TEMOSIDE Capsules (Temozolomide)

Transcription

1 Published on: 22 Sep 2014 TEMOSIDE Capsules (Temozolomide) Composition TEMOSIDE Capsules 20 Each capsule contains: Temozolomide IP. 20 mg TEMOSIDE Capsules 100 Each capsule contains: Temozolomide IP. 100 mg TEMOSIDE Capsules 250 Each capsule contains: Temozolomide IP. 250 mg Dosage Form Oral capsule Pharmacology Pharmacodynamics Temozolomide is an antineoplastic agent ( other alkylating agents ).Temozolomide is not directly active but undergoes rapid non-enzymatic conversion at physiologic ph to the reactive compound 5- ( 3-methyltriazen-1-yl)imidazoe-4-carboxamide (MTIC ). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation ( methylation ) occurs mainly at the O 6 and N 7 positions of guanine. Pharmacokinetics Absorption Temozolomide is rapidly and completely absorbed after oral administration, with a peak plasma concentration ( C max ) achieved in a median T max of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and the area under the curve (AUC ) decreased by 32% and 9%, respectively, and median T max increased by 2-fold ( from 1hour to 2.25 hours ) when temozolomide was administered after a modified high-fat breakfast. A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary central nervous system ( CNS ) malignancies showed that 150 mg/m 2 temozolomide for injection administered over 90 minutes is bioequivalent to 150 mg/m 2 temozolomide oral capsules with respect to both the C max and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m 2, the geometric mean C max values for temozolomide and MTIC were 7.3 mcg/ml and 276 ng/ml, respectively. Following a single oral dose of 150 mg/m2, the geometric mean C max values for temozolomide and MTIC were 7.5 mcg/ml and 282 ng/ml, respectively. Following a single 90-minute intravenous infusion of 150 mg/m 2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg hr/ml

2 and 891 ng hr/ml, respectively. Following a single oral dose of 150 mg/m 2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg hr/ml and 864 ng hr/ml, respectively. Distribution Temozolomide has a mean apparent volume of distribution of 0.4 L/kg ( coefficient of variation % (CV ) =13% ). It is weakly bound to human plasma proteins ; the mean percent-bound of drug-related total radioactivity is 15%. Metabolism and Elimination Temozolomide is spontaneously hydrolysed at the physiologic ph to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolysed to 5-amino-imidazole-4-carboxamide ( AIC ), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome (CY ) P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. Excretion About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in faeces. The majority of the recovery of radioactivity in urine is unchanged temozolomide ( 5.6% ), AIC ( 12% ), temozolomide acid metabolite ( 2.3% ), and unidentified polar metabolite(s ) ( 17% ). Overall clearance of temozolomide is about 5.5 L/hr/m 2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m 2 /day. Special Populations Analysis of the population-based pharmacokinetics of temozolomide revealed that plasma temozolomide clearance was independent of age, renal function or tobacco use. Women have an approximately 5% lower clearance ( adjusted for body surface area ) for temozolomide than men. The effect of race on the pharmacokinetics of temozolomide has not been studied. Effect of Renal Impairment A population pharmacokinetic analysis indicated that creatinine clearance ( CrCL ) over the range of 36 to 130 ml/min/m 2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function ( CrCL 2 ). Caution should be exercised when temozolomide is administered to patients with severe renal impairment. Temozolomide has not been studied in patients on dialysis. Effect of Hepatic Impairment A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment ( Child-Pugh class I-II ) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment. Effect of Other Drugs on Temozolomide Pharmacokinetics In a multiple-dose study, administration of temozolomide capsules with ranitidine did not change the C max or AUC values for temozolomide or MTIC. A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5%. A population analysis did not demonstrate any influence of co-administered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists or phenobarbital on the clearance of orally administered temozolomide. Administration of temozolomide with food resulted in a 33% decrease in the C max and a 9% decrease in the AUC. As it cannot be excluded that the change in the C max is clinically significant, temozolomide should be administered without food.

3 Indications TEMOSIDE Capsules are indicated for the treatment of the following: Adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy ( RT ) and then as maintenance treatment. Children (aged 3 years or older ), adolescents and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. Dosage And Administration Adult Patients with Newly Diagnosed Glioblastoma Multiforme TEMOSIDE Capsules are administered in combination with focal RT (concomitant phase ) followed by up to six cycles of TEMOSIDE Capsules maintenance (monotherapy ) phase. Concomitant Phase TEMOSIDE Capsules are administered orally at a dose of 75 mg/m 2 daily for 42 days concomitant with focal RT (60 Gy administered in 30 fractions ). No dose reductions are recommended, but delay or discontinuation in the administration of TEMOSIDE Capsules should be decided weekly according to the haematological and non-haematological toxicity criteria. Administration of TEMOSIDE Capsules can be continued throughout the 42-days concomitant period ( up to 49 days ) if all of the following conditions are met: Absolute neutrophil count (ANC ) 1.5 x 10 9 /l Thrombocyte count 100 x 10 9 /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. Administration of TEMOSIDE Capsules 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: Temozolomide dosing interruption or discontinuation during concomitant RT and temozolomide Toxicity Temozolomide Interruption * Temozolomide Discontinuation ANC 0.5 and 9/L 9/L Platelet count 10 and 9/L 9/L CTC non-haematological toxicity (except for alopecia, nausea, vomiting ) CTC Grade 2 CTC Grade 3 or 4 CTC=Common Toxicity Criteria. * Treatment with concomitant temozolomide could be continued when all of the following conditions are met: ANC /L ; platelet count /L ; and, CTC non-haematological toxicity Grade 1 ( except for alopecia, nausea, vomiting ). Maintenance Phase Cycle 1 In this cycle, 4 weeks after completing the temozolomide+rt phase, TEMOSIDE Capsules are administered for an additional six cycles of maintenance treatment. Dosage in Cycle 1 ( maintenance ) is 150 mg/m 2 once daily for 5 days, followed by 23 days without treatment.

4 Cycles 2-6 At the start of Cycle 2, the dose of TEMOSIDE Capsules can be escalated to 200 mg/m 2, if the CTC non-haematologic toxicity for Cycle 1 is Grade 2 ( except for alopecia, nausea and vomiting ), ANC is /L, and the platelet count is /L. The dose remains at 200 mg/m 2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Dose reduction or discontinuation during maintenance Dose reductions of TEMOSIDE Capsules during the maintenance 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 TEMOSIDE Capsules ) or within 48 hours of that day, and weekly until the ANC is above /L ( 1500/ L ) and the platelet count exceeds /L ( 1,00,000/ L ). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst non-haematologic toxicity during the previous cycle. Table 2: Temozolomide dose levels for maintenance treatment Dose Level Dose ( mg/m 2 /day ) Remarks Reduction for prior toxicity Dose during Cycle Dose during Cycles 2-6 in the absence of toxicity Table 3: Temozolomide dose reduction or discontinuation during maintenance treatment Toxicity Reduce Temozolomide by One Dose Level * Discontinue Temozolomide ANC 9/L See footnote Platelet count 9/L See footnote CTC non-haematological toxicity (except for alopecia, nausea, vomiting ) CTC Grade 3 CTC Grade 4 CTC=Common Toxicity Criteria. * Temozolomide dose levels are listed in Table 2. Temozolomide is to be discontinued if dose reduction to 2 is required or if 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, TEMOSIDE Capsules are administered orally at a dose of 200 mg/m 2 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/m 2 once daily, to be increased in the second cycle to 200 mg/m 2 once daily, for 5 days if there is no haematological toxicity. Patients with Refractory Anaplastic Astrocytoma For adults, the initial dose is TEMOSIDE Capsules 150 mg/m 2 once daily for 5 consecutive days per 28-days treatment

5 cycle. For adult patients, if both the nadir and day of dosing ( day 29, day 1 of next cycle ) ANC are /L ( 1,500/ L ) and both the nadir and day 29, day 1 of next cycle platelet counts are /L ( 1, 00,000/ L ), the TEMOSIDE Capsules dose may be increased to 200 mg/m 2 /day for 5 consecutive days per 28-days treatment cycle. During treatment, 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 the ANC is above /L ( 1,500/ L ) and the platelet count exceeds /L ( 1,00,000/ L ). The next cycle of TEMOSIDE Capsules should not be started until the ANC and platelet count exceed these levels. If the ANC falls to 9/L ( 1,000/ L ) or the platelet count is 9/L ( 50,000/ L ) during any cycle, the next cycle should be reduced by 50 mg/m 2 but should not be below 100 mg/m 2, the lowest recommended dose ( see Table 4 ). TEMOSIDE Capsules therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. Table 4: Dosing modification table Table 5: Daily dose calculations by body surface area Total body surface area (m 2 ) 75 mg/m 2 (mg daily ) 150 mg/m 2 (mg daily ) 200 mg/m 2 (mg daily ) (mg daily )

6 Administration TEMOSIDE Capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened up or chewed. If vomiting occurs after the dose is administered, a second dose should not be administered that day. Anti-emetic therapy may be administered prior to and/or following administration of TEMOSIDE Capsules. Special Populations Paediatric population In patients 3 years of age or older, temozolomide is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited. The safety and efficacy of temozolomide 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 temozolomide was comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of temozolomide in patients with severe hepatic impairment ( Child's Class C ) or with renal impairment. Based on the pharmacokinetic properties of temozolomide, 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 temozolomide is administered in these patients. Elderly patients Based on a population pharmacokinetic analysis in patients years of age, clearance of temozolomide is not affected by age. However, elderly patients (> 70 years of age ) appear to be at increased risk of neutropenia and thrombocytopenia. Contraindications Temozolomide is contraindicated in patients who have a history of hypersensitivity reactions ( such as urticaria, allergic reaction ) to any of its components. Temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC ), since both drugs are metabolized to 5-( 3methyltriazen-1-yl ) -imidazole- 4-carboxamide ( MTIC ). Temozolomide is contraindicated in patients with severe myelosuppression and in pregnancy and lactation

7 Warnings And Precautions Drug Interactions In a separate phase I study, administration of temozolomide 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 temozolomide with food resulted in a 33 % decrease in C max and a 9% decrease in area under the curve ( AUC ). As it cannot be excluded that the change in C max is clinically significant, temozolomide 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 temozolomide. Administration of valproic acid decreases the oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known. No studies have been conducted to determine the effect of temozolomide on the metabolism or elimination of other medicinal products. However, since temozolomide 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 temozolomide in combination with other myelosuppressive agents may increase the likelihood of myelosuppression. Paediatric Population Interaction studies have only been performed in adults. Myelosuppression Patients treated with temozolomide 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 medications associated with aplastic anaemia, including carbamazepine, phenytoin and trimethoprim/ sulphamethoxazole, complicates assessment. Prior to dosing, patients must have an ANC /L and a platelet count /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 then weekly until the ANC is above /L and platelet count exceeds /L. In clinical trials, geriatric patients and women have been shown to have a higher risk of developing myelosuppression. Myelodysplastic Syndrome Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have been observed. Pneumocystis jirovecii Pneumonia Patients who received concomitant temozolomide 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 temozolomide 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 temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, 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 temozolomide, in particular in combination with dexamethasone or other steroids. Anti-Emetic Therapy

8 Nausea and vomiting are very commonly associated with temozolomide. Anti-emetic therapy may be administered prior to or following administration of temozolomide. 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 in the maintenance 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 Tests Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment. For the 28-days treatment cycles, a complete blood count should be obtained prior to treatment on day 1 and on day 22 ( 21 days after the first dose ) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below /l and the platelet count falls below /l If the ANC falls to 9/l or the platelet count is 9/l during any cycle, the next cycle should be reduced by one dose level. Dose levels include 100 mg/m 2, 150 mg/m 2, and 200 mg/m 2. The lowest recommended dose is 100 mg/m 2. Hepatic Impairment Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment. Renal Impairment Caution should be exercised when temozolomide is administered to patients with severe renal impairment. Pregnancy Pregnancy Category D Temozolomide can cause foetal harm when administered to a pregnant woman. In preclinical studies in rats and rabbits receiving 150 mg/m 2 temozolomide, teratogenicity and/or foetal toxicity were demonstrated. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide. Lactation It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women of Childbearing Potential Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving temozolomide. Pediatric Use There is no clinical experience with the use of temozolomide in children under the age of 3 years. Experience in older children and adolescents are very limited.

