Submission Control No: 117171

Date of Revision:

June 18, 2008

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 5 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 20 SPECIAL HANDLING INSTRUCTIONS 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 22

PHARMACEUTICAL INFORMATION 22 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 27 TOXICOLOGY 30 REFERENCES 42

PART III: CONSUMER INFORMATION. 43

(r)

TEMODAL

(temozolomide)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

TEMODAL is contraindicated in patients who have a history of hypersensitivity reaction to its components or to dacarbazine (DTIC). The use of TEMODAL is not recommended in patients with severe myelosuppression.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

TEMODAL IS AN ALKYLATING ANTITUMOR DRUG TO BE USED ONLY BY QUALIFIED PHYSICIANS TRAINED IN THE FIELD OF ONCOLOGY. SEVERE MYELOSUPPRESSION CAN OCCUR, AND IS A DOSE-LIMITING SIDE-EFFECT. TEMODAL MAY HAVE TO BE DISCONTINUED OR THE DOSE MAY HAVE TO BE ADJUSTED (SEE DOSAGE AND ADMINISTRATION)

.

General

The treating physician should use his discretion with respect to the use of TEMODAL in patients with poor performance status, severe debilitating diseases or infection when the risk of treatment outweighs the potential benefit to the patient.

Drug Interactions:

Antiemetic therapy may be administered prior to or following administration of TEMODAL. Analyses of data obtained from population pharmacokinetics in the phase II studies demonstrated that administration of TEMODAL with ranitidine or with food did not result in clinically significant alterations in the extent of absorption of TEMODAL. Co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital did not alter the clearance of TEMODAL. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TEMODAL. The combination of TEMODAL with other chemotherapeutic agents has not been fully evaluated. Combination with other alkylating agents is likely to result in increased myelosuppression.

Gastrointestinal

Antiemetic therapy: Nausea and vomiting are very commonly associated with TEMODAL, and guidelines are provided: Patients with newly diagnosed glioblastoma multiforme: anti-emetic prophylaxis is recommended prior to the initial dose of concomitant TEMODAL, anti-emetic prophylaxis is strongly recommended during the maintenance phase. Patients with recurrent or progressive glioma: Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.

Hepatic/Biliary/Pancreatic

In the absence of formal studies in patients suffering from severe hepatic dysfunction the treating physician should use his discretion in weighing the benefits of using TEMODAL in this patient population against the potential risks.

Renal

In the absence of formal studies in patients suffering from severe renal failure the treating physician should use his discretion in weighing the benefits of using TEMODAL in this patient population against the potential risks.

Respiratory

Patients who received concomitant TEMODAL and radiotherapy in a pilot trial for the prolonged 42 day schedule were shown to be at particular risk for developing Pneumocystis carinii pneumonia. Thus prophylaxis against Pneumocystis carinii pneumonia (PCP) is required for all patients receiving concomitant TEMODAL and radiotherapy for the 42 day regimen (with a maximum of 49 days). There may be a higher occurrence of PCP when TEMODAL is administered during a longer dosing regimen. However, all patients receiving TEMODAL, particularly patients receiving steroids should be observed closely for the development of PCP regardless of the regimen.

Sexual Function/Reproduction

Male Patients

: TEMODAL can have genotoxic effects. Effective contraception should also be used by male patients taking TEMODAL. Men being treated with TEMODAL are advised not to father a child during or up to 6 months after treatment and to seek advice on cryoconservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with TEMODAL.

Special Populations

Pregnant Women: There are no studies in pregnant women. In preclinical studies in rats and rabbits administered 150 mg/m2, teratogenicity and/or fetal toxicity were demonstrated. Therefore, TEMODAL should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risks to the fetus. Women of childbearing potential should be advised to avoid pregnancy while they are receiving TEMODAL therapy and in the six months after discontinuation of treatment.

Nursing Women:

It is not known whether TEMODAL is excreted in human milk. Lactating mothers should be advised to stop lactation while under treatment.

Pediatrics (<18 years and >3 years)

: The safety and effectiveness of TEMODAL in paediatric patients has not yet been fully established.

Geriatrics (> 70 years of age)

: Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients.

