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TEMOZOLOMIDE RELIANCE 180 MG HARD CAPSULES

Active substance(s): TEMOZOLOMIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Temozolomide Reliance 180 mg hard capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 180 mg temozolomide.
Excipient with known effect:
Each 180 mg hard capsule contains 150.84 mg of anhydrous lactose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Hard capsule.
The 180 mg hard capsules have an opaque white body, an opaque brown cap, and are
imprinted with black ink. The cap is imprinted with “Temozolomide”. The body is
imprinted with "180 mg".

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Temozolomide Reliance 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 Reliance 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 Reliance 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 CTC Grade 2
(except for alopecia, nausea,
vomiting)

CTC Grade 3 or 4

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

cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of
each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations
during the monotherapy phase should be applied according to Tables 2 and 3.
During treatment a complete blood count should be obtained on Day 22 (21 days after
the first dose of TMZ). The dose should be reduced or administration discontinued
according to Table 3.

Table 2. TMZ dose levels for monotherapy treatment
Dose
level

TMZ dose
(mg/m2/day
)

Remarks

–1

100

Reduction for prior toxicity

0

150

Dose during Cycle 1

1

200

Dose during Cycles 2-6 in absence of
toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment
Toxicity

Reduce TMZ by 1 dose Discontinue TMZ
levela

Absolute neutrophil count

< 1.0 x 109/l

See footnote b

Thrombocyte count

< 50 x 109/l

See footnote b

CTC non-haematological Toxicity

CTC Grade 3

CTC Grade 4b

(except for
vomiting)

alopecia,

nausea,

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 Reliance hard capsules should be administered in the fasting state.
The capsules must be swallowed whole with a glass of water and must not be opened
or chewed.
If vomiting occurs after the dose is administered, a second dose should not be
administered that day.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Hypersensitivity to dacarbazine (DTIC).
Severe myelosuppression (see section 4.4).

4.4

Special warnings and precautions for use

Opportunistic infections and reactivation of infections
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation
of infections (such as HBV, CMV) have been observed during the treatment with
TMZ (see section 4.8).

Pneumocystis jirovecii pneumonia
Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42day 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 reportedin patients treated
with TMZ (see section 4.8). Baseline liver function tests should be performed prior to
treatment initiation. If abnormal, physicians should assess the benefit/risk prior to
initiating temozolomide including the potential for fatal hepatic failure. For patients
on a 42 day treatment cycle liver function tests should be repeated midway during this
cycle. For all patients, liver function tests should be checked after each treatment
cycle. For patients with significant liver function abnormalities, physicians should
assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks
or more after the last treatment with temozolomide.

Malignancies
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid
leukaemia, have also been reported very rarely (see section 4.8).
Anti-emetic therapy
Nausea and vomiting are very commonly associated with TMZ.
Anti-emetic therapy may be administered prior to or following administration of
TMZ.
Adult patients with newly-diagnosed glioblastoma multiforme
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant
phase and it is strongly recommended during the monotherapy phase.
Patients with recurrent or progressive malignant glioma
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment
cycles may require anti-emetic therapy.
Laboratory parameters
Patients treated with TMZ may experience myelosuppression, including prolonged
pancytopenia, which may result in aplastic anemia, which in some cases has resulted
in a fatal outcome. In some cases, exposure to concomitant medicinal products
associated with aplastic anemia, including carbamazepine, phenytoin, and
sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the
following laboratory parameters must be met: ANC ≥ 1.5 x 109/l and platelet count ≥
100 x 109/l. A complete blood count should be obtained on Day 22 (21 days after the
first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 109/l and
platelet count> 100 x 109/l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x
109/l during any cycle, the next cycle should be reduced one dose level (see section
4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest
recommended dose is 100 mg/m2.
Paediatric population
There is no clinical experience with use of TMZ in children under the age of 3 years.
Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).
Elderly patients (> 70 years of age)
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia,
compared with younger patients. Therefore, special care should be taken when TMZ
is administered in elderly patients.
Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months
after receiving the last dose and to seek advice on cryoconservation of sperm prior to
treatment (see section 4.6).
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
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 should be administered without food.
Based on an analysis of population pharmacokinetics, co-administration of
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2
receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Coadministration with valproic acid was associated with a small but statistically
significant decrease in clearance of TMZ.
No studies have been conducted to determine the effect of TMZ on the metabolism or
elimination of other medicinal products. However, since TMZ does not undergo
hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect
the pharmacokinetics of other medicinal products (see section 5.2).
Use of TMZ in combination with other myelosuppressive agents may increase the
likelihood of myelosuppression.
Paediatric population
Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no data in pregnant women. In preclinical studies in rats and rabbits
receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated
(see section 5.3). Temozolomide should not be administered to pregnant women. If
use during pregnancy must be considered, the patient should be apprised of the
potential risk to the foetus.
Breast-feeding
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should
be discontinued while receiving treatment with TMZ.
Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to
avoid pregnancy while they are receiving TMZ.
Male fertility
TMZ can have genotoxic effects. Therefore, men being treated with it should be
advised not to father a child up to 6 months after receiving the last dose and to seek
advice on cryoconservation of sperm prior to treatment, because of the possibility of
irreversible infertility due to therapy with TMZ.

4.7

Effects on ability to drive and use machines
TMZ has minor influence on the ability to drive and use machines due to fatigue and
somnolence (see section 4.8).

4.8

Undesirable effects

Clinical trial experience
In patients treated with TMZ, whether used in combination with RT or as
monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as
monotherapy in patients with recurrent or progressive glioma, the reported very
common adverse reactions were similar: nausea, vomiting, constipation, anorexia,
headache and fatigue. Convulsions were reported very commonly in the newlydiagnosed glioblastoma multiforme patients receiving monotherapy, and rash was
reported very commonly in newly-diagnosed glioblastoma multiforme patients
receiving TMZ concurrent with RT and also as monotherapy, and commonly in
recurrent glioma. Most haematologic adverse reactions were reported commonly or
very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4
laboratory findings is presented after each table.
In the tables undesirable effects are classified according to System Organ Class and
frequency. Frequency groupings are defined according to the following convention:
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to <
1/100). ); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). Within each
frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Newly-diagnosed glioblastoma multiforme
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed
glioblastoma multiforme during the concomitant and monotherapy phases of
treatment.
Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in
patients with newly-diagnosed glioblastoma multiforme

System organ class

TMZ + concomitant RT

TMZ monotherapy

n=288*

n=224

Infections and infestations
Common:

Infection, Herpes simplex, wound Infection, candidiasis oral
infection, pharyngitis, candidiasis
oral
Herpes simplex, herpes zoster,
influenza–like symptoms

Uncommon:
Blood and lymphatic system disorders
Common:

Neutropenia,
thrombocytopenia, Febrile
thrombocytopenia,
lymphopenia, leukopenia
leukopenia

neutropenia,
anaemia,

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Cushingoid

Cushingoid

Endocrine disorders
Uncommon:

Metabolism and nutrition disorders
Very common:

Anorexia

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase Hyperglycaemia, weight increased
increased, weight increased

Psychiatric disorders
Common:

Anxiety, emotional lability, insomnia Anxiety, depression,
lability, insomnia

Uncommon:

Agitation,
apathy,
behaviour Hallucination, amnesia
disorder, depression, hallucination

emotional

Nervous system disorders
Very common:

Headache

Convulsions, headache

Common:

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

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

neuropathy,
paresthesia,
speech disorder, tremor
Uncommon:

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

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

Eye disorders
Visual field defect,
blurred, diplopia

vision

Common:

Vision blurred

Uncommon:

Hemianopia, visual acuity reduced, vision Visual acuity reduced, eye pain,
disorder, visual field defect, eye pain
eyes dry

Ear and labyrinth disorders
Common:

Hearing impairment

Hearing impairment, tinnitus

Uncommon:

Otitis media, tinnitus, hyperacusis, Deafness, vertigo, earache
earache

Cardiac disorders
Uncommon:

Palpitation

Vascular disorders
Common:

Haemorrhage, oedema, oedema leg

Haemorrhage,
deep
thrombosis, oedema leg

venous

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary,
oedema peripheral

oedema,

Respiratory, thoracic and mediastinal disorders
Common:

Dyspnoea, coughing

Dyspnoea, coughing

Uncommon:

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

Gastrointestinal disorders
Very common:

Constipation, nausea, vomiting

Common:

Stomatitis, diarrhoea, abdominal Stomatitis, diarrhoea, dyspepsia,
pain, dyspepsia, dysphagia
dysphagia, mouth dry

Uncommon:

Constipation, nausea, vomiting

Abdominal
distension,
fecal
incontinence,
gastrointestinal
disorder (NOS), gastroenteritis,

haemorrhoids
Skin and subcutaneous tissue disorders
Very common:

Rash, alopecia

Rash, alopecia

Common:

Dermatitis,
pruritus

Uncommon:

Skin exfoliation, photosensitivity Erythema, pigmentation abnormal,
reaction, pigmentation abnormal
sweating increased

dry

skin,

erythema, Dry skin, pruritus

Musculoskeletal and connective tissue disorders
Muscle
weakness,
arthralgia,
musculoskeletal pain, myalgia

Common:

Muscle weakness, arthralgia

Uncommon:

Myopathy,
back
pain, Myopathy, back pain
musculoskeletal pain, myalgia

Renal and urinary disorders
Common:

Micturition
incontinence

frequency,

urinary Urinary incontinence

Uncommon:

Dysuria

Reproductive system and breast disorders
Uncommon:

Impotence

Vaginal haemorrhage,menorrhagia,
amenorrhea, vaginitis, breast pain

General disorders and administration site conditions
Very common:

