TEMOZOLOMIDE ACCORD

Temozolomide Accord should only be prescribed by physicians experienced in the oncological treatment of brain tumours. 4). Posology Adult patients with newly-diagnosed glioblastoma multiforme Temozolomide Accord 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 temozolomide administration should be decided weekly according to haematological and non- haematological toxicity criteria.

5 x 109/l - thrombocyte count ≥ 100 x 109/l - common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting). During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. 5 x 109/l; thrombocyte count ≥ 100 x 109/l; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting). Monotherapy phase Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment.

Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. 5 x 109/l, and the thrombocyte count is ≥ 100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.

Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3. Table 2. TMZ dose levels for monotherapy treatment Dose level TMZ dose (mg/m2 /day) Remarks –1 100 Reduction for prior toxicity 0 150 Dose during Cycle 1 1 200 Dose during Cycles 2-6 in absence of toxicity Table 3.

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, pharyngitisa, candidiasis oral Uncommon: Opportunistic infection (including PCP), sepsis†, meningoencephalitis herpetic†, CMV infection, CMV reactivation, hepatitis B virus†, 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 anaemia†, 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 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 disordere, visual field defect, diplopia, eye pain Uncommon: Visual acuity reduced, eyes dry Ear and labyrinth disorders Common: Deafnessf, vertigo, tinnitus, earacheg 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 failure†, 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 failure†, hepatic injury, hepatitis, cholestasis, hyperbilirubinemia Skin and subcutaneous tissue disorders Very Common: Rash, alopecia Common: Erythema, dry skin, pruritus 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 Table 4.

8). Pneumocystis jirovecci 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.

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.

1. Hypersensitivity to dacarbazine (DTIC). 4).