9 Geriatric Use Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 years and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. In the anaplastic astrocytoma study population, patients who were 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy than patients under 70 years of age. Therefore, special care should be taken when temozolomide is administered in elderly patients. In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients ( aged Male Patients Temozolomide can have genotoxic effects. Therefore, men being treated with it 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 because of the possibility of irreversible infertility due to therapy with temozolomide. Lactose This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose malabsorption should not take this medicine. Effects on the Ability to Drive and Use Machines Temozolomide has minor influence on the ability to drive and use machines due to fatigue and somnolence. Undesirable Effects In patients treated with temozolomide, 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. Rash was reported very commonly in newly diagnosed glioblastoma multiforme patients receiving temozolomide 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 the system organ class and frequency. Frequency groupings are defined according to the following convention: very common ( 1/10 ); common ( 1/100 to <1/10); and, 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 6: Treatment-emergent events during concomitant and monotherapy treatment phases in patients with newly diagnosed glioblastoma multiforme System Organ Class Temozolomide + Concomitant RT n = 288 * Temozolomide Monotherapy n = 224 Infections and infestations

10 Infection, Herpes simplex, wound infection, pharyngitis, candidiasis oral Infection, candidiasis oral Urinary tract infection Herpes simplex, herpes zoster, influenzalike symptoms Blood and lymphatic system disorders Neutropenia, thrombocytopenia, lymphopenia, leucopenia Febrile neutropenia, thrombocytopenia, anaemia, leucopenia Febrile neutropenia, anaemia ymphopenia, petechiae Endocrine disorders Cushingoid Cushingoid Metabolism and nutrition disorders Very common: Anorexia Anorexia Hyperglycaemia, weight decreased Weight decreased Psychiatric disorders Hypokalaemia, alkaline phosphatase increased, weight increased Hyperglycaemia, weight increased Anxiety, emotional lability, insomnia Anxiety, depression, emotional lability, insomnia Psychiatric disorders Agitation, apathy, behaviour disorder, depression, hallucination Hallucination, amnesia Very common: Headache Convulsions, headache Eye disorders Convulsions, consciousness decreased, somnolence, aphasia, balance impaired, dizziness, confusion, memory impairment, concentration impaired, neuropathy, paraesthesia, speech disorder, tremor Status epilepticus, extrapyramidal disorder, hemiparesis, ataxia, cognition impaired, dysphasia, gait abnormal, hyperaesthesia, hypoaesthesia, neurological disorder ( NOS ), peripheral neuropathy Hemiparesis, aphasia, balance impaired, somnolence, confusion, dizziness, memory impairment, concentration impaired, dysphasia, neurological disorder not otherwise specified ( NOS ), neuropathy, peripheral neuropathy, paraesthesia, speech disorder, tremor Hemiplegia, ataxia, coordination abnormal, gait abnormal, hyperaesthesia, sensory disturbance Vision blurred Visual field defect, vision blurred, diplopia

11 Hemianopia, visual acuity reduced, vision disorder, visual field defect, eye pain Visual acuity reduced, eye pain, eyes dry Ear and labyrinth disorders Hearing impairment Hearing impairment, tinnitus Otitis media, tinnitus, hyperacusis, earache Deafness, vertigo, earache Cardiac disorders Palpitation Vascular disorders Haemorrhage, oedema, oedema leg Haemorrhage, deep venous thrombosis, oedema leg Cerebral haemorrhage, hypertension Embolism pulmonary, oedema, oedema peripheral Respiratory, thoracic and mediastinal disorders Dyspnoea, coughing Dyspnoea, coughing Pneumonia, upper respiratory infection, nasal congestion Pneumonia, sinusitis, upper respiratory infection, bronchitis Gastrointestinal disorders Very common: Constipation, nausea, vomiting Constipation, nausea, vomiting Stomatitis, diarrhoea, abdominal pain, dyspepsia, dysphagia Stomatitis, diarrhoea, dyspepsia, dysphagia, mouth dry Abdominal distension, faecal incontinence, gastrointestinal disorder ( NOS ), gastroenteritis, haemorrhoids Skin and subcutaneous tissue disorders Very common: Rash, alopecia Rash, alopecia Dermatitis, dry skin, erythema, pruritus Dry skin, pruritus Skin exfoliation, photosensitivity reaction, pigmentation abnormal Erythema, pigmentation abnormal, sweating increased Musculoskeletal and connective tissue disorders Muscle weakness, arthralgia Muscle weakness, arthralgia, musculoskeletal pain, myalgia Myopathy, back pain, musculoskeletal pain, myalgia Myopathy, back pain

12 Renal and urinary disorders Micturition frequency, urinary incontinence Urinary incontinence Dysuria Reproductive system and breast disorders Impotence Vaginal haemorrhage, menorrhagia, amenorrhoea, vaginitis, breast pain General disorders and administration site conditions Very common: Fatigue Fatigue Investigations Allergic reaction, fever, radiation injury, face oedema, pain, taste perversion, weakness Asthenia, flushing, hot flushes, condition aggravated, rigors, tongue discolouration, parosmia, thirst Allergic reaction, fever, radiation injury, pain, taste perversion, weakness Asthenia, face oedema, pain, condition aggravated, rigors, tooth disorder, taste perversion Alanine transaminase (ALT ) increased ALT increased Hepatic enzymes increased, Gammaglutamyl transpeptidase (GGT ) increased, aspartate transaminase (AST ) increased * A patient, who was randomized to the RT arm only, received temozolomide + RT. Laboratory Results Myelosuppression ( neutropenia and thrombocytopenia ), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, 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 temozolomide. 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 7 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of temozolomide. Table 7: Adverse reactions in patients with recurrent or progressive malignant glioma Infections and infestations Rare: Opportunistic infections, including PCP

13 Blood and lymphatic system disorders Very common: Neutropenia or lymphopenia ( Grade 3 4 ), thrombocytopenia ( Grade 3 4 ) Pancytopenia, anaemia ( Grade 3-4 ), leucopenia Metabolism and nutrition disorders Very common: Anorexia Weight decrease Nervous system disorders Very common: Headache Somnolence, dizziness, paraesthesia, paresis, ataxia, Respiratory, thoracic and mediastinal disorders Dyspnoea Gastrointestinal disorders Very common: Vomiting, nausea, constipation Diarrhoea, abdominal pain, dyspepsia Skin and subcutaneous tissue disorders Very rare: Rash, pruritus, alopecia Erythema multiforme, erythroderma, urticaria, exanthema General disorders and administration site conditions Very common: Very rare: Fatigue Fever, asthenia, rigors, malaise, pain, taste perversion Allergic reactions, including anaphylaxis, angio-oedema, oedema peripheral, adrenal hypercorticism Laboratory Results Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17% of patients, respectively, treated for malignant glioma. This led to hospitalization and/or discontinuation of temozolomide 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 leucopenia may increase the risk of infection. Gender A study reported that there were higher rates of Grade 4 neutropenia (ANC <0.5 x 109/l), and thrombocytopenia (<20 x 109/l), in women versus men in the first cycle of therapy. In studies for the recurrent glioma data set and newly diagnosed glioblastoma multiforme, Grade 4 neutropenia and Grade 4 thrombocytopenia occurred more in female than

14 male subjects in the first cycle of therapy. Postmarketing Experience Antineoplastic agents and, notably, alkylating agents, have been associated with a potential risk of myelodysplastic syndrome and secondary malignancies, including leukaemia. Very rare cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have been reported in patients treated with regimens that included temozolomide. Prolonged pancytopenia, which may result in aplastic anaemia, has been reported very rarely. Allergic reactions, including anaphylaxis, have been reported. Erythema multiforme has been reported, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely. Cases of interstitial pneumonitis/pneumonitis, pulmonary fibrosis and fatal respiratory failure have been reported very rarely. There have been reported cases of hepatotoxicity, including elevations of liver enzymes, hyperbilirubinaemia, cholestasis and hepatitis. Opportunistic infections including Pneumocystis carinii pneumonia ( PCP ) have also been reported. Cases of interstitial pneumonitis/pneumonitis, alveolitis, and pulmonary fibrosis have been reported. Prolonged pancytopenia, which may result in aplastic anemia, has been reported, and in some cases has resulted in a fatal outcome. Overdosage Doses of 500, 750, 1,000 and 1,250 mg/m 2 ( total dose per cycle over 5 days ) have been evaluated clinically in patients. Dose-limiting toxicity was haematologic and was reported with any dose, but is expected to be more severe at higher doses. An overdose of 2,000 mg per day for 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 more than 5 days of treatment ( up to 64 days ), with adverse reactions reported, including bone marrow suppression (which in some cases was severe and prolonged ) and infections, and resulted in death. In the event of an overdose, haematologic evaluation is needed. Supportive measures should be provided as necessary. Shelf-Life 2 years Storage And Handling Instructions Store below 25 C Packaging Information Temoside 20 Capsules: Container pack of 5 Capsules Temoside 100 Capsules: Container pack of 5 Capsules Temoside 250 Capsules: Container pack of 5 Capsules Last updated: January 2012 Last reviewed: Nov 2013 TEMOSIDE Capsules

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