Monitoring and Laboratory Tests

Prior to dosing, on Day 1 of each cycle, the following values must be met: absolute neutrophil count (ANC) >1.5 x 109/L and platelets >100 x 109/L. A complete blood count must also be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC is above 1.5 x 109/L and platelet count exceeds 100 x 109/L. If the 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 by one dose level, based upon the nadir blood count (see "DOSAGE AND ADMINISTRATION"). Dose levels include 100 mg/m2, 150 mg/m2 and 200 mg/m2. The lowest recommended dose is 100 mg/m2.

DRUG INTERACTIONS

Antiemetic therapy may be administered prior to or following administration of TEMODAL. Analyses of data obtained from population pharmacokinetics in the phase II studies demonstrated that administration of TEMODAL with ranitidine or with food did not result in clinically significant alterations in the extent of absorption of TEMODAL. Co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital did not alter the clearance of TEMODAL. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TEMODAL. The combination of TEMODAL with other chemotherapeutic agents has not been fully evaluated. Combination with other alkylating agents is likely to result in increased myelosuppression.

Drug-Food Interactions

TEMODAL interactions with food have not been established.

Drug-Herb Interactions

TEMODAL interactions with herbal products have not been established.

Drug-Laboratory Interactions

TEMODAL interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Adults Patients with Newly Diagnosed Glioblastoma Multiforme:

Concomitant Phase

TEMODAL is administered orally at 75 mg/m2 daily for 42 days concomitant with radiotherapy (60 Gy administered in 30 fractions) followed by maintenance TEMODAL for 6 cycles. No dose reductions are recommended; however, dose interruptions may occur based on patient tolerance. The TEMODAL dose can be continued throughout the 42 day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count >= 1.5 x 109 /L platelet count >= 100 x109 /L common toxicity criteria (CTC) non-hematological toxicity <= Grade 1 (except for alopecia, nausea and vomiting). During treatment a complete blood count should be obtained weekly. TEMODAL dosing should be interrupted or discontinued during concomitant phase according to the hematological and non-hematological toxicity criteria as noted in Table 7.

Maintenance Phase

Four weeks after completing the TEMODAL + RT (Radiotherapy) phase, TEMODAL is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) 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-hematologic 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 platelet count is >= 100 x 109/L. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions during the maintenance phase should be applied according to Tables 8 and 9. During treatment a complete blood count should be obtained on day 22 (21 days after the first dose of TEMODAL). The TEMODAL dose should be reduced or discontinued according to Table 9.

Malignant Gliomas Showing Recurrence or Progression After Standard Therapy:

Adult patients: In patients previously untreated with chemotherapy, TEMODAL capsules are administered orally at a dose of 200 mg/m2 once daily for 5 days per 28-day cycle. For patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily for 5 days, to be increased in the second cycle to 200 mg/m2 once daily for 5 days, providing there is no hematologic toxicity (see "WARNINGS AND PRECAUTIONS"). In the reference controlled trial of GBM, the majority of patients treated with TEMODAL (90%) received more than one cycle and 22% of patients received 6 or more cycles. These patients received a total of 484 cycles of TEMODAL in total; 60% of cycles at 200 mg/m2/day and 36% at 150 mg/m2/day. In the single arm AA trial, 93% of patients received more than one cycle and 25% of patients continued on study for 12 months or greater. Eighty-eight percent of patients were receiving either their initial dose or a higher dose at the last cycle. However, limited experience is available on the prolonged use of TEMODAL in this patient population.

Administration

Prior to dosing and during treatment, proper hematologic monitoring must be performed (see "WARNINGS AND PRECAUTIONS") to ensure that the following laboratory parameters are met: absolute neutrophil count (ANC) >1.5 x 109/L and platelets >100 x 109/L. If the 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. Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose is 100 mg/m2. Dose modification for TEMODAL should be based on toxicities according to nadir ANC or platelet counts. Since women taking TEMODAL were reported to have a higher incidence of grade 4 neutropenia and thrombocytopenia than men in the first cycle of therapy, they must be closely monitored for abnormal neutrophil and platelet counts. TEMODAL therapy can be continued until disease progression. TEMODAL should be administered in the fasting state, at least one hour before a meal. Antiemetic therapy may be administered prior to or following administration of TEMODAL. If vomiting occurs after the dose is administered, a second dose should not be administered.

OVERDOSAGE

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 hematological and was reported at 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 events reported were pancytopenia, pyrexia, multi-organ failure and death. There are reports of patients who have taken more than 5 consecutive days of treatment (up to 64 consecutive 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, hematologic evaluation is needed. Supportive measures should be provided as necessary.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Temozolomide is an imidazotetrazine alkylating agent with antitumor activity that can be used orally. It undergoes rapid chemical conversion in the systemic circulation at physiologic pH to the active compound, MTIC (monomethyl triazeno imidazole carboxamide). 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. After oral administration to adult patients, temozolomide is absorbed rapidly with peak plasma concentrations reached as early as 20 minutes post-dose (mean Tmax range between 0.5 and 1.5 hours). Plasma concentrations are dose-dependent, while plasma clearance, volume of distribution and half-life are independent of dose. Temozolomide demonstrates low protein binding (10% to 20%), and thus is not expected to interact with highly protein bound agents. After oral administration of 14C labelled temozolomide, mean fecal elimination of 14C over 7 days post- dose was 0.8% indicating complete absorption. Following oral administration, approximately 5% to 10% of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as AIC (4-amino-5-imidazole-carboxamide hydrochloride) or unidentified polar metabolites. Analysis of population based pharmacokinetics of temozolomide revealed that plasma temozolomide clearance was independent of age, renal function, hepatic function, or tobacco use. Pediatric patients (<18 years old and >3 years old) had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1000 mg/m2 per cycle both in children and in adults.

STORAGE AND STABILITY

Store between 15deg and 30degC. Protect from moisture.

SPECIAL HANDLING INSTRUCTIONS

TEMODAL capsules must not be opened or chewed, but are to be swallowed whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membrane. In the case of accidental contact with skin or mucous membrane, flush with water. KEEP OUT OF REACH OF CHILDREN.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each TEMODAL capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg temozolomide. Non-medicinal ingredients: colloidal silicon dioxide, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid; capsule shells contain gelatin, sodium lauryl sulfate and, titanium dioxide and are branded with black printing ink consisting of shellac, propylene glycol, ammonium hydroxide, black iron oxide and sometimes potassium hydroxide.

5 mg capsule shells also contain FD & C blue no. 2 and yellow iron oxide. 20 mg capsule shells also contain yellow iron oxide. 100 mg also contains red iron oxide. 140 mg capsule shells also contain FD & C blue no. 2. 180 mg capsule shells also contain yellow and red iron oxides.

mg:

Size No. 3 capsules with opaque green cap and opaque white body. The cap is imprinted in black ink with "TEMODAL", the body is imprinted in black ink with 2 stripes, "5 mg", and the Schering Plough logo. Bottles of 5 or 20 capsules.

mg:

Size No. 2 capsules with yellow cap and opaque white body. The cap is imprinted in black ink with "TEMODAL", the body is imprinted in black ink with 2 stripes, "20 mg", and Schering- Plough logo. Bottles of 5 or 20 capsules.

mg:

Size No. 1 capsules with opaque pink cap and opaque white body. The cap is imprinted in black ink with "TEMODAL", the body is imprinted in black ink with 2 stripes, "100 mg", and the Schering-Plough logo. Bottles of 5 or 20 capsules.

mg:

Size No. 0 capsules with a blue cap and opaque white body. The cap is imprinted in black ink with ''TEMODAL'', the body is imprinted in black ink with 2 stripes, "140 mg", and the Schering-Plough logo. Bottles of 5 or 20 capsules.

mg:

Size No. 0 capsules with an opaque orange cap and opaque white body. The cap is imprinted in black ink with ''TEMODAL'', the body is imprinted in black ink with 2 stripes, "180 mg", and the Schering-Plough logo. Bottles of 5 or 20 capsules.

mg:

Size No. 0 capsules with opaque white cap and opaque white body. The cap is imprinted in black ink with "TEMODAL", the body is imprinted in black ink with 2 stripes, "250 mg" and the Schering-Plough logo. Bottles of 5 or 20 capsules.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Temozolomide Chemical name: Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide,3,4-dihydro-3-methyl- 4-oxo Molecular formula: C6H6N6O2 Molecular mass: 194.15 Structural formula: Physicochemical properties:

Physical form:

Temozolomide is a white to light pink/light tan powder.

