TEMODAL 20mg capsules medication leaflet

Temodal 2.5 mg/ml powder for solution for infusion

Each vial contains 100 mg of temozolomide.

After reconstitution, 1 ml solution for infusion contains 2.5 mg temozolomide.

Each vial contains 55.2 mg sodium.

For the full list of excipients, see section 6.1.

Powder for solution for infusion.

White powder.

Temodal 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, suchas glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression afterstandard therapy.

Temodal should only be prescribed by physicians experienced in the oncological treatment of braintumours.

Anti-emetic therapy may be administered (see section 4.4).

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by upto 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered 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 ordiscontinuation of TMZ administration should be decided weekly according to haematological andnon-haematological toxicity criteria.

TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if allof 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 betemporarily interrupted or permanently discontinued during the concomitant phase according to thehaematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation duringconcomitant radiotherapy and TMZ

Toxicity TMZ interruptiona TMZ discontinuation

Absolute neutrophil count  0.5 and < 1.5 x 109/l < 0.5 x 109/l

Thrombocyte count 9 9 10 and < 100 x 10 /l < 10 x 10 /l

CTC non-haematological toxicity

CTC Grade 2 CTC Grade 3 or 4(except for alopecia, nausea, vomiting)a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophilcount  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 to6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 daysfollowed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 ifthe CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, nausea andvomiting), 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 subsequentcycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequentcycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phaseshould 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 Remarks(mg/m2/day)-1 100 Reduction for prior toxicity0 150 Dose during Cycle 11 200 Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity Reduce TMZ by 1 dose levela Discontinue TMZ

Absolute neutrophil count < 1.0 x 109/l See footnote b

Thrombocyte count < 50 x 109/l See footnote b

CTC non-haematological Toxicity

CTC Grade 3 CTC Grade 4b(except for alopecia, nausea, vomiting)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 isadministered at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatmentinterruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if thereis no haematological toxicity (see section 4.4)

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignantglioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacyof 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 thosewith mild or moderate hepatic impairment. No data are available on the administration of TMZ inpatients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on thepharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients withsevere hepatic impairment or any degree of renal impairment. However, caution should be exercisedwhen TMZ is administered in these patients.

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ isnot affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk ofneutropenia and thrombocytopenia (see section 4.4).

Temodal 2.5 mg/ml powder for solution for infusion must be administered only by intravenousinfusion. It must not be given by other routes of administration, such as the intrathecal, intramuscular,or subcutaneous route. Temodal 2.5 mg/ml powder for solution for infusion may be administered inthe same IV line with 0.9% Sodium Chloride injection. It is incompatible with dextrose solutions.

The appropriate dose of TMZ should be infused intravenously using a pump over a period of90 minutes.

As with other similar chemotherapeutic agents, caution is recommended to avoid extravasation. Localinjection site adverse reactions, which were mostly mild and short-lived were reported in patientsreceiving Temodal 2.5 mg/ml powder for solution for infusion. Preclinical studies did not showpermanent tissue damage (see sections 4.8 and 5.3).

Temodal is also available as a hard capsule formulation (oral use). Temodal 2.5 mg/ml powder forsolution for infusion, given as an intravenous infusion over 90 minutes, is bioequivalent to the hardcapsule formulation (see section 5.2).

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).

Opportunistic infections and reactivation of infections

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

Meningoencephalitis herpetic

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

Pneumocystis jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedulewere 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-dayregimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, theyare 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 observedclosely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure havebeen reported in patients using TMZ, in particular in combination with dexamethasone or othersteroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has beenreported. Experts in liver disease should be consulted before treatment is initiated in patients withpositive hepatitis B serology (including those with active disease). During treatment patients should bemonitored and managed appropriately.

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (seesection 4.8). Baseline liver function tests should be performed prior to treatment initiation. Ifabnormal, physicians should assess the benefit/risk prior to initiating temozolomide including thepotential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests shouldbe repeated midway during this cycle. For all patients, liver function tests should be checked aftereach treatment cycle. For patients with significant liver function abnormalities, physicians shouldassess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more afterthe last treatment with temozolomide.

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, havealso 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 isstrongly 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 mayrequire anti-emetic therapy.

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia,which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In somecases, exposure to concomitant medicinal products associated with aplastic anaemia, includingcarbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior todosing, 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) orwithin 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 shouldbe reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and200 mg/m2. The lowest recommended dose is 100 mg/m2.

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience inolder 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 withyounger patients. Therefore, special care should be taken when TMZ is administered in elderlypatients.

Female patients

Women of childbearing potential have to use effective contraception to avoid pregnancy while theyare receiving TMZ, and for at least 6 months following completion of treatment.

Male patients

Men being treated with TMZ should be advised not to father a child for at least 3 months afterreceiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (seesection 4.6).

This medicinal product contains 55.2 mg sodium per vial, equivalent to 2.8 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult. This should be taken intoconsideration by patients on a controlled sodium diet.

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in theextent of absorption of temozolomide or the exposure to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC).

Based on an analysis of population pharmacokinetics in phase II trials, co-administration ofdexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, orphenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associatedwith 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 ofother medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits lowprotein 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 ofmyelosuppression.

Interaction studies have only been performed in adults.

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).

Temodal 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.

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinuedwhile receiving treatment with TMZ.

Women of childbearing potential have to use effective contraception to avoid pregnancy while theyare receiving TMZ, and for at least 6 months following completion of treatment.

TMZ can have genotoxic effects. Therefore, men being treated with it should use effectivecontraceptive measures and be advised not to father a child for at least 3 months after receiving thelast dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibilityof irreversible infertility due to therapy with TMZ.

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

Clinical trial experience with hard capsules

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

Table 4.

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

Grade 1 or 2 (0 - 5 episodes of vomiting in 24 hours) and were either self-limiting or readilycontrolled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listedin Table 4. These reactions are classified according to System Organ Class and frequency. Frequencygroupings 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 frequencygrouping, undesirable effects are presented in order of decreasing seriousness.

Table 4. Adverse reactions in patients treated with temozolomide

Common: Infections, herpes zoster, pharyngitisa, candidiasis oral

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

Neoplasm benign, malignant, and unspecified

Uncommon: Myelodysplastic syndrome (MDS), secondarymalignancies, including myeloid leukaemia

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

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

Common: Allergic reaction

Uncommon: Anaphylaxis

Common: Cushingoidc

Uncommon: Diabetes insipidus

Very common: Anorexia

Common: Hyperglycaemia

Uncommon: Hypokalaemia, alkaline phosphatase increased

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

Uncommon: Behaviour disorder, emotional lability, hallucination,apathy

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

Table 4. Adverse reactions in patients treated with temozolomide

Common: Ataxia, balance impaired, cognition impaired,concentration impaired, consciousness decreased,dizziness, hypoesthesia, memory impaired, neurologicdisorder, neuropathyd, paraesthesia, somnolence, speechdisorder, taste perversion, tremor

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

Common: Hemianopia, vision blurred, vision disordere, visual fielddefect, diplopia, eye pain

Uncommon: Visual acuity reduced, eyes dry

Ear and labyrinth disorders

Common: Deafnessf, vertigo, tinnitus, earacheg

Uncommon: Hearing impairment, hyperacusis, otitis media

Uncommon: Palpitation

Common: Haemorrhage, embolism pulmonary, deep veinthrombosis, hypertension,

Uncommon: Cerebral haemorrhage, flushing, hot flushes

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

Uncommon: Respiratory failure†, interstitialpneumonitis/pneumonitis, pulmonary fibrosis, nasalcongestion

Very common: Diarrhoea, constipation, nausea, vomiting

Common: Stomatitis, abdominal painh, dyspepsia, dysphagia

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

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

Very Common: Rash, alopecia

Common: Erythema, dry skin, pruritus

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome,angioedema, erythema multiforme, erythroderma, skinexfoliation, photosensitivity reaction, urticaria,exanthema, dermatitis, sweating increased, pigmentationabnormal

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

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

Table 4. Adverse reactions in patients treated with temozolomide

Common: Micturition frequency, urinary incontinence

Uncommon: Dysuria

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

Very common: Fatigue

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

Uncommon: Condition aggravated, rigors, face oedema, tonguediscolouration, thirst, tooth disorder

Common: Liver enzymes elevationj, weight decreased, weightincreased

Uncommon: Gamma-glutamyltransferase increased

Common: Radiation injuryka Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcalb Includes gastroenteritis, gastroenteritis viralc Includes cushingoid, Cushing syndromed Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathye Includes visual impairment, eye disorderf Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateralg Includes earache, ear discomforth Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomforti Includes oedema peripheral, peripheral swellingj Includes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepaticenzymes increasedk Includes radiation injury, radiation skin injury† Including cases with fatal outcome

Newly-diagnosed glioblastoma multiforme

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity formost cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverseevents were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4neutrophil abnormalities including neutropenic events were observed in 8 % of the patients. Grade 3or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14 % ofthe patients who received TMZ.

Recurrent or progressive malignant glioma

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patientstreated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with thenadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence ofcumulative myelosuppression was observed. The presence of thrombocytopenia may increase the riskof bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 malesubjects for whom nadir platelet counts were available. There were higher rates of Grade 4neutropenia (ANC < 0.5 x 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/l), 9 % vs 3 %, inwomen vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4neutropenia 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 malesubjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle oftherapy.

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma orrecurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Althoughthe data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ inchildren under the age of 3 years has not been established.

Clinical trial experience with IV

Temodal 2.5 mg/ml powder for solution for infusion delivers equivalent TMZ dose and exposure toboth TMZ and its active metabolite MTIC as the corresponding Temodal hard capsules (seesection 5.2). Adverse reactions reported during the two studies with the intravenous formulation(n=35) but not in studies using hard capsules, were infusion site reactions: pain, irritation, pruritus,warmth, swelling, and erythema, as well as haematoma.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluatedclinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but isexpected 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 formore than 5 days of treatment (up to 64 days) with adverse events reported including bone marrowsuppression, with or without infection, in some cases severe and prolonged and resulting in death. Inthe event of an overdose, haematological evaluation is needed. Supportive measures should beprovided as necessary.

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to theactive monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought tobe due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring atthe N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair ofthe 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/m2) once daily, starting the first dayof RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed bymonotherapy TMZ (150 - 200 mg/m2) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jiroveciipneumonia (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 %) inthe 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-rankp < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 % vs10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZmonotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrateda 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 < .000126%

RT+TMZ10%

RT Only12.1 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 performancestatus (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 theother 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 endpointwas progression-free survival (PFS) defined by MRI scans or neurological worsening. In thenon-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was2.1 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 thanfor procarbazine (21 % vs 8 %, respectively - chi-square p = 0.008) with median PFS of 2.89 and1.88 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 survivingpatients 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 timeto worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). Themedian times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than forprocarbazine (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 thetreatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. Themedian PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on thecentral 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 ITTpopulation was 44 % with a median event-free survival of 4.6 months, which was similar to the resultsfor the progression-free survival. For the eligible histology population, the efficacy results weresimilar. Achieving a radiological objective response or maintaining progression-free status wasstrongly associated with maintained or improved quality of life.

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma orrecurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Toleranceto TMZ is similar to adults.

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 to5amino-imidazole4carboxamide (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 ofguanine. 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.

In an open-label, two-way crossover bioequivalence study of the pharmacokinetics of oral andintravenous TMZ in patients with primary CNS malignancies, Temodal 2.5 mg/ml powder for solutionfor infusion administered over 90 minutes was found to be bioequivalent for Cmax and AUC of TMZand MTIC as compared to Temodal hard capsules, following administration of 150 mg/m2 dose. Mean

Cmax values for TMZ and MTIC were 7.4 µg/ml and 320 ng/ml, respectively, following 90 minuteintravenous infusion. Mean AUC (0 → ) values for TMZ and MTIC were 25 µg*h/ml and1,004 ng*h/ml, respectively.

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reachedas early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oraladministration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 %indicating complete absorption.

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact withhighly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidlyand 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.

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 theurine 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 andhalf-life are independent of dose.

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance wasindependent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasmapharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to thoseobserved 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.

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted inrats 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 anddogs 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, becausethe doses implicated in retinal degeneration were in the lethal dose range, and no comparable effecthas 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 anddog 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. Avariety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal celladenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes wereevident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with theoccurrence of first tumours within 3 months of initiating dosing. This latency period is very short evenfor an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosomeaberration tests showed a positive mutagenicity response.

The intravenous formulation produced local irritation at the site of injection in both rabbits and rats.

The irritation was transient and not associated with lasting tissue damage.

Mannitol (E421)

Threonine

Polysorbate 80

Sodium citrate (for pH adjustment)

Hydrochloric acid concentrated (for pH adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial: 4 years

Reconstituted solution: after reconstitution the chemical and physical in-use stability has beendemonstrated for 14 hours at 25°C, including infusion time.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place incontrolled and validated aseptic conditions.

Store in a refrigerator (2 °C - 8 °C).

For storage conditions of the reconstituted medicinal product, see section 6.3.

Clear type I glass vial sealed with bromobutyl rubber stopper and aluminium overseal withpeach-coloured flip-off bonnet. Each vial contains 100 mg TMZ.

Temodal 2.5 mg/ml is supplied as a pack of 1 vial.

Caution must be exercised in handling Temodal 2.5 mg/ml powder for solution for infusion. The useof gloves and aseptic technique is required. If Temodal 2.5 mg/ml comes into contact with skin ormucosa, it should be washed immediately and thoroughly with soap and water.

Each vial must be reconstituted with 41 ml sterilised water for injections. The resulting solutioncontains 2.5 mg/ml TMZ. The vials should be gently swirled and not shaken. The solution should beinspected and any vial containing visible particulate matter should not be used. A volume up to 40 mlreconstituted solution should be withdrawn, according to the total prescribed dose and transferred intoan empty 250 ml infusion bag (PVC or polyolefin). The pump tubing should be attached to the bag,the tubing purged and then capped. Temodal 2.5 mg/ml must be administered by intravenous infusiononly over a period of 90 minutes.

Temodal 2.5 mg/ml powder for solution for infusion may be administered in the same IV line with0.9% Sodium Chloride injection. It is incompatible with dextrose solutions.

In the absence of additional data, this medicinal product must not be mixed with other medicinalproducts or infused simultaneously through the same intravenous line.

This medicinal product is for single use only. Any unused medicinal product or waste material shouldbe disposed of in accordance with local requirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/98/096/023

Date of first authorisation: 26 January 1999

Date of latest renewal: 17 December 2008

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

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