Temintas 5 mg/20 mg/100 mg/ 250mg Hard gelatin capsules

TEMINTAS is indicated for the following:

• adult patients with newly diagnosed glioblastoma multiforme after debulking surgery concomitantly with radiotherapy and then as adjuvant treatment.
• recurrent malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma after debulking surgery.
• advanced metastatic malignant melanoma.

Adult patients with newly diagnosed glioblastoma multiforme: TEMINTAS is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide monotherapy (adjuvant phase).

Concomitant phase

TEMINTAS 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 will be made, but delay or discontinuation of TEMINTAS administration will be decided weekly according to haematological and non-haematological toxicity criteria. The TEMINTAS dose can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met: absolute neutrophil count u2265 1,5 x 109 / litre, thrombocyte count u2265 100 x 109/litre, Common Toxicity Criteria (CTC) non-haematological toxicity u2264 Grade 1 (except for alopecia, nausea and vomiting). During treatment a complete blood count should be obtained weekly.

TEMINTAS administration should be interrupted or discontinued during concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1 TEMINTAS Dosing Interruption or Discontinuation during Concomitant Radiotherapy and TEMINTAS Adjuvant (Monotherapy) Phase

Four weeks after completing the TEMINTAS + Radiotherapy phase, TEMINTAS is administered for up to 6 cycles of monotherapy treatment. Dosage in Cycle 1 (adjuvant/monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC non-haematological toxicity for Cycle I is Grade u2264 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is u2265 1,5 x 109/litre, and the thrombocyte count is u2265 100 x 109/litre. 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 adjuvant/monotherapy phase should be applied according to Tables 2 and 3.

Toxicity

TEMINTAS Interruption a

TEMINTAS Discontinuation

Absolute Neutrophil Count

u2265 0,5 and < 1,5 x 109/litre

< 0,5 x 109/litre

Thrombocyte Count

u2265 10 and < 100 x 109/litre

< 10 x 109/litre

CTC Non-hematological Toxicity (except for alopecia, nausea, vomiting)

CTC Grade 2

CTC Grade 3 or 4

a: Treatment with concomitant TEMINTAS could be continued when all of the following conditions are met: absolute neutrophil count u2265 1,5 x 109/litre; thrombocyte count u2265 100 x 109/litre; CTC non-haematological toxicity u2264 Grade 1 (except for alopecia, nausea, vomiting) CTC = Common Toxicity Criteria

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TEMINTAS). The TEMINTAS dose should be reduced or discontinued according to Table 3.

Table 2 TEMINTAS Dose Levels for Adjuvant Treatment

Dose Level Dose (mg/m2/day) Remarks

-1 100 Reduction for prior toxicity

0 150 Dose during Cycle 1

1 200 Dose during Cycles 2 to 6 in absence of toxicity

Table 3 TEMINTAS Dose Reduction or Discontinuation during Adjuvant treatment

Toxicity Reduce TEMINTAS by 1 Dose Level a Discontinue TEMINTAS

Absolute Neutrophil Count < 1,0 x 109/litre

See footnote b

Thrombocyte Count < 50 x 109/litre

See footnote b

CTC Non-haematological Toxicity (except for alopecia, nausea, vomiting)

CTC Grade 3

CTC Grade 4

b: TEMINTAS 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

CTC = Common Toxicity Criteria

Adult patients: In patients previously untreated with chemotherapy, TEMINTAS is administered orally at a dose of 200 mg/m2 once daily for 5 days per 28-day cycle. In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 daily, provided that the absolute neutrophil count (ANC) is u2265 1,5 x 109/u2113 and the thrombocyte count is u2265 100 x 109/u2113 on day 1 of the next cycle.

Paediatric patients: In patients 3 years of age and older, previously untreated with chemotherapy, TEMINTAS is administered orally at a dose of 200 mg/m2, once daily for the first 5 days per 28-day cycle. Paediatric patients previously treated with chemotherapy should receive an initial dose of 150 mg/m2 once daily for 5 days, increased to 200 mg/m2 once daily at the next cycle; provided there is no haematological toxicity. Children under 3 years (see section 4.4):

• For Glioblastoma multiforme: TEMINTAS should not be used in children under the age of 3 years.
• For Melanoma: TEMINTAS should not be used in children under the age of 18 years.

TEMINTAS should be administered in the fasting state, at least one hour before a meal. Anti-emetic therapy may be administered prior to or following administration.

If vomiting occurs after the dose is administered, a second dose should not be administered that day. TEMINTAS capsules must not be opened or chewed, but are to be swallowed whole with a glass of water. If a capsule becomes damaged, contact of the powder contents with skin or mucous membranes should be avoided. Therapy with TEMINTAS can be continued until disease progression for a maximum of two years.

TEMINTAS is contra-indicated:

• in patients who have a history of hypersensitivity reaction to its components or to dacarbazine (DTIC)
• in patients with severe myelosuppression
• in patients who are pregnant or lactating (see section 4.6).

It has been reported that patients who received concomitant TEMINTAS and radiotherapy for the prolonged 42 day schedule were shown to be at particular risk for developing Pneumocystis carinii pneumonia (PCP). Thus, prophylaxis against Pneumocystis carinii pneumonia is required for all patients receiving concomitant TEMINTAS and radiotherapy 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 u2264 1.

u2022 Paediatric use (see section 4.2): For Glioblastoma multiforme: Should not be used in children under the age of 3 years. There is limited experience in children over the age of 3 years with glioma. For Melanoma: Should not be used in children under the age of 18 years.

u2022 Elderly patients: Older patients (> 70 years of age) may be at an increased risk of developing neutropenia and thrombocytopenia.

u2022 Gastro-intestinal disturbances: Nausea and vomiting may occur frequently, may be mild to moderate in severity.

u2022 Myelosuppression: Grade 3 or Grade 4 thrombocytopenia and neutropenia may occur. This may lead to hospitalisation or discontinuation of therapy. Myelosuppression usually occurs within the first few cycles, with the nadir between day 21 and 28, and recovery usually within 1 to 2 weeks. Cumulative myelosuppression does not occur.

u2022 Vomiting: Nausea and vomiting are very commonly associated with TEMINTAS and guidelines are provided: Patients with newly diagnosed glioblastoma multiforme:

• anti-emetic prophylaxis is recommended prior to the initial dose of concomitant TEMINTAS.
• anti-emetic prophylaxis is strongly recommended during the adjuvant phase.

Patients with recurrent or progressive glioma: Patients who have severe vomiting (Grade 3 or 4) may require anti-emetic therapy before initiating TEMINTAS treatment.

u2022 Laboratory parameters: Prior to dosing, the following laboratory parameters must be met:

• ANC u2265 1,5 x 109/ u2113 and platelet count u2265 100 x 109/ u2113.
• 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 is above 1,5 x 109/ u2113 and the platelet count exceeds 100 x 109/ u2113.
• If the ANC falls to < 1,0 x 109/ u2113 or the platelet count is < 50 x 109/ u2113 during any cycle, the next cycle should be reduced one dose level.
• Dose levels include 100 mg/m2, 150 mg/m2 and 200 mg/m2.
• The lowest recommended dose is 100 mg/m2.

u2022 Hepatic or renal dysfunction: The pharmacokinetics of temozolomide are comparable in patients with normal hepatic function and in those with mild or moderate hepatic dysfunction. No data is available on the administration of TEMINTAS in patients with severe hepatic dysfunction (Childu2019s Class III) or with renal dysfunction. Based on the pharmacokinetic properties of TEMINTAS, dose reductions are not generally necessary in patients with severe hepatic dysfunction or renal dysfunction. However, caution should be exercised when administering TEMINTAS to these patients.

u2022 Lactose intolerance TEMINTAS contains lactose. Patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not take TEMINTAS.

The use of TEMINTAS in combination with other myelosuppressive agents may increase the likelihood of myelosuppression. Administration with ranitidine or with food does not cause a clinically significant alteration in the extent of absorption of TEMINTAS. Co-administration with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists or phenobarbital does not alter the clearance of TEMINTAS. Co-administration with valproic acid is associated with decrease in the clearance of TEMINTAS.

Safety of TEMINTAS during pregnancy and lactation has not been established. TEMINTAS is contra-indicated for use during pregnancy and lactation (see section 4.3). TEMINTAS is teratogenic or may cause foetal toxicity.

Women of childbearing potential should be advised not to fall pregnant while they are receiving TEMINTAS, or in the six months after discontinuation of TEMINTAS. It is not known whether TEMINTAS is excreted in breast milk; therefore, it should not be used by women who are lactating. Use of TEMINTAS in male patients: Effective contraception should also be used by male patients who are on therapy with TEMINTAS. TEMINTAS can have genotoxic effects. Men being treated with TEMINTAS should be advised not to father a child during therapy, or for up to 6 months after discontinuation of TEMINTAS, because of the possibility of irreversible infertility due to therapy with TEMINTAS, men should be counselled to seek medical advice on cryoconservation.

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 TEMINTAS due to fatigue and somnolence.

The following side-effects may occur with the use of TEMINTAS:

Table 4: Treatment emergent adverse events in patients with newly diagnosed glioblastoma multiforme during the concomitant and adjuvant phases of treatment.

System Organ TEMINTAS + Concomitant TEMINTAS Adjuvant Therapy Class Radiotherapy

Infections and Infestations

Frequent: Oral candidiasis, Herpes simplex, infection, pharyngitis, wound infection

Oral candidiasis, infection

Less frequent: Herpes simplex, Herpes zoster, influenza-like symptoms

Blood and the lymphatic system disorders

Frequent: Leukopenia, lymphopenia, neutropenia, thrombocytopenia

Anaemia, febrile neutropenia, leukopenia, thrombocytopenia

Less frequent: Anaemia, febrile neutropenia

Lymphopenia, petechiae

Endocrine disorders

Less frequent: Cushingoid

Cushingoid

Metabolism and nutrition disorders

Frequent: Anorexia, hyperglycaemia, weight decreased

Anorexia, weight decreased

Less frequent: Hypokalaemia, alkaline phosphatase increased, weight increased

Hyperglycaemia, weight increased

Psychiatric disorders

Frequent: Anxiety, emotional lability, insomnia

Anxiety, depression, emotional lability, insomnia

Less frequent: Agitation, apathy, behaviour disorder, depression, hallucination

Hallucination, amnesia

Nervous system disorders

Frequent: Headache, dizziness, aphasia, impaired balance, impaired

Headache, convulsions, dizziness, aphasia, impaired balance, impaired

concentration, confusion, decreased consciousness, convulsions, memory impairment, neuropathy, paraesthesia, somnolence, speech disorder, tremor

concentration, confusion, dysphasia, hemiparesis, memory impairment, neurological disorder (NOS), neuropathy, peripheral neuropathy, paraesthesia, somnolence, speech disorder, tremor

Less frequent: Ataxia, impaired cognition, dysphasia, extrapyramidal disorder, abnormal gait, hemiparesis, hyperesthesia, hypoaesthesia, neurological disorder (NOS), peripheral neuropathy, status epilepticus

Ataxia, abnormal coordination, abnormal gait, hemiplegia, hyperaesthesia, sensory disturbance

Eye disorders

Frequent: Vision blurred

Vision blurred, diplopia, visual field defect

Less frequent: Eye pain, hemianopia, vision disorder, reduced visual acuity, visual field defect

Eye pain, eyes dry, reduced visual acuity

Ear and labyrinth disorders

Frequent: Hearing impairment

Hearing impairment, tinnitus

Less frequent: Earache, hyperacusis, tinnitus, otitis media

Deafness, earache, vertigo

Cardiac disorders

Less frequent: Palpitation

Vascular disorders

Frequent: Oedema, leg oedema, Leg oedema, haemorrhage, deep

haemorrhage

Less frequent: Hypertension, cerebral haemorrhage

Oedema, peripheral oedema, pulmonary embolism

Respiratory, thoracic and mediastinal disorders

Frequent: Coughing, dyspnoea

Coughing, dyspnoea

Less frequent: Pneumonia, upper respiratory infection, nasal congestion

Pneumonia, sinusitis, upper respiratory infection, bronchitis

Gastrointestinal disorders

Frequent: Constipation, nausea, vomiting, abdominal pain, diarrhoea, dyspepsia, dysphagia, stomatitis

Constipation, nausea, vomiting, diarrhoea, dyspepsia, dysphagia, dry mouth, stomatitis

Less frequent: Abdominal distension, faecal incontinence, gastrointestinal disorder (NOS), gastroenteritis, haemorrhoids

Skin and subcutaneous tissue disorders

Frequent: Alopecia, rash, Dermatitis, dry skin, erythema, pruritus

Alopecia, rash, dry skin, pruritus

Less frequent: Photosensitivity reaction, abnormal pigmentation, skin exfoliation

Erythema, abnormal pigmentation, increased sweating

Musculoskeletal and connective tissue disorders

Frequent: Arthralgia, muscle weakness

Arthralgia, musculoskeletal pain, myalgia, muscle weakness

Less frequent: Back pain, musculoskeletal pain, myalgia, myopathy

Back pain, myopathy

Renal and urinary disorders

Frequent: Frequent micturition, urinary incontinence

Urinary incontinence

Less frequent: Dysuria

Reproductive system and breast disorders

Less frequent: Impotence

Amenorrhoea, breast pain, menorrhagia, vaginal haemorrhage, vaginitis

General disorders and administration site conditions

Frequent: Fatigue, fever, pain, allergic reaction, radiation injury, facial oedema, taste perversion

Fatigue, Fever, pain, allergic reaction, radiation injury, taste perversion

Less frequent: Flushing, hot flushes, asthenia, condition aggravated, rigors, tongue discoloration, parosmia, thirst

Asthenia, condition aggravated, pain, rigors, tooth disorder, face oedema, taste perversion

Investigation

Frequent: ALT increased

ALT increased

Less frequent: Gamma GT increased, hepatic enzymes increased, AST increased

Laboratory results: Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic medicines, including TEMINTAS, has been observed. It has been reported that 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 TEMINTAS.

Table 5: Adverse reactions in patients with recurrent anaplastic astrocytoma, glioblastoma multiforme or malignant melanoma:

Nervous system disorders

Frequent: Fatigue, headache, somnolence, asthenia, dizziness and paraesthesia

Gastro-intestinal disorders: Frequent: Nausea, vomiting, constipation, anorexia, diarrhoea, abdominal pain, dyspepsia

Blood and lymphatic system disorders

Frequent: Thrombocytopenia, neutropenia, anaemia, leucopenia and lymphopenia

Frequency unknown: Pancytopenia, secondary malignancies including myeloid leukaemia

Skin and subcutaneous tissue disorders

Frequent: Rash, alopecia, pruritus, petechiae

Less frequent: Erythema multiforme

Respiratory, thoracic and mediastinal disorders

Frequent: Dyspnoea

Infections and infestations

Less frequent: Opportunistic infections including Pneumocystis jiroveci pneumonia (PCP)

Immune system disorders

Less frequent: Anaphylaxis

Frequency unknown: Allergic reactions

General

Frequent: Fever, pain, malaise, weight decrease, rigors

Less frequent: Myelodysplastic syndrome (MDS)

Laboratory results It has been reported that Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for glioma and 20 % and 22 %, respectively of patients with metastatic melanoma. This led to hospitalisation and/or discontinuation of Temozolomide in 8 % and 4 %, respectively, of patients with glioma and 3 % and 1,3 %, respectively, of those with melanoma. Myelosuppression was predictable (usually within the first few cycles, with the nadir between Day 21 and 28), and recovery was usually within 1 to 2 weeks. No evidence of cumulative myelosuppression was observed.

Post-Marketing Experience Allergic reactions including anaphylaxis have been reported Cases of erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome have also been observed. There have been reported cases of hepatotoxicity including elevations of liver enzymes, hyperbilirubinaemia, cholestasis and hepatitis. Cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP) have been reported. Cases of herpes simplex encephalitis, including cases of fatal outcomes, have also been reported. Cases of interstitial pneumonitis/pneumonitis and pulmonary fibrosis have been reported.

Dose-limiting toxicity is haematological, which is more severe at higher doses. Overdose may cause pancytopenia, pyrexia, multi-organ failure, bone marrow suppression, with or without infection which can become severe and prolonged and resulting in death. In the event of an overdose, a haematological evaluation is needed. Supportive measures should be provided as necessary.