Solubility:

Temozolomide is sparingly soluble in dimethyl sulfoxide and slightly soluble in water, 0.01 M hydrochloric acid, pH 2.1 buffer, pH 3.9 buffer, pH 5.6 buffer, dichloromethane, acetone, Tween 80, acetonitrile, methanol and polyethylene glycol. Temozolomide is insoluble in toluene and very slightly soluble in ethyl acetate and ethanol.

pKa/pH:

Temozolomide contains no functional groups that can be protonated or deprotonated between pH 1 and pH 13, and therefore, does not have a dissociation constant (pKa) in this pH range. The pH of a 10 mg/ml aqueous dispersion of temozolomide is about 5.8.

Partition coefficient:

Temozolomide partitions primarily into the organic phase and the pH of the aqueous phase has little, if any effect, on the partition coefficient.

Solvent Partition Coefficient (octanol/aqueous)

water 22.4

phosphate buffer pH 7.0 (0.1 M) 22.0

0.1N HCl 20.8

Melting point: Temozolomide does not show a true melting point but undergoes decomposition from about 182E to 200EC.

CLINICAL TRIALS

Newly Diagnosed Glioblastoma Multiforme

Five hundred and seventy-three patients were randomised to receive either temozolomide (TEMODAL) + Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide + RT arm received concomitant temozolomide (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 maintenance temozolomide (150 or 200 mg/m2) on day 1 -5 of every 28 -day cycle for 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis carinii pneumonia (PCP) prophylaxis was required during RT and combined temozolomide therapy, and was to continue until recovery of lymphopenia to grade <1. Temozolomide 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 temozolomide + 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 favor of the temozolomide arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + temozolomide arm. The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a statistically significant improved overall survival compared with radiotherapy alone. (Figure 1).

HR (95% C.I.) = 1.59 (1.33 - 1.91)

log-rank p-value < .0001

RT+TM Z

RT O nly

Figure 1

Kaplan-Meier Curves for Overall Survival (Intent To Treat) ITT Population

Malignant Gliomas Showing Recurrence or Progression After Standard Therapy: Consistent patient selection criteria were used in the 3 phase II studies. In all trials, adult patients $18 years of age with histologically confirmed supratentorial GBM or AA at first relapse, a baseline Karnofsky performance status (KPS) of at least 70, and a life expectancy >12 weeks were eligible. Patients had unequivocal evidence of tumor recurrence or progression (first relapse) and evaluable enhancing residual disease. They failed a conventional course of radiation therapy for initial disease and no more than one prior regimen of adjuvant chemotherapy (with either a single agent or a regimen containing a nitrosourea). In the phase II studies, consistent criteria based on neuroimaging and clinical neurologic examination were used to define overall response and to determine disease progression for the progression-free survival analysis. Objective assessments of overall response were based upon tumor assessments interpreted in light of steroid use and, to a lesser extent, neurologic status. Overall response was based on the following: Complete response (CR): Disappearance of all enhancing tumor (measurable or non- measurable) on consecutive MRI scans at least one month apart, off steroids except for physiologic doses which may have been required following prolonged therapy and neurologically stable or improved. Partial response (PR): For patients with lesions which were either all measurable or all nonmeasurable, greater than or equal to a 50% reduction (<100%) in the sum of the products of the largest perpendicular diameters of contrast enhancement for all measurable lesions or +2 rating (definitely better) for all non-measurable lesions on consecutive MRI scans at least one month apart, steroids stable for 7 days prior to each scan at the same dose administered at the time of the previous scan or at a reduced dose, and neurologically stable or improved. No new lesions could arise. Progressive disease (PD): Greater than or equal to a 25% increase in size of the product of the largest perpendicular diameters of contrast enhancement for any measurable lesions or -2 rating (definitely worse) for any non-measurable lesions or any new tumor on MRI scans, steroids stable for 7 days prior to each scan at the same dose administered at the time of the previous scan or at an increased dose, with or without neurologic progression. The investigator had to carefully exclude non-tumor-related causes of clinical or radiological worsening (i.e. pseudoprogression). Stable disease (SD): All other situations. Temozolomide has been shown to be effective in prolonging progression-free survival and maintaining or improving health-related quality of life (HQL) in adult patients with recurrent high grade glioma. Both patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) experienced clinically meaningful efficacy and HQL benefits. In an open-label, active-reference study in which patients received either temozolomide or procarbazine, temozolomide demonstrated efficacy in GBM patients at first relapse based on improvements in progression-free survival, event-free survival and overall survival relative to the reference agent, procarbazine. This study was not designed nor powered to make statistically valid comparisons between the two drugs. Two hundred ten patients were determined by central review as having histologically confirmed GBM or gliosarcoma and comprise the eligible histology population. In the temozolomide group, the median age was 52 years and 69% were male. Karnofsky performance status was $80 in 70% of patients. At the time of initial diagnosis, 86% of patients in the temozolomide group had undergone surgical resection, with all patients subsequently receiving radiation therapy. Chemotherapy was administered in 65% of patients in the temozolomide group. The median time from initial diagnosis to first relapse was 7.0 months for temozolomide patients. At first relapse, 20% of patients had surgical resection. Results from this controlled trial are summarized in the table below:

Efficacy Results: Controlled Study

Objective response (partial response; PR) as determined by Gd-MRI scan after independent central review was achieved in 5% (6/112) of temozolomide patients and 6% (6/113) of procarbazine patients. Including stable disease (SD), the objective response (PR and SD) rate was 46% for temozolomide and 33% for procarbazine. In patients with prior exposure to chemotherapy, the benefit of temozolomide was limited to those with KPS $80. In patients who were progression-free at 6 months, quality of life was maintained or improved. Results from a large, non-comparative trial provide further evidence of the efficacy of temozolomide in patients with relapsing GBM. Of the 128 patients with eligible histologies, all but two had GBM, the remaining two had gliosarcoma. The median age was 54 years and 62% were male. Karnofsky performance status was $ 80 in 57%. At the time of initial diagnosis, 89% of patients underwent surgical resection, with all patients subsequently receiving radiation therapy. Eighty-six percent of patients were treated with standard dose fractionation. Nitrosourea-based chemotherapy was administered in 29% of patients. The median time from initial diagnosis to first relapse was 8.1 months. At first relapse, 13% of patients had surgical resection. The primary endpoint, progression-free survival at 6 months, was 19% (95% CI: 12%-26%) for the intent-to-treat (ITT) population. The median progression-free survival was 2.1 months. Median overall survival was 5.4 months. The objective response (CR/PR) as determined by Gd-MRI scan after independent central review was 8% (11/138) for the ITT population. Including stable disease, the objective response (CR, PR and SD) was 51% (71/138). Both overall response as objectively assessed and maintenance in progression-free status were associated with HQL benefits. In a large phase II study, temozolomide demonstrated clinically meaningful efficacy in AA patients in relapse. A total of 162 patients were enrolled and comprise the ITT population. A total of 111 patients was determined by central review as having histologically confirmed AA or AOA (anaplastic oligoastrocytoma) and comprises the eligible histology population who received temozolomide. Fifty one patients were excluded from the eligible histology population. The median age was 42 years and 57% were male. Karnofsky performance status was $80 in 67%. At the time of initial diagnosis, 68% of patients underwent surgical resection, with all patients subsequently receiving radiation therapy. Ninety-one percent of patients were treated with standard dose fractionation. Nitrosourea-based chemotherapy was administered in 60% of patients. The median time from initial diagnosis to first relapse was 14.9 months. At first relapse, 18% of patients had surgical resection. Progression-free survival at 6 months was 46% (95% CI: 39%-54%). The median progression- free survival was 5.4 months. Twenty four percent of patients remained progression-free after 12 months. The median overall survival was 14.6 months. Fifty-eight percent of patients remained alive after 12 months. The objective response rate (CR/PR) as determined by Gd-MRI scan after independent central review was 35% (13 CR and 43 PR) for the ITT population. Including stable disease, the objective response rate (CR, PR and SD) was 61% (99/162). For the 13 complete responders, the progression-free survival range was 11 to 26 months, with 7 patients remaining in complete response beyond 16 months; the overall survival for these patients ranged from 15 to 30 months, with 8 patients alive beyond 20 months. For the 43 partial responders, the median progression- free survival was 11 months and the median overall survival was 21 months.

DETAILED PHARMACOLOGY ANIMAL PHARMACOLOGY

Pharmacodynamics

The anti-tumor properties of temozolomide have been demonstrated in vitro and in vivo, with tumor cell lines and xenograft models. The cytotoxicity of temozolomide results from DNA methylation and correlates specifically with the O6-methylation of guanine residues. Temozolomide showed marked in vivo anti-tumor activity in murine xenograft models. Murines with subcutaneous or intracranial implanted human CNS tumor were either long term, tumor-free survivors or their tumors had substantial growth delays. Among a panel of human tumor cell lines, U373MG astrocytoma and U87MG glioblastoma were revealed as the most sensitive to temozolomide. In another in vitro study, with a broader profile of human glioma and medulloblastoma, CNS cell lines were as sensitive as U373MG astrocytoma to temozolomide. In another study, temozolomide given orally to mice in early stage subcutaneous implanted astrocytoma xenograft model revealed dose-dependent anti-tumor activity: 60-100% of mice were tumor-free on Day 54. Of 60 U251 glioblastoma xenografts treated with temozolomide, all 57 surviving animals showed complete tumor regression. Temozolomide showed greater tumor growth delay than BCNU or procarbazine with all four CNS tumor xenografts models studied. Some studies showed that temozolomide would have potential synergistic effects with other cytotoxic drugs such as O6-Benzylguanine, cisplatin, topotecan, 3-aminobenzamine or chloroethylnitrosoureas. Temozolomide safety pharmacology was assessed in cell lines, mice, rats and dogs. It was shown that it affected hematological parameters, increased total bilirubin and g-glutamyl- transferase. Temozolomide also decreased food consumption, body weight and body weight gain; it even produced weight loss. Temozolomide did not affect the blood pressure and electrocardiogram in dogs. Temozolomide did not cause gastric mucosal lesions nor affect intestinal transit after a single oral dose. Temozolomide caused a moderate inhibition of gastric emptying. It increased urine volume and BUN values and decreased urine osmolality in rats. Finally, temozolomide had CNS effects when given at lethal doses: hypoactivity, hunched posture, partial closure of the eyes, tremors, prostration, emesis and salivation.

Pharmacokinetics

Temozolomide is hydrolysed at physiological pH to MTIC, the metabolite responsible for DNA alkylation. The latter then breaks down into a reactive methyl-diazonium cation and AIC. AIC is an intermediate on the biosynthetic pathway to purines and ultimately to nucleic acids. Temozolomide is stable in acidic pH (<5) and labile at pH >7, and MTIC is unstable at pH <7 and more stable at alkaline pH. Temozolomide was given to mice, rats and dogs under various forms of administration: orally (PO), intraperitonealy (IP), intraarterialy (IA) and intravenously (IV) to determine its pharmacokinetics properties. It also has been studied in vitro in an aqueous buffer to assess its rate of chemical degradation. Cmax was attained in mice 10 minutes after temozolomide PO and IP administration. Following oral administration in rats, temozolomide was rapidly absorbed and was completely bioavailable 0.25 hours later. Its mean half-life was found to be 1.2 hours and it was independent of the route of administration. This value was lower than the value reported for the degradation in aqueous buffer due to the renal clearance contribution. Terminal phase half-life of temozolomide was similar in sick rats, compared to the value found in healthy rats. The volume of distribution at steady state was larger than in healthy rats and is probably due to the hyperpermeable state and neovascularization of the tumor. Following PO dosing in healthy dogs, temozolomide was rapidly and completely absorbed. Its absolute bioavailability ranged from 95 to 110%. Bioavailability of the toxicology capsule was compared to the clinical capsule in dogs. There was no significant formulation effects seen in Cmax or AUC(I) but there was a decrease in Tmax value indicating a more rapid absorption following administration of the clinical capsule. Temozolomide was mainly excreted in urine and in small amounts in feces. 1.39% (IV) and 1.45% (PO) of the radiocarbon administered to rats was excreted in bile collected 48 hours postdose. After repeated administration, AUC(tf) values for Day 1 and Day 5 of each cycle were the same for all dose levels in both rat and dog except for the 800 mg/m2 given to male rats where the mean AUC(tf) value was higher for Day 5. Since temozolomide was shown to have a short elimination half-life, no accumulation with multiple dosing was expected. Tissue distribution was assessed in rats in two studies. 14C-temozolomide extensively distributed to all tissues. In both studies, high concentrations of radiocarbon were noted in tissues at the late sampling times due to the incorporation of 14C-AIC into the purine biosynthetic pool. Results suggest that temozolomide crosses the blood-brain barrier rapidly and is present in the cerebrospinal fluid. Concentrations in brain and testes appeared highest at 1 hour postdose then decreased slowly; higher levels of radioactivity remained in the kidneys, liver, large and small intestinal wall, salivary gland and testes. No difference was found in tissue concentration related to gender. No metabolites were identified in mouse during an in vitro study. In an in vivo study, it was found that 39% of temozolomide was excreted unchanged and that a small amount of TMA (temozolomide acid metabolite) was also excreted. No other metabolites were seen. In rat, no metabolites were detected through 6 hours. Females excreted the same percentage of parent drug as males did. For dogs, temozolomide represented about 30% of the radiocarbon in plasma by 8 hours postdose.

HUMAN PHARMACOLOGY

Clinical Pharmacology

Temozolomide was rapidly and completely absorbed when administered orally at therapeutic doses to humans. Cmax and AUC increased in a dose-proportional manner. No accumulation occurred on multiple dosing. The volume of distribution, clearance, and half-life were dose- independent, had very low coefficient of variation, and were predictable and reproducible. The major pathways for elimination of temozolomide from plasma were non-enzymatic hydrolysis to MTIC and renal excretion of parent drug. TMA was the only metabolite of significance and accounted for <3% of the dose excreted in urine. Cytochrome P450 (CYP450)-mediated metabolism as assessed by measuring TMA levels did not contribute significantly to the plasma clearance of temozolomide. Consequently, clearance of temozolomide should not be affected to a clinically meaningful degree by interaction of concurrent medications with specific isozymes of CYP450 nor would administration of temozolomide alter by competitive inhibition the metabolism of other drugs. Analysis of data from phase II studies confirmed that clearance of temozolomide was unaffected by 7 medications commonly used by this patient population (i.e., phenytoin, phenobarbital, carbamazepine, dexamethasone, H2-receptor antagonists, prochlorperazine, and ondansetron). Valproic acid was associated with a statistically significant (p=0.019) but clinically insignificant 4.7% decrease in the clearance of temozolomide. Renal disease should not affect temozolomide clearance. This is in agreement with experimental data which demonstrated that age, renal function, hepatic function and use of tobacco did not alter clearance of temozolomide. Female patients had a clinically insignificantly lower clearance of temozolomide than did male patients. Administration of temozolomide with food delayed absorption of temozolomide and resulted in a clinically insignificant 9% decrease in exposure. Compared to adults, pediatric patients over three years of age had higher plasma temozolomide concentrations. This is probably due to their higher body surface area to weight ratio. MTIC degrades to AIC at a much faster rate than its rate of formation from temozolomide. Following oral dosing with temozolomide, the plasma t1/2 for MTIC was the same as that for temozolomide (1.8 hours). Since the volume of distribution for temozolomide and MTIC are approximately the same, the AUC for MTIC could be predicted. The AUC for MTIC was approximately 2-4% of that of temozolomide. Pharmacodynamic evaluations indicated that the primary hematologic toxicities of temozolomide (severe thrombocytopenia and neutropenia) were uncommon during the first cycle. Increasing dose and AUC of temozolomide were associated with an increased incidence of neutropenia and thrombocytopenia. Patients >70 years of age appeared to be at increased risk of neutropenia, although the number of patients in this age subgroup was small (8 patients). The incidence of thrombocytopenia and neutropenia was approximately three times higher in females. Pediatric patients appeared to tolerate higher plasma concentrations of temozolomide before reaching dose limiting toxicity. This is likely due to increased bone marrow reserves in pediatric patients.

