Temozolomide Teva - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Temozolomide Teva 5 mg hard capsules

Temozolomide Teva 20 mg hard capsules

Temozolomide Teva 100 mg hard capsules

Temozolomide Teva 140 mg hard capsules

Temozolomide Teva 180 mg hard capsules

Temozolomide Teva 250 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Temozolomide Teva 5 mg hard capsules

Each hard capsule contains 5 mg temozolomide.

Excipient with known e ffect

Each hard capsule contains 87 mg of lactose.

Temozolomide Teva 20 mg hard capsules

Each hard capsule contains 20 mg temozolomide.

Excipients with known e ffect

Each hard capsule contains 72 mg of lactose and sunset yellow FCF (E110).

Temozolomide Teva 100 mg hard capsules

Each hard capsule contains 100 mg temozolomide.

Excipient with known effect

Each hard capsule contains 84 mg of lactose.

Temozolomide Teva 140 mg hard capsules

Each hard capsule contains 140 mg temozolomide.

Excipient with known effect

Each hard capsule contains 117 mg of lactose.

Temozolomide Teva 180 mg hard capsules

Each hard capsule contains 180 mg temozolomide.

Excipient with known effect

Each hard capsule contains 150 mg of lactose.

Temozolomide Teva 250 mg hard capsules

Each hard capsule contains 250 mg temozolomide.

Excipient with known effect

Each hard capsule contains 209 mg of lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Temozolomide Teva 5 mg hard capsules

The hard capsules have a white opaque body and cap with two stripes in green ink on the cap and with “T 5 mg” in green ink on the body. Each capsule is approximately 16 mm in length.

Temozolomide Teva 20 mg hard capsules

The hard capsules have a white opaque body and cap with two stripes in orange ink on the cap and with “T 20 mg” in orange ink on the body. Each capsule is approximately 18 mm in length.

Temozolomide Teva 100 mg hard capsules

The hard capsules have a white opaque body and cap with two stripes in pink ink on the cap and with “T 100 mg” in pink ink on the body. Each capsule is approximately 19.5 mm in length.

Temozolomide Teva 140 mg hard capsules

The hard capsules have a white body and cap with two stripes in blue ink on the cap and with “T 140 mg” in blue ink on the body. Each capsule is approximately 22 mm in length.

Temozolomide Teva 180 mg hard capsules

The hard capsules have a white opaque body and cap with two stripes in red ink on the cap and with “T 180 mg” in red ink on the body. Each capsule is approximately 22 mm in length.

Temozolomide Teva 250 mg hard capsules

The hard capsules have a white opaque body and cap with two stripes in black ink on the cap and with “T 250 mg” in black ink on the body. Each capsule is approximately 22 mm in length.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Temozolomide Teva 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 Teva 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 Teva is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:

• – absolute neutrophil count (ANC) > 1.5 × 109/1

• – thrombocyte count > 100 × 109/1

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

4.4 Special warnings and precautions for use

Opportunistic infections and reactivation of infections

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

Meningoencepha­litis herpetic

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

Pneumocystis , jirovecii pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade < 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using TMZ, in particular in combination with dexamethasone or other steroids.

HBV

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

Hepatotoxicity

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

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, phenytoin, and sulfamethoxazo­le/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC > 1.5 × 109/1 and platelet count > 100 × 109/l. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 × 109/l and platelet count > 100 × 109/l. If ANC falls to < 1.0 × 109/l or the platelet count is < 50 × 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose is 100 mg/m2.

Paediatric population

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.

Female patients

Women of childbearing potential have to use effective contraception to avoid pregnancy while they are 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 after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Excipient(s)

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicine.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Temozolomide Teva 20 mg hard capsules

Sunset yellow FCF (E110)

The excipient sunset yellow FCF (E110) included in the capsules shell may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

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

Administration of TMZ with food resulted in a 33% decrease in Cmax and a 9% decrease in area under the curve (AUC).

As it cannot be excluded that the change in Cmax is clinically significant, Temozolomide Teva should be administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m2 TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temozolomide Teva should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

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

Women of childbearing potential

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

Male fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Clinical trial experience

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

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4. Adverse reactions in patients treated with temozolomide
Infections and infestations
Common:	Infections, herpes zoster, pharyngitis3, candidiasis oral
Uncommon:	Opportunistic infection (including PCP), sepsis1', meningoencephalitis herpetic1, CMV infection, CMV reactivation, hepatitis B virus1, herpes simplex, infection reactivation, wound infection, gastroenteritisb
Neoplasm benign, malignant, and unspecified
Uncommon:	Myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia
Blood and lymphatic system disorders
Common:	Febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia
Uncommon:	Prolonged pancytopenia, aplastic anaemia1, pancytopenia, petechiae
Immune system disorders
Common:	Allergic reaction
Uncommon:	Anaphylaxis
Endocrine disorders
Common:	Cushingoidc
Uncommon:	Diabetes insipidus
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Hyperglycaemia
Uncommon:	Hypokalaemia, alkaline phosphatase increased

Table 4. Adverse reactions in patients treated with temozolomide
Psychiatric disorders
Common:	Agitation, amnesia, depression, anxiety, confusion, insomnia
Uncommon:	Behaviour disorder, emotional lability, hallucination, a­pathy
Nervous system disorders
Very common:	Convulsions, hemiparesis, aphasia/dysphasia, headache
Common:	Ataxia, balance impaired, cognition impaired, concentration impaired, consciousness decreased, dizziness, hypoesthesia, memory impaired, neurologic disorder, neuropathyd, paraesthesia, somnolence, speech disorder, taste perversion, tremor
Uncommon:	Status epilepticus, hemiplegia, extrapyramidal disorder, parosmia, gait abnormality, hyperaesthesia, sensory disturbance, coordination abnormal
Eye disorders
Common:	Hemianopia, vision blurred, vision disorder6, visual field defect, diplopia, eye pain
Uncommon:	Visual acuity reduced, eyes dry
Ear and labyrinth disorders
Common:	Deafnessf, vertigo, tinnitus, earache8
Uncommon:	Hearing impairment, hyperacusis, otitis media
Cardiac disorders
Uncommon:	Palpitation
Vascular disorders
Common:	Haemorrhage, embolism pulmonary, deep vein thrombosis, hypertension
Uncommon:	Cerebral haemorrhage, flushing, hot flushes
Respiratory, thoracic and mediastinal disorders
Common:	Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, upper respiratory infection
Uncommon:	Respiratory failure1', interstitial pneumonitis/pne­umonitis, pulmonary fibrosis, nasal congestion
Gastrointestinal disorders
Very common:	Diarrhoea, constipation, nausea, vomiting
Common:	Stomatitis, abdominal painh, dyspepsia, dysphagia
Uncommon:	Abdominal distension, faecal incontinence, gastrointestinal disorder, haemorrhoids, mouth dry
Hepatobiliary disorders
Uncommon:	Hepatic failure1, hepatic injury, hepatitis, cholestasis, hyperbilirubinemia
Skin and subcutaneous tissue disorders
Very Common:	Rash, alopecia
Common:	Erythema, dry skin, pruritus

Table 4. Adverse reactions in patients treated with temozolomide
Uncommon:	Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reaction, urticaria, exanthema, dermatitis, sweating increased, pigmentation abnormal
Not known:	Drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Common:	Myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia
Renal and urinary disorders
Common:	Micturition frequency, urinary incontinence
Uncommon:	Dysuria
Reproductive system and breast disorders
Uncommon:	Vaginal haemorrhage, menorrhagia, amenorrhoea, vaginitis, breast pain, impotence
General disorders and administration site conditions
Very common:	Fatigue
Common:	Fever, influenza-like symptoms, asthenia, malaise, pain, oedema, oedema peripherali
Uncommon:	Condition aggravated, rigors, face oedema, tongue discolouration, thirst, tooth disorder
Investigations
Common:	Liver enzymes elevationj, weight decreased, weight increased
Uncommon:	Gamma-glutamyltransferase increased
Injury, poisoning and procedural complications
Common:	Radiation injuryk

a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal

b Includes gastroenteritis, gastroenteritis viral

c Includes cushingoid, Cushing syndrome

d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathy

e Includes visual impairment, eye disorder

f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral

g Includes earache, ear discomfort

h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort

i Includes oedema peripheral, peripheral swelling

j Includes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased k Includes radiation injury, radiation skin injury

^ Including cases with fatal outcome

Newly-diagnosed glioblastoma multiforme

Laboratory results

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

Recurrent or progressive malignant glioma

Laboratory results

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

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 × 109/l), 12% vs 5%, and thrombocytopenia (< 20 × 109/l), 9% vs 3%, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 neutropenia occurred in 8% of female vs 4% of male subjects and Grade 4 thrombocytopenia in 8% of female vs 3% of male subjects in the first cycle of therapy. In a study of 288 subjects with newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3% of female vs 0% of male subjects and Grade 4 thrombocytopenia in 1% of female vs 0% of male subjects in the first cycle of therapy.

Paediatric population

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

Reporting of suspected adverse reactions

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

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents – other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286). Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 – 200 mg/m2) on Days 1 – 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jirovecii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.

TMZ was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the TMZ + RT arm.

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

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

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] >  70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral TMZ. One was a non-comparative trial in 138 patients (29% received prior chemotherapy), and the other was a randomised active-controlled trial of TMZ vs procarbazine in a total of 225 patients (67% received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the noncomparative trial, the PFS at 6 months was 19%, the median progression-free survival was 2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8%.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for TMZ than for procarbazine (21% vs 8%, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the TMZ arm (60 %) compared with the procarbazine arm (44%) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS > 80.

Data on time to worsening of neurological status favoured TMZ over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for TMZ than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46%. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35% (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44% with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

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

5.2 Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O6 and N7 positions of guanine.

Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo , the t1/2 of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

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

Distribution

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

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30% of that in plasma, which is consistent with animal data.

Elimination

The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5% to 10% of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

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

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3– and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60% to 100% of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule contents

Lactose

Sodium starch glycolate Type A

Colloidal anhydrous silica

Tartaric acid

Stearic acid

Capsule shell

Gelatin

Titanium dioxide (E171)

Temozolomide Teva 5 mg hard capsules

Printing ink

Shellac

Propylene Glycol

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigo carmine (E132) aluminium lake

Temozolomide Teva 20 mg hard capsules

Printing ink

Shellac

Propylene glycol

Titanium dioxide (E171)

Sunset yellow FCF Aluminium Lake (E110)

Temozolomide Teva 100 mg hard capsules

Printing ink

Shellac

Propylene Glycol

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Temozolomide Teva 140 mg hard capsules

Printing ink

Shellac

Propylene Glycol

Indigo carmine (E132) aluminium lake

Temozolomide Teva 180 mg hard capsules

Printing ink

Shellac

Propylene Glycol

Red iron oxide (E172)

Temozolomide Teva 250 mg hard capsules

Printing ink

Shellac

Black iron oxide (E172)

Propylene Glycol

Ammonium hydroxide (E527)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package.

Do not store above 30 °C.

Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature and contents of container

Amber glass bottle with white polypropylene child-resistant screw cap equipped with an induction seal of polyethylene containing 5 or 20 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temozolomide Teva comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

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

7. MARKETING AUTHORISATION HOLDER

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/606/001–012

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

Date of latest renewal: