents of the pack 
 
Temozolomide Accord 5 mg hard capsules have a white body, a green cap, and are imprinted ‘TMZ’ 
on cap and ‘5’ on body with black ink.   
 
Temozolomide Accord 20 mg hard capsules have a white body, a yellow cap, and are imprinted 
‘TMZ’ on cap and ‘20’ on body with black ink. 
 
Temozolomide Accord 100 mg hard capsules have a white body, a pink cap, and are imprinted ‘TMZ’ 
on cap and ‘100’ on body with black ink. 
 
Temozolomide Accord 140 mg hard capsules have a white body, a blue cap, and are imprinted ‘TMZ’ 
on cap and ‘140’ on body with black ink. 
 
Temozolomide Accord 180 mg hard capsules have a white body, a maroon cap, and are imprinted 
‘TMZ’ on cap and ‘180’ on body with black ink. 
 
Temozolomide Accord 250 mg hard capsules have a white body, a white cap, and are imprinted 
‘TMZ’ on cap and ‘250’ on body with black ink. 
 
The hard capsules are dispensed in amber glass bottles containing 5 or 20 capsules. 
Each carton contains 1 bottle. 
 
The hard capsules are dispensed in sachet containing 1 capsule. 
Each carton contains 5 or 20 sachets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Accord Healthcare S.L.U.  
World Trade Center, Moll de Barcelona, s/n,  
Edifici Est 6ª planta,  
08039 Barcelona,  



139

Spain 
Manufacturer 
Accord Healthcare Limited 
Sage House, 319 Pinner Road, 
North Harrow, 
Middlesex,  
HA1 4HF, 
United Kingdom 
 
Accord Healthcare Polska Sp.z o.o., 
ul. Lutomierska 50,95-200 Pabianice, Poland 
 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET