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Drug Details

TEMODAL

Drug Class Description
Alkylating cytotoxics.
Generic Name
Temozolomide
Presentation
Hard capsule. The 5 mg hard capsules have an opaque white body, an opaque green cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “5 mg”, the Schering-Plough logo and two stripes. The 20 mg hard capsules have an opaque white body, an opaque yellow cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “20 mg”, the Schering-Plough logo and two stripes. The 100 mg hard capsules have an opaque white body, an opaque pink cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “100 mg”, the Schering-Plough logo and two stripes. The 140 mg hard capsules have an opaque white body, a blue cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “140 mg”, the Schering-Plough logo and two stripes. The 180 mg hard capsules have an opaque white body, an opaque orange cap, and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “180 mg”, the Schering-Plough logo and two stripes. The 250 mg hard capsules have an opaque white body and cap and are imprinted with black ink. The cap is imprinted with “Temodal”. The body is imprinted with “250 mg”, the Schering-Plough logo and two stripes.
Description
Each hard capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg temozolomide. Excipient: 5 mg contains 132.8 mg of anhydrous lactose. 20 mg contains 182.2 mg of anhydrous lactose. 100 mg contains 175.7 mg of anhydrous lactose. 140 mg contains 246 mg of anhydrous lactose. 180 mg contains 316.3 mg of anhydrous lactose. 250 mg contains 154.3 mg of anhydrous lactose.
Indications
Temodal hard capsules are 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.

Adult Dosage

Temodal hard capsules should only be prescribed by physicians experienced in the oncological treatment of brain tumours.

Anti-emetric therapy may be administered.

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal hard capsules are 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 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. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ
Toxicity	TMZ interruption^a	TMZ discontinuation
Absolute neutrophil count	0.5 and < 1.5 x 10⁹ /l	< 0.5 x 10⁹ /l
Thrombocyte count	10 and < 100 x 10⁹ /l	< 10 x 10⁹ /l
CTC non-haematological toxicity (except for alopecia, nausea, vomiting)	CTC Grade 2	CTC Grade 3 or 4
a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 1.5 x 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. At the start of Cycle 2, the dose is escalated to 200 mg/m²if the CTC non-haematological toxicity for Cycle 1 is Grade 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is 1.5 x 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. TMZ dose reduction or discontinuation during monotherapy treatment
Toxicity	Reduce TMZ by 1 dose level^a	Discontinue TMZ
Absolute neutrophil count	< 1.0 x 10⁹ /l	See footnote b
Thrombocyte count	< 50 x 10⁹ /l
CTC non-haematological Toxicity (except for alopecia, nausea, vomiting)	CTC Grade 3	CTC Grade 4^b
a: TMZ dose levels are listed in Table 2. b: TMZ is to be discontinued if:• dose level -1 (100 mg/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 is administered orally at a dose of 200 mg/m² once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m² once daily, to be increased in the second cycle to 200 mg/m² once daily, for 5 days if there is no haematological toxicity.

Special populations

Paediatric patients

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma, There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children is very limited.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child's Class C) or with renal impairment. Based on the pharmacokinetic properties ofTMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age , clearance of TMZ is not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia.

Method of administration

Temodal hard capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

Child Dosage
Paediatric patients: In patients 3 years of age or older, Temodal is administered orally at a dose of 200 mg/m 2 once daily for 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, with escalation to 200 mg/m 2 once daily at the next cycle if there is no haematologic toxicity. Fasting, swallowing and antiemetic precautions as adult dose.
Contra Indications
Hypersensitivity to the active substance, or to any of the excipients

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression
Special Precautions
Pneumocystis carinii pneumonia

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

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely.

Anti-emetic therapy:

Nausea and vomiting are very commonly associated with TMZ. Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

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

Patients with recurrent or progressive malignant glioma

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

Laboratory parameters

Prior to dosing, the following laboratory parameters must be met: ANC 1.5 x 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) or within 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 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.

Pediatric use

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.

Elderly patients (> 70 years of age)

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

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment.

Lactose

This medicinal product contains lactose.Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicines.
Interactions
Interaction studies have only been performed in adults.

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

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

As it cannot be excluded that the change in C_max is clinically significant, Temodal 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

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

Adverse Drug Reactions

Clinical trial experience

In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions, were reported commonly or very commonly in both indications (Tables 4 and 5): the frequency of grade 3-4 laboratory findings is presented after each table..

In the tables undesirable effects are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common ( 1/10); Common ( 1/100 to < 1/10); Uncommon ( 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Newly-diagnosed glioblastoma multiforme

Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

Table 4. Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newlydiagnosed glioblastoma multiforme
System Organ Class	TMZ + concomitant RT n=288*	TMZ monotherapy n=224
Infections and infestations
Common:	Infection, Herpes simplex , wound infection, pharyngitis, candidiasis oral	Infection, candidiasis oral
Uncommon:		Herpes simplex , herpes zoster, influenza–like symptoms
Blood and lymphatic system disorders
Common:	Neutropenia, thrombocytopenia, lymphopenia, leukopenia	Febril neutropenia, thrombocytopenia, anaemia, leukopenia
Uncommon:	Febrile neutropenia, anaemia	Lymphopenia, petechiae
Endocrine disorders
Uncommon:	Cushingoid	Cushingoid
Metabolism and nutrition disorders
Very common:	Anorexia	Anorexia
Common:	Hyperglycaemia, weight decreased	Weight decreased
Uncommon:	Hypokalemia, alkaline phosphatase increased, weight increased	Hyperglycaemia, weight increased
Psychiatric disorders
Common:	Anxiety, emotional lability, insomnia	Anxiety, depression, emotional lability, insomnia
Uncommon:	Agitation, apathy, behaviour disorder, depression, hallucination	Hallucination, amnesia
Nervous system disorders
Very common:	Headache	Convulsions, headache
Common:	Convulsions, consciousness decreased, somnolence, aphasia, balance impaired, dizziness, confusion, memory impairment, concentration impaired, neuropathy, paresthesia, speech disorder, tremor	Hemiparesis, aphasia, balance impaired, somnolence, confusion, dizziness, memory impairment, concentration impaired, dysphasia, neurological disorder (NOS), neuropathy, peripheral neuropathy, paresthesia, speech disorder, tremor
Uncommon:	Status epilepticus, extrapyramidal disorder, hemiparesis, ataxia, cognition impaired, dysphasia, gait abnormal, hyperesthesia, hypoesthesia, neurological disorder (NOS), peripheral neuropathy	Hemiplegia, ataxia, coordination abnormal, gait abnormal, hyperesthesia, sensory disturbance
Eye disorders
Common:	Vision blurred	Visual field defect, vision blurred, diplopia
Uncommon:	Hemianopia, visual acuity reduced, vision disorder, visual field defect, eye pain	Visual acuity reduced, eye pain, eyes dry
Ear and labyrinth disorders
Common:	Hearing impairment	Hearing impairment, tinnitus
Uncommon:	Otitis media, tinnitus, hyperacusis, earache	Deafness, vertigo, earache
Cardiac disorders
Uncommon:	Palpitation
Vascular disorders
Common:	Haemorrhage, oedema, oedema leg	Haemorrhage, deep venous thrombosis, oedema leg
Uncommon:	Cerebral haemorrhage, hypertension	Embolism pulmonary, oedema, oedema peripheral
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea, coughing	Dyspnoea, coughing
Uncommon:	Pneumonia, upper respiratory infection, nasal congestion	Pneumonia, sinusitis, upper respiratory infection, bronchitis
Gastrointestinal disorders
Very common:	Constipation, nausea, vomiting	Constipation, nausea, vomiting
Common:	Stomatitis, diarrhoea, abdominal pain, dyspepsia, dysphagia	Stomatitis, diarrhoea, dyspepsia, dysphagia, mouth dry
Uncommon:		Abdominal distension, fecal incontinence, gastrointestinal disorder (NOS), gastroenteritis, haemorrhoids
Skin and subcutaneous tissue disorders
Very common:	Rash, alopecia	Rash, alopecia
Common:	Dermatitis, dry skin, erythema, pruritus	Dry skin, pruritus
Uncommon:	Skin exfoliation, photosensitivity reaction, pigmentation abnormal	Erythema, pigmentation abnormal, sweating increased
Musculoskeletal and connective tissue disorders
Common:	Muscle weakness, arthralgia	Muscle weakness, arthralgia, musculoskeletal pain, myalgia
Uncommon:	Myopathy, back pain, musculoskeletal pain, myalgia	Myopathy, back pain
Renal and urinary disorders
Common:	Micturition frequency, urinary incontinence	Urinary incontinence
Uncommon:		Dysuria
Reproductive system and breast disorders
Uncommon:	Impotence	Vaginal haemorrhage, menorrhagia, amenorrhea, vaginitis, breast pain
General disorders and administration site conditions
Very common:	Fatigue	Fatigue
Common:	Allergic reaction, fever, radiation injury, face oedema, pain, taste perversion	Allergic reaction, fever, radiation injury, pain, taste perversion
Uncommon:	Asthenia, flushing, hot flushes, condition aggravated, rigors, tongue discolouration, parosmia, thirst	Asthenia, face oedema, pain, condition aggravated, rigors, tooth disorder, taste perversion
Investigations
Common:	ALT increased	ALT increased
Uncommon:	Hepatic enzymes increased, Gamma GT increased, AST increased

*A patient who was randomised to the RT arm only, received TMZ + RT.

Laboratory results

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

Recurrent or progressive malignant glioma

In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of Temodal.

Table 5. Adverse reactions in patients with recurrent or progressive malignant glioma
Infections and infestations
Rare:	Opportunistic infections, including PCP
Blood and lymphatic system disorders
Very common:	Neutropenia or lymphopenia (grade 3-4), thrombocytopenia (grade 3-4)
Uncommon:	Pancytopenia, anaemia (grade 3-4), leukopenia
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Weight decrease
Nervous system disorders
Very common:	Headache
Common:	Somnolence, dizziness, paresthesia
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea
Gastrointestinal disorders
Very common:	Vomiting, nausea, constipation
Common:	Diarrhoea, abdominal pain, dyspepsia
Skin and subcutaneous tissue disorders
Common:	Rash, pruritus, alopecia
Very rare:	Erythema multiforme, erythroderma, urticaria, exanthema
General disorders and administration site conditions
Very common:	Fatigue
Common:	Fever, asthenia, rigors, malaise, pain, taste perversion
Very rare:	Allergic reactions, including anaphylaxis, angioedema

Laboratory results

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

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 10⁹/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 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.

Post -Marketing Experience

Antineoplastic agents, and notably alkylating agents, have been associated with a potential risk of myelodysplastic syndrome (MDS) and secondary malignancies, including leukaemia.Very rare cases of MDS and secondary malignancies, including myeloid leukaemia have been reported in patients treated with regimens that included TMZ. Prolonged pancytopenia, which may result in aplastic anaemia has been reported very rarely. Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely.

Cases of interstitial pneumonitis/pneumonitis have been reported very rarely.