TOXICOLOGY

Acute Toxicity

Acute toxicity studies were conducted in both mice and rats. In single dose studies conducted in mice, calculated LD50 values were 891 (males) and 1072 (females) mg/m2 for oral administration and 1297 (males) and 891 (females) mg/m2 for intraperitoneal administration of temozolomide. In rats, LD50 values were 1937 mg/m2 when temozolomide was given orally and 1414 mg/m2 for intraperitoneal administration. Antemortem observations for both mice and rats included hypoactivity, hunched posture and partial closure of the eyes (dose >=1000 mg/m2 generally). Tremors (>=1000 mg/m2 PO, >= 2000 mg/m2 IP), prostration (>=2000 mg/m2) and ataxia (>=4000 mg/m2 IP) were also observed in mice. At necropsy, dark-red areas were observed in the stomachs of male mice at doses >=3000 mg/m2 (PO) or >=2000 mg/m2 (IP) and in female mice at doses >=1000 mg/m2 of temozolomide. Observations for rats included abnormal or few feces (>=1500 mg/m2 PO) and dyspnea (>=2500 mg/m2 PO). When doses reached 5000 mg/m2 orally or more, poor appetite, thin appearance, few or abnormal feces, anorexia and dyspnea were noted. Anorexia and swollen heads were also noted in rats at intraperitoneal doses of >=2000 mg/m2 of temozolomide. At necropsy, dark-red areas were observed in the stomach of rats at oral doses >=1500 mg/m2 and intraperitoneal doses >=2000 mg/m2. Dark areas were also noted in the brain, reproductive organs, lymph nodes, lung, pancreas, cecum and subcutaneous tissue at oral doses >=1500 mg/m2. At intraperitoneal doses >=2000 mg/m2, dark areas were observed in the small intestine (males, 4000 mg/m2), lymph nodes, lung and subcutaneous tissue. Clinical observations in dogs which received a total dose of 3500 mg/m2 of temozolomide over 6 days included emesis, hypoactivity, ataxia, polypnea, mydriasis and discolored mucoid feces. At necropsy, dark-red areas were observed in the stomach and dark-red to brown material in the gastrointestinal tract. Emesis, salivation and abnormal or few feces were noted in dogs administered single oral doses >=200 mg/m2 of temozolomide. All dogs which received 200 or 400 mg/m2 survived the 14-day observation period; dogs administered 600, 1000 or 1500 mg/m2 of temozolomide died or were sacrificed in poor condition before the 14-day period was completed. Necropsy observations at doses 1000 mg/m2 included dark areas in the stomach, lymph nodes, cecum, small intestine, heart, urinary bladder and subcutaneous tissue. There was no gross lesion observed at doses <1000 mg/m2.

Multiple-Dose Toxicity

The toxicity of temozolomide was evaluated in single-cycle, three-cycle and six-cycle studies, in rats and dogs. Results are reported in the following tables.

RATS DOGS

DOSES TOXIC EFFECTS DOSES TOXIC EFFECTS

50 mg/m2 * 1 death (male)

• 9 mean body weight for females (terminal sacrifice)

• 9 weekly food consumption and body weight gain

• 9 mean thymus weight (females)

• 9 testes weights (terminal sacrifice)

• lymphoid depletion of thymus (interim)

• mammary gland carcinoma and carcinoma in situ (few females)

50 mg/m2 * emesis

NO-OBSERVABLE-EFFECT LEVEL

These studies demonstrated that temozolomide was absorbed in a dose-related manner, without sex differences and no evidence of accumulation. The overall carcinogenic potential of temozolomide in rats does not appear significantly different from other chemotherapeutic drugs. Hematologic changes seem to be cyclic: they happened after dosing and were followed by a recovery period.

Carcinogenicity

Carcinogenicity studies of temozolomide have not been conducted. However, the results of the six-cycle study in rats can be used to evaluate the carcinogenic potential of temozolomide. Many types of neoplasms were observed in the six-cycle rat study. They included mammary carcinoma, carcinoma in situ, keratoacanthoma of the skin and basal cell adenoma. Mesenchymal neoplasms included fibrosarcoma, malignant schwannoma, endometrial stromal sarcoma, sarcoma, hemangiosarcoma and fibroma. No tumors or indication of preneoplastic changes were observed in the dog studies. Considering that temozolomide is a prodrug of an alkylating agent, MTIC, its carcinogenic potential is not unexpected.

Mutagenicity

Temozolomide was found to be mutagenic in two studies: an Ames Assay for bacterial mutagenicity and a human peripheral blood lymphocyte assay. Additional in vitro toxicity studies are not being conducted as both assays were positive for mutagenic potential, and neoplasia has been observed in vivo. Since these findings are consistent with other drugs in this class, it is unlikely that in vivo assays would provide additional information that could impact the clinical use of temozolomide or aid in the assessment of human risk. Therefore, no in vivo mutagenic potential studies were conducted.

Reproductive Toