Temozolomide Sandoz

1.

NAME OF THE MEDICINAL PRODUCT

Temozolomide Sandoz 5 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 5 mg temozolomide.

Excipients:

Each hard capsule contains 168 mg of anhydrous lactose.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

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

The cap is imprinted with “TMZ”. The body is imprinted with “5”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temozolomide Sandoz 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

Temozolomide Sandoz 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

Temozolomide Sandoz 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 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 10 9 /l

2

thrombocyte count ≥ 100 x 10 9 /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 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.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma

3

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 population

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 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 Sandoz 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.

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.

4

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 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 section 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

5

Interaction studies have only been performed in adults.

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, Temozolomide Sandoz

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 Fertility, 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). Temozolomide Sandoz

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

6

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

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

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

commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT

and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions

were reported commonly or very commonly in both indications (Tables 4 and 5); the frequency of

grade 3-4 laboratory findings is presented after each table.

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); not known (cannot be estimated from the available

data).

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, thrombo-

cytopenia, 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

Common:

Convulsions, consciousness

Hemiparesis, aphasia,

7

decreased, somnolence, aphasia,

balance impaired, dizziness,

confusion, memory impairment,

concentration impaired,

neuropathy, paresthesia, speech

disorder, tremor

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

Constipation, nausea,

vomiting

Common:

Stomatitis, diarrhoea, abdominal

pain, dyspepsia, dysphagia

Stomatitis, diarrhoea,

dyspepsia, dysphagia, mouth

dry

Uncommon:

Abdominal distension, fecal

incontinence, gastrointestinal

disorder (NOS),

gastroenteritis, haemorrhoids

Skin and subcutaneous tissue disorders

Very Common:

Rash, alopecia

Common:

Dermatitis, dry skin, erythema,

pruritus

Dry skin, pruritus

8

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 temozolomide + 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.

9

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 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.

10

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: 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.

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).

11

Figure 1

Kaplan-Meier curves for overall survival ( intent-to-treat populati

on)

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 arm

However, n

o unacceptable risks appear to be present in this patient group.

s.

Recurrent or progressive malignant glioma

T

other was a randomized active-cont

re

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

TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of survi

p

(chi-square p = 0.019).

K

for

ving

atients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44 %)

In patients with prior chemotherapy a benefit was indicated in those with a

PS ≥ 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time

to worsening of performance

m

procarbazine (log rank p = < 0.01 to 0.0

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in

treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The

the

12

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

MZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the

rolled trial of TMZ vs procarbazine in a total of 225 patients (67 %

ceived prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint

status (decrease to a KPS of < 70 or a decrease by at least 30 points). The

edian times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for

3).

median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on

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

the

ITT

opulation was 44 % with a median event-free survival of 4.6 months, which was similar to the results

ession-free survival. For the eligible histology population, the efficacy results were

imilar. Achieving a radiological objective response or maintaining progression-free status was

p

for the progr

s

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

grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance

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

b

cytotoxicity of MTIC is thought t

N

23 %, respectively. In vivo , the t 1/2 of MTIC was similar to that of temozolomide, 1.8 hr.

iosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The

o be primarily due to alkylation of DNA mainly at the O 6 and

positions of guanine. Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly with peak concentrations reached

as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral

administration of 14 C-labelled TM

Z, mean faecal excretion of C over 7 days post-dose was 0.8 %

14

in

dicating complete absorption.

D

istribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact w

highly protein-bound substances.

ith

P

and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on

of TMZ was approximately 30 % of that in plasma, which is consis

ET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly

AUC

tent with animal data.

Elim ation

in

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 t

urine over 24 hours, and the remainder excreted as temozolomide acid,

5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.

he

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution a

half-life are independent of dose.

nd

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 thos

observed in patients with normal hepatic function.

e

13

recurrent high

to

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose

(MTD) was 1,000 mg/m per

2

cycle both in children and in adults.

5.3 Preclinical safety data

S

ra

testes, the gastrointestinal tract and, at higher doses, wh

d

exce t for adverse events

th

has been observed

ingle-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in

ts and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system,

ich were lethal to 60 % to 100 % of rats and

ogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility,

p on the male reproductive system and retinal degeneration. However, because

e doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect

in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genot

dog than to humans, and the clin

Dose-related r

variety of neo

a

evident in dog

occurren

even for an alkylating agen

oxic alkylating agent. TMZ is more toxic to the rat and

ical dose approximates the minimum lethal dose in rats and dogs.

eductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A

plasms, including mammary carcinomas, keratocanthoma of the skin and basal cell

denoma were observed in the 6 cycle rat study while no tumours or pre-neoplastic changes were

studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the

ce of first tumours within three months of initiating dosing. This latency period is very short

t.

Results of the Ames/sal

aberrati

monella and Human Peripheral Blood Lymphocyte (HPBL) chromosome

on tests showed a positive mutagenicity response.

6.

PH

ARMACEUTICAL PARTICULARS

6.1 List of excipien

ts

Capsule contents

Anhydrous lactose

ous silica

odium starch glycolate type A

tearic acid

C

apsule shell

Gelatin

T

Yellow iron oxide (E 172)

Indigo carmine (E132)

W

itanium dioxide (E 171)

ater

P

Shellac

Black iron oxide (E 172)

rinting ink

Potassium hydroxide

6

.2 Incompatibilities

N

ot applicable.

6

.3 Shelf life

2 years.

14

Colloidal anhydr

S

Tartaric acid

S

6.4 Special precautions for storage

Store in the original package.

K

eep the bottles tightly closed in order to protect from moisture.

6

.5 Nature and contents of container

Type III amber glass or HDPE bottle with polypropylene chil

2

The bottles contain a desiccant di

The carton contains

d-resistant closure containing 5 or

0 hard capsules.

one bottle.

sc.

Not all pac

k sizes may be marketed.

6

.6 Special precautions for disposal and other handling

C

s

mu a, it should be washed immediately and thoroughly with soap and water.

apsules should not be opened. If a capsule becomes damaged, contact of the powder contents with

kin or mucous membrane must be avoided. If Temozolomid Sandoz comes into contact with skin or

cos

P

locked cupboard. Accidental ingestion can be leth

atients should be advised to keep capsules out of the reach and sight of children, preferably in a

al for children.

A

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

7

.

MARKETING AUTHORISATION HOLDER

Sandoz Pharmaceuticals GmbH

Raiffeisenstraße 11

83607 Holzkirchen

Germany

8.

MARKETING AUTHORISATION NUMBER(S)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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/

15

1.

NAME OF THE MEDICINAL PRODUCT

Temozolomide Sandoz 20 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 20 mg temozolomide.

Excipients:

Each hard capsule contains 14.6 mg of anhydrous lactose.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

The hard capsules have a white coloured body, a yellow coloured cap, and are imprinted with black

ink. The cap is imprinted with “TMZ”. The body is imprinted with “20”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Temozolomide Sandoz 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

Temozolomide Sandoz 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

Temozolomide Sandoz 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 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 10 9 /l

16