Temozolomide Capsules 100 mg Taj Pharma

.NAME OF THE MEDICINAL PRODUCT

Temozolomide capsules 5mg Taj Pharma
Temozolomide capsules 20mg Taj Pharma
Temozolomide capsules 100mg Taj Pharma
Temozolomide capsules 140mg Taj Pharma
Temozolomide capsules 180mg Taj Pharma
Temozolomide capsules 250mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Each hard capsule contains
Temozolomide USP                                      5mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

b) Each hard capsule contains
Temozolomide USP                                    20mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

c) Each hard capsule contains
Temozolomide USP                                    100mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

d) Each hard capsule contains
Temozolomide USP                                    140mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

e) Each hard capsule contains
Temozolomide USP                                    180mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

f) Each hard capsule contains
Temozolomide USP                                     250mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard gelatin capsules.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Temozolomide capsules 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 capsules 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 capsules 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 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.

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/m² if 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.

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 (see section 4.4)

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ 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 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 of TMZ, 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 (see section 4.4).

Method of administration

Temozolomide capsules 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.

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 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.

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.

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 (see section 4.6).

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 medicine.

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 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 capsules 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 capsules 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 should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.

Male fertility

TMZ 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 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

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); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000). 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.

*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 Temozolomide capsules.

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.

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.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

^† Including cases with fatal outcome

* Frequencies estimated based on relevant clinical trials.

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.

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 PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents – Other alkylating agents.

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 non-comparative 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 t_1/2 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 (t_1/2) 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 PARTICULARS
   
   6.1 List of excipients
   Lactose, Sodium starch glycolate, Tartaric acid, Stearic acid, Gelatin, Titanium dioxide, Sodium laurilsulfate, Shellac, Propylene glycol, Red iron oxide, Yellow iron oxide & Titanium dioxide.

 6.2 Incompatibilities

Not applicable.

6.3  Shelf life
3 years

6.4 Special precautions for storage

Bottle presentation

Do not store above 30 °C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Do not store above 30 °C.

6.5 Nature and contents of container
Bottle presentation

Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules.

The carton contains one bottle.

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate.

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton.

The carton contains 5 or 20 hard capsules, individually sealed in sachets.

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 capsules 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.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Temozolomide capsules 5mg Taj Pharma
Temozolomide capsules 20mg Taj Pharma
Temozolomide capsules 100mg Taj Pharma
Temozolomide capsules 140mg Taj Pharma
Temozolomide capsules 180mg Taj Pharma
Temozolomide capsules 250mg Taj Pharma

temozolomide

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor, pharmacist or
• This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Temozolomide is and what it is used for
2. What you need to know before you take Temozolomide
3. How to take Temozolomide
4. Possible side effects
5. How to store Temozolomide
6. Contents of the pack and other information

1.             What Temozolomide is and what it is used for

Temozolomide is an anti-cancer medicine.

Temozolomide capsules are taken to treat specific forms of brain tumours:

• adults with newly diagnosed specific form of brain tumour (glioblastoma multiforme).
• Temozolomide is first used together with radiotherapy (concomitant phase of treatment) and after that alone (monotherapy phase of treatment).
• children 3 years and older and adult patients with specific forms of brain tumour (e.g. glioblastoma multiforme or astrocytoma) that has returned or where the cancer has spread after standard therapy.

2.             What you need to know before you take Temozolomide

Do not take Temozolomide

• if you are allergic to temozolomide or any of the other ingredients of this medicine (listed in section 6).
• if you have had an allergic reaction to another anti-cancer medicine called Signs of allergic reaction include feeling itchy, breathlessness or wheezing, swelling of the face, lips, tongue or throat.
• if you have a reduced number of blood cells, such as your white

blood cell count and platelet count. These blood cells are important for fighting infection and for proper blood clotting. Your doctor will check your blood to make sure you have enough of these cells before you begin treatment.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Temozolomide,

• as you should be observed closely for the development of a serious form of chest infectioncalled Pneumocystis jirovecii pneumonia (PCP). If you are a newly-diagnosed patient (glioblastoma multiforme) you may be receiving temozolomide for 42 days in combination with In this case, your doctor will also prescribe medicine to help you prevent this typeof pneumonia (PCP).
• if you have ever had or might now have a hepatitis B This is because Temozolomide could cause hepatitis B to become active again, which can be fatal in some cases.
• Patients will be carefully checked by their doctor for signs of this infection before treatment.
• if you have anaemia, low blood count (such as white blood cell count and platelet count), or blood clotting problems before treatment, or develop them during Your doctor may need to reduce the dose of your medicine or interrupt your treatment, or you may need other treatment. Your doctor will decide whether any change in your treatment is needed. In some cases, it may be necessary to stop treatment with temozolomide. Your blood will be tested regularly to monitor your condition. If you develop fever or symptoms of an infection contact your doctor immediately.
• you may have a small risk of other changes in blood cells, including
• if you feel sick or vomit, which are very common side effects of Temozolomide (see section 4).

If you vomit frequently before or during treatment, ask your doctor about medicines to help prevent vomiting or control the vomiting and the best time to take temozolomide until the vomiting is under control. If you vomit after your dose, do not take a second dose on the same day.

• if you develop fever or symptoms of an infection, contact your doctor
• if you are older than 70 years of Older patients are more prone to infections, increased bruising or bleeding.
• if you have liver or kidney problems as your dose of temozolomide may need to be

Children and adolescents

Do not give this medicine to children under the age of 3 years because it has not been studied. There is limited information in patients over 3 years of age who have taken Temozolomide.

Other medicines and Temozolomide

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy, breast-feeding and fertility

If you are pregnant or, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. This is because you must not be treated with Temozolomide during pregnancy unless clearly indicated by your doctor.

Effective contraceptive precautions must be taken by both male and female patients who are taking Temozolomide(see also “Male fertility” below).

You must not breast-feed whilst you are being treated with Temozolomide.

Male fertility

Temozolomidemay cause permanent infertility. Male patients should use effective contraception and not father a child for up to 6 months after stopping treatment. It is recommended to seek advice on conservation of sperm prior to treatment.

Ask your doctor for advice before taking any medicine.

Driving and using machines

When you take temozolomide you may feel tired or sleepy. In this case, do not drive or use any tools or machines or cycle until you see how this medicine affects you (see section 4).

Temozolomide contains lactose

The capsules contain lactose (a kind of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3.             How to take Temozolomide

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How to open sachet

Open the sachet by folding and tearing along the fold line with the notch in the corner of the sachet. Temozolomide should only be prescribed by specialists experienced in brain tumours.

Dosage and duration of treatment

Your doctor will decide the correct dose of temozolomide for you to take, based on your size (height and weight) and whether you have had chemotherapy treatment. You may be given other medicines to take before and/or after temozolomide to avoid or control vomiting.

Take your prescribed dose of Temozolomide once a day. Take the dose on an empty stomach; for example, at least one hour before you plan to eat breakfast. Swallow the capsule(s) whole with a glass of water. Do not open, crush or chew the capsules.

If a capsule is damaged, avoid contact of the powder with your skin, eyes or nose. Avoid inhaling the powder. If you accidentally get some in your eyes or nose, flush the area with water.

If you are taking Temozolomide in combination with radiotherapy (newly diagnosed patients):

While the radiotherapy is ongoing your doctor will start temozolomide at a dose of 75 mg/m² and the actual daily dose you take will depend on your height and weight. You will take this dose every day for 42 days (up to 49 days) in combination with radiotherapy. Based on your blood counts and how you tolerate temozolomide, the dose may be delayed or stopped.

Once the radiotherapy is completed, you will interrupt treatment for 4 weeks to give your body a chance to recover.

Then there may be up to 6 treatment cycles, and each one lasts 28 days. You will take your new dose of temozolomide capsules initially at 150 mg/m² once daily for the first five days (“dosing days”) of each cycle, followed by 23 days without temozolomide; this adds up to a 28 day treatment cycle.

After day 28, the next cycle will begin, in which you will again take this medicine once daily for five days followed by 23 days without temozolomide. Based on your blood counts and how you tolerate temozolomide during each treatment cycle, the dose may be adjusted, delayed or stopped.

If you are taking Temozolomide capsules alone (without radiotherapy):

A treatment cycle with Temozolomide comprises 28 days. You will take the capsules once daily for the first five days (“dosing days”) followed by 23 days without temozolomide, adding up to the 28 day treatment cycle.

After day 28, the next cycle will begin, in which you will again take this medicine once daily for five days followed by 23 days without temozolomide. Before each new treatment cycle, your blood will be tested to see if the temozolomide dose needs to be adjusted.

If you have not been treated before with chemotherapy, you will take your first dose of temozolomide at 200 mg/m² once daily for the first five days (“dosing days”) followed by 23 days without temozolomide. If you have been treated before with chemotherapy, you will take your first dose of temozolomide at 150 mg/m² once daily for the first five days (“dosing days”) followed by 23 days without temozolomide.

Depending on your blood test results, your doctor may adjust your dose for the next cycle.

Each time you start a new treatment cycle, be sure you understand exactly how many capsules of each strength you need to take each day and how many days you will receive this dose.

All patients

Temozolomide comes in different strength capsules (shown on the outer label in mg). Each strength has a different colour cap. Depending on the dose of temozolomide that your doctor prescribes, you may have to take several capsules on each dosing day of the treatment cycle.

• Be sure you understand exactly how many capsules you need to take of each Ask your doctor or pharmacist to write down the number of each strength (including colour) that you need to take each dosing day.
• Be sure you know exactly which days are your dosing
• Be sure you review the dose with your health care provider each time you start a new

Sometimes the dose or the mix of capsules you need to take will be different from the last cycle.

• Once you take the medicine home, if you are confused or unsure about how to take your dose, call for re-instruction before beginning the treatment cycle. Errors in how you take this medicine may have serious health

If you take more Temozolomide than you should

If you accidentally take more capsules than you were told to, contact your doctor, pharmacist or nurse immediately.

If you forget to take Temozolomide

Take the missed dose as soon as possible during the same day. If a full day has gone by, check with your doctor. Do not double the next dose to make up for a forgotten dose, unless your doctor tells you to do so.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.             Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Patients taking temozolomide in combination with radiation therapy may experience different side effects than patients taking temozolomide alone.

Contact your doctor immediately if you have any of the following:

• a severe allergic reaction (rash which might be itchy, wheezing or other breathing difficulty),
• uncontrolled bleeding,
• Seizures (convulsions),
• fever,
• chills,
• severe headache that does not go

Temozolomide treatment can cause a reduction in certain kinds of blood cells. This may cause you to have increased bruising or bleeding, anaemia (a shortage of red blood cells), fever, and/or a reduced resistance to infections. The reduction of blood cells is usually temporary, but in some cases may be for longer and may lead to a very severe form of anaemia (aplastic anaemia). Your doctor will monitor your blood regularly for any changes, and will decide if any specific treatment is needed. In some cases, your temozolomide dose will be reduced or discontinued.

The following side effects may occur if you are a newly diagnosed patient taking Temozolomidefor a specific brain tumour (glioblastoma multiforme) in combination treatment with radiotherapy and then later taking temozolomide on its own. Medical attention may be required. Very common side effects (may affect more than 1 in 10 people):

• Headache
• constipation
• feeling and/or being sick
• rash
• hair loss
• loss of appetite
• tiredness

Common side effects (may affect up to 1 in 10 people):

• Abnormal liver function tests,
• changes in blood cells,
• fits, change in mental status or alertness, sleepiness, difficulty with your balance, dizziness, confusion, forgetfulness, difficulty concentrating, tingling sensation, “pins and needles”, difficulty speaking or understanding language, shaking,
• abnormal or blurred vision, double-vision
• loss of hearing, ringing noise in the ear
• shortness of breath, cough
• sores or ulcers in the mouth, diarrhoea, stomach pain, heartburn, difficulty swallowing, dry mouth
• frequent urination, difficulty with holding your urine or urine leakage
• skin irritation or redness, dry skin, itching
• muscle weakness, painful joints, muscle aches and pains
• increased sugar in the blood, loss of weight
• infections, wound infection, sore throat, fungal infections in the mouth, cold sores
• bleeding, fluid retention, swollen legs, blood clots
• allergic reaction, fever, radiation injury, facial swelling, pain, changes in sense of taste
• anxiety, depression, changing emotions, inability to fall asleep or stay asleep,

Uncommon side-effects (may affect up to 1 in 100 people):

• raised liver enzymes (your doctor will check this)
• palpitations (abnormal heart beats)
• flu-like symptoms, red spots under the skin
• long or repeated fits, tremors or jerking movement, partial paralysis, difficulty with your coordination and balance, changes in sensation of touch
• partial loss of vision, dry or painful eyes
• infection of the middle ear, pain or discomfort in the ears from loud noises, earache, deafness, feeling that one’s surroundings are spinning
• pneumonia, inflammation of your sinuses, bronchitis, blocked nose, a cold or the flu
• bloated stomach, difficulty controlling your bowel movements, haemorrhoids (piles)
• pain with urination
• peeling skin, increased skin sensitivity to sunlight, change in skin colour, increased sweating
• muscle damage, back pain
• low potassium level in the blood, weight gain
• shingles, flu-like symptoms
• bleeding within the brain, high blood pressure, blood clot in the lung, swelling
• weakness, swollen face, shivering, change in your sense of taste, tooth disorder
• sexual impotence, vaginal bleeding, absent or heavy menstrual periods, vaginal irritation, breast pain,
• mood swings, depression, hallucination and memory loss
• discolouration of your tongue
• change in your sense of smell
• thirst

The following side effects may occur if you are taking only temozolomide (patients treated for brain tumours that have come back or that have spread)

Very common (may affect more than 1 in 10 people):

Abnormal blood values, headache, feeling or being sick, constipation, loss of appetite, tiredness

Common (may affect up to 1 in 10 people):

Sleepiness, dizziness, tingling sensation, diarrhoea, stomach pain, indigestion, rash, itching, hair loss, weight loss, fever, weakness, shivering, feeling unwell, pain, change in taste, shortness of breath

Uncommon (may affect up to 1 in 100 people):

Changes in blood cells

Rare (may affect up to 1 in 1,000 people):

Cough. Infections including agents causing pneumonia.

Very rare (may affect up to 1 in 10,000 people):\

Skin redness, an itchy rash with raised yellow or white lumps that are surrounded by red inflammation, skin eruption, allergic reactions.

Other side effects:

Cases of elevations of liver enzymes have been commonly reported. Cases of increased bilirubin, problems with bile flow (cholestasis), hepatitis and injury to the liver, including fatal liver failure, have been uncommonly reported.

Very rare cases of lung side effects have been observed with temozolomide. Patients usually present with shortness of breath and cough. Tell your doctor if you notice any of these symptoms.

Very rare cases of rash with skin swelling, including on the palms of the hands and soles of the feet, or painful reddening of the skin and/or blisters on the body or in the mouth have been observed. Tell your doctor immediately if this occurs.

Very rarely, patients taking temozolomide and medicines like it may have a small risk of other changes in blood cells, including leukaemia.

New or reactivated (recurring) cytomegalovirus infections and reactivated hepatitis B virus infections have been uncommonly reported. Cases of brain infections caused by herpes virus (meningoencephalitis herpetic), including fatal cases, have been uncommonly reported. Cases of sepsis (when bacteria and their toxins circulate in the blood and start to damage the organs) have been uncommonly reported.

Cases of diabetes insipidus have been uncommonly reported. Symptoms of diabetes insipidus include passing a lot of urine and feeling thirsty.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5.             How to store Temozolomide

Keep this medicine out of the sight and reach of children, preferably in a locked cupboard. Accidentally ingestion can be lethal for children.

Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

Bottle

Do not store above 25°C. Store in the original bottle.

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

Sachet

Do not store above 25 °C.

Store in the original package in order to protect from moisture.

Tell your pharmacist if you notice any change in the appearance of the capsules.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information
What Temozolomide contains

a) Each hard capsule contains
Temozolomide USP                                      5mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

b) Each hard capsule contains
Temozolomide USP                                    20mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

c) Each hard capsule contains
Temozolomide USP                                    100mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

d) Each hard capsule contains
Temozolomide USP                                    140mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

e) Each hard capsule contains
Temozolomide USP                                    180mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

f) Each hard capsule contains
Temozolomide USP                                     250mg
Excipient                                                        q.s
Colours: Approved Colours used in capsule shells

The other ingredients are Lactose, Sodium starch glycolate, Tartaric acid, Stearic acid, Gelatin, Titanium dioxide, Sodium laurilsulfate, Shellac, Propylene glycol, Red iron oxide, Yellow iron oxide & Titanium dioxide. What Temozolomide looks like and contents of the pack.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).