Fatigue

Fatigue

Common:

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

Uncommon:

Asthenia, flushing, hot flushes, Asthenia, face oedema, pain,
condition aggravated, rigors, tongue condition aggravated, rigors, tooth
discolouration, parosmia, thirst
disorder,

Investigations
Common:

ALT increased

Uncommon:

Hepatic enzymes increased, Gamma
GT increased, AST increased

ALT increased

*A patient who was randomised to the RT arm only, received TMZ + RT.
Laboratory results

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

Opportunistic infections, including PCP

Blood and lymphatic system disorders
Very common:

Neutropenia or lymphopenia (grade 3-4),
thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders
Very common:

Anorexia

Common:

Weight decrease

Nervous system disorders
Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

Respiratory, thoracic and mediastinal disorders
Common:

Dyspnoea

Gastrointestinal disorders
Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

Skin and subcutaneous tissue disorders
Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,
exanthema

General disorders and administration site conditions
Very common:

Fatigue

Common:

Fever, asthenia, rigors, malaise, pain, taste
perversion

Very rare:

Allergic reactions,
angioedema

including

anaphylaxis,

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.

The following additional serious adverse reactions have been identified during postmarketing exposure:

Table 6. Summary of events reported with temozolomide in the post-marketing setting
Infections and infestations*
Uncommon:

cytomegalovirus infection, infection
reactivation such as cytomegalovirus, hepatitis
B virus†

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

*

Including cases with fatal outcome
Frequencies estimated based on relevant clinical trials.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V.
4.9

Overdose
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have
been evaluated clinically in patients. Dose-limiting toxicity was haematological and
was reported with any dose but is expected to be more severe at higher doses. An
overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one
patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ
failure and death. There are reports of patients who have taken the recommended dose
for more than 5 days of treatment (up to 64 days) with adverse events reported
including bone marrow suppression, with or without infection, in some cases severe

and prolonged and resulting in death. In the event of an overdose, haematological
evaluation is needed. Supportive measures should be provided as necessary.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC
code: 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 activecontrolled 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 progressionfree 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 rapidely, with peak
concentrations reached as early as 20 minutes post-administration (mean time
between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean
faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete
absorption.
Distribution
TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to
interact with highly protein-bound substances.
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain
barrier rapidly and is present in the CSF. CSF penetration was confirmed in one

patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in
plasma, which is consistent with animal data.
Elimination
The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C
elimination is renal. Following oral administration, approximately 5 % to 10 % of the
dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as
temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar
metabolites.
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of
distribution and half-life are independent of dose.
Special populations
Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ
clearance was independent of age, renal function or tobacco use. In a separate
pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to
moderate hepatic impairment were similar to those observed in patients with normal
hepatic function.
Paediatric patients had a higher AUC than adult patients; however, the maximum
tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3

Preclinical safety data
Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies
were conducted in rats and dogs. The primary targets of toxicity included the bone
marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses,
which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina
occurred. Most of the toxicity showed evidence of reversibility, except for adverse
events on the male reproductive system and retinal degeneration. However, because
the doses implicated in retinal degeneration were in the lethal dose range, and no
comparable effect has been observed in clinical studies, this finding was not
considered to have clinical relevance.
TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more
toxic to the rat and dog than to humans, and the clinical dose approximates the
minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and
platelets appear to be sensitive indicators of toxicity. A variety of neoplasms,
including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma
were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes
were evident in dog studies. Rats appear to be particularly sensitive to oncogenic
effects of TMZ, with the occurrence of first tumours within 3 months of initiating
dosing. This latency period is very short even for an alkylating agent.
Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL)
chromosome aberration tests showed a positive mutagenicity response.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule content:
anhydrous lactose,
colloidal anhydrous silica,
sodium starch glycolate type A,
tartaric acid,
stearic acid.
Capsule shell:
180 mg:
gelatin,
titanium dioxide (E 171),
sodium lauryl sulfate,
Iron oxide yellow (E 172),
Iron oxide red (E 172)
Printing ink:
Shellac ,
Dehydrated Alcohol,
Isopropyl Alcohol,
Butyl Alcohol
propylene glycol,
Strong ammonia solution,
potassium hydroxide,
black iron oxide (E 172).
Purified water

6.2

Incompatibilities
Not applicable.

6.3

Shelf life

24 Months

6.4

Special precautions for storage
Do not store above 30 °C.
Store in the original bottle in order to protect from moisture.
Keep the bottle tightly closed.

6.5

Nature and contents of container
Type III amber glass bottles with polypropylene child-resistant closures containing 5
hard capsules.
The carton contains one bottle.

6.6

Special precautions for disposal
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 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

Reliance Genemedix Ltd.
Address: 8TH FLOOR 105
WIGMORE STREET
LONDON, W1U 1QY
Country: UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 42244/0004

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

17/04/2014

10

DATE OF REVISION OF THE TEXT
14/12/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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