Temodal

1.

NAME OF THE MEDICINAL PRODUCT

Temodal 5 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 5 mg temozolomide.

Excipient: Each hard capsule contains 132.8 mg of anhydrous lactose.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

The hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink.

The cap is imprinted with “Temodal”. The body is imprinted with "5 mg", the Schering-Plough logo and

two stripes.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal hard capsules 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

Temodal hard capsules 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

Temodal hard capsules 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/m 2 daily for 42 days concomitant with focal radiotherapy

(60 Gy administered in 30 fractions). No dose reductionsare 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 10 9 /l

- thrombocyte count ≥ 100 x 10 9 /l

2

- 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 interruption a

TMZ discontinuation

Absolute neutrophil count ≥ 0.5 and < 1.5 x 10 9 /l

< 0.5 x 10 9 /l

Thrombocyte count

≥ 10 and < 100 x 10 9 /l

< 10 x 10 9 /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 10 9 /l; thrombocyte count ≥ 100 x 10 9 /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/m 2 once daily for 5 days followed

by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m 2 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 10 9 /l, and the thrombocyte count is ≥ 100 x 10 9 /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/m 2 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/m 2 /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

level a

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 10 9 /l

See footnote b

Thrombocyte count

< 50 x 10 9 /l

See footnote b

CTC non-haematological Toxicity

(except for alopecia, nausea, vomiting) CTC Grade 3

CTC Grade 4 b

a: TMZ dose levels are listed in Table 2.

b: TMZ is to be discontinued if:

• dose level -1 (100 mg/m 2 ) still results in unacceptable toxicity

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

reduction.

3

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/m 2 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/m 2 once daily, to be increased in the second cycle to 200 mg/m 2 once daily, for 5 days if

there is no haematological toxicity (see section 4.4)

Special populations

Paediatric patients

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma.

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in

older children is very limited (see sections 4.4 and 5.1).

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 hepaticimpairment. No data are available on the administration of TMZ in

patients with severe hepatic impairment (Child’s Class C) or with renalimpairment. 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 renalimpairment. 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

Temodal 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 substanceor to any of the excipients.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Pneumocystis carinii 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 carinii 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.

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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.

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

Prior to dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x 10 9 /l and platelet count

≥ 100 x 10 9 /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 10 9 /l and platelet count > 100 x 10 9 /l. If

ANC falls to < 1.0 x 10 9 /l or the platelet count is < 50 x 10 9 /l during any cycle, the next cycle should be

reduced one dose level (see section 4.2). Dose levels include 100 mg/m 2 , 150 mg/m 2 , and 200 mg/m 2 .

The lowest recommended dose is 100 mg/m 2 .

Paediatric use

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

Interaction studies have only been performed in adults.

5

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 C max and a 9 % decrease in area under

the curve (AUC).

As it cannot be excluded that the change in C max is clinically significant, Temodal should be

administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of

dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H 2 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.

4.6 Pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m 2

TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal hard capsules

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. Women of childbearing potential should be

advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Lactation

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

No studies on the effects on the ability to drive and use machines have been performed. The ability to

drive and use machines may be impaired in patients treated with TMZ due to fatigue and somnolence.

4.8 Undesirable effects

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT

for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or

progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting,

constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-

diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very

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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). Within each frequency grouping,

undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma

multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases

in patients with newly-diagnosed glioblastoma multiforme

System Organ Class

TMZ + concomitant RT

n=288*

TMZ monotherapy

n=224

Infections and infestations

Common:

Infection , Herpes simplex , wound

infection, pharyngitis, candidiasis oral

Infection, candidiasis oral

Uncommon:

Herpes simplex , herpes zoster,

influenza–like symptoms

Blood and lymphatic system disorders

Common:

Neutropenia, thrombocytopenia,

lymphopenia, leukopenia

Febril neutropenia,

thrombocytopenia, anaemia,

leukopenia

Uncommon:

Febrile neutropenia, anaemia

Lymphopenia, petechiae

Endocrine disorders

Uncommon:

Cushingoid

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Hyperglycaemia, weight decreased

Weight decreased

Uncommon:

Hypokalemia, alkaline phosphatase

increased, weight increased

Hyperglycaemia, weight increased

Psychiatric disorders

Common:

Anxiety, emotional lability, insomnia

Anxiety, depression, emotional

lability, insomnia

Uncommon:

Agitation, apathy, behaviour disorder,

depression, hallucination

Hallucination, amnesia

Nervous system disorders

Very common:

Headache

Convulsions, headache

7

Common:

Convulsions, consciousness decreased,

somnolence, aphasia, balance impaired,

dizziness, confusion, memory

impairment, concentration impaired,

neuropathy, paresthesia, speech disorder,

tremor

Hemiparesis, aphasia, balance

impaired, somnolence, confusion,

dizziness, memory impairment,

concentration impaired, dysphasia,

neurological disorder (NOS),

neuropathy, peripheral neuropathy,

paresthesia, speech disorder, tremor

Uncommon:

Status epilepticus, extrapyramidal

disorder, hemiparesis, ataxia, cognition

impaired, dysphasia, gait abnormal,

hyperesthesia, hypoesthesia, neurological

disorder (NOS), peripheral neuropathy

Hemiplegia, ataxia, coordination

abnormal, gait abnormal,

hyperesthesia, sensory disturbance

Eye disorders

Common:

Vision blurred

Visual field defect, vision blurred,

diplopia

Uncommon:

Hemianopia, visual acuity reduced, vision

disorder, visual field defect, eye pain

Visual acuity reduced, eye pain, eyes

dry

Ear and labyrinth disorders

Common:

Hearing impairment

Hearing impairment, tinnitus

Uncommon:

Otitis media, tinnitus, hyperacusis,

earache

Deafness, vertigo, earache

Cardiac disorders

Uncommon:

Palpitation

Vascular disorders

Common:

Haemorrhage, oedema, oedema leg

Haemorrhage, deep venous

thrombosis, oedema leg

Uncommon:

Cerebral haemorrhage, hypertension

Embolism pulmonary, oedema,

oedema peripheral

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, coughing

Uncommon:

Pneumonia, upper respiratory infection,

nasal congestion

Pneumonia, sinusitis, upper

respiratory infection, bronchitis

Gastrointestinal disorders

Very common:

Constipation, nausea, vomiting

Common:

Stomatitis, diarrhoea, abdominal pain,

dyspepsia, dysphagia

Stomatitis, diarrhoea, dyspepsia,

dysphagia, mouth dry

Uncommon:

Abdominal distension, fecal

incontinence, gastrointestinal disorder

(NOS), gastroenteritis, haemorrhoids

Skin and subcutaneous tissue disorders

8

Very common:

Rash, alopecia

Common:

Dermatitis, dry skin, erythema, pruritus

Dry skin, pruritus

Uncommon:

Skin exfoliation, photosensitivity

reaction, pigmentation abnormal

Erythema, pigmentation abnormal,

sweating increased

Musculoskeletal and connective tissue disorders

Common:

Muscle weakness, arthralgia

Muscle weakness, arthralgia,

musculoskeletal pain, myalgia

Uncommon:

Myopathy, back pain, musculoskeletal

pain, myalgia

Myopathy, back pain

Renal and urinary disorders

Common:

Micturition frequency, urinary

incontinence

Urinary incontinence

Uncommon:

Dysuria

Reproductive system and breast disorders

Uncommon:

Impotence

Vaginal haemorrhage, menorrhagia,

amenorrhea, vaginitis, breast pain

General disorders and administration site conditions

Very common:

Fatigue

Common:

Allergic reaction, fever, radiation injury,

face oedema, pain, taste perversion

Allergic reaction, fever, radiation

injury, pain, taste perversion

Uncommon:

Asthenia, flushing, hot flushes, condition

aggravated, rigors, tongue discolouration,

parosmia, thirst

Asthenia, face oedema, pain,

condition aggravated, rigors, tooth

disorder, taste perversion

Investigations

Common:

ALT increased

Uncommon:

Hepatic enzymes increased, Gamma GT

increased, AST increased

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

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most

cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events

were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil

abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3 or Grade 4

thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % of the patients

who received TMZ.

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were

gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually

9

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 Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma

Infections and infestations

Rare:

Opportunistic infections, including PCP

Blood and lymphatic system disorders

Very common:

Neutropenia or lymphopenia (grade 3-4),

thrombocytopenia (grade 3-4)

Uncommon:

Pancytopenia, anaemia (grade 3-4), leukopenia

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Weight decrease

Nervous system disorders

Very common:

Headache

Common:

Somnolence, dizziness, paresthesia

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea

Gastrointestinal disorders

Very common:

Vomiting, nausea, constipation

Common:

Diarrhoea, abdominal pain, dyspepsia

Skin and subcutaneous tissue disorders

Common:

Rash, pruritus, alopecia

Very rare:

Erythema multiforme, erythroderma, urticaria,

exanthema

General disorders and administration site conditions

Very common:

Fatigue

Common:

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

Very rare:

Allergic reactions, including anaphylaxis, angioedema

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients

treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %,

respectively. Myelosuppression was predictable (usually within the first few cycles, with the nadir

between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of

cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of

bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

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 10 9 /l), 12 % vs 5 %, and thrombocytopenia (< 20 x 10 9 /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

10

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.

Post-Marketing Experience

Antineoplastic agents, and notably alkylating agents, have been associated with a potential risk of

myelodysplastic syndrome (MDS) and secondary malignancies, including leukaemia. Very rare cases of

MDS and secondary malignancies, including myeloid leukaemia have been reported in patients treated

with regimens that included TMZ. Prolonged pancytopenia, which may result in aplastic anaemia has

been reported very rarely .

Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely.

Cases of interstitial pneumonitis/pneumonitis have been reported very rarely.

4.9 Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m 2 (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

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 O 6 position of guanine with additional alkylation also occurring at the N 7

position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the

methyl adduct.

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/m 2 ) 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/m 2 ) 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 carinii

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.

11

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).

HR (95% C.I.) = 1.59 (1.33 – 1.91)

log-rank p-value < .0001

26%

RT+TMZ

10%

RT Only

12.1

14.6

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).

12

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 patients

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 O 6 and N 7 positions of guanine. Relative

to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo , the t 1/2

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 14 C-labelled TMZ, mean faecal excretion of 14 C over 7 days post-dose was 0.8 %

indicationg 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 (t 1/2 ) in plasma is approximately 1.8 hours. The major route of 14 C 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

13

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/m 2 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 :

gelatin,

titanium dioxide (E 171),

sodium laurilsulfate,

yellow iron oxide (E 172),

indigo carmine (E 132),

Printing ink:

shellac,

propylene glycol,

purified water,

ammonium hydroxide,

potassium hydroxide,

black iron oxide (E 172).

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 °C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 °C.

6.5 Nature and contents of container

Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 -or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene

terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton.

The carton contains 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 Temodal 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 reach and sight of children, preferably in a locked

cupboard. Accidental ingestion can be lethal for children.

Any unused product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

SP Europe

Rue de Stalle 73

B-1180 Bruxelles

Belgium

15

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/98/096/001

EU/1/98/096/002

EU/1/98/096/024

EU/1/98/096/025

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 January 1999.

Date of last renewal: 26 January 2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA) http://www.emea.europa.eu/

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1.

NAME OF THE MEDICINAL PRODUCT

Temodal 20 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 20 mg temozolomide.

Excipient: Each hard capsule contains 182.2 mg of anhydrous lactose.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule

The hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink.

The cap is imprinted with “Temodal”. The body is imprinted with "20 mg", the Schering-Plough logo

and two stripes.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Temodal hard capsules 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

Temodal hard capsules 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

Temodal hard capsules 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/m 2 daily for 42 days concomitant with focal radiotherapy

(60 Gy administered in 30 fractions). No dose reductionsare 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 10 9 /l

- thrombocyte count ≥ 100 x 10 9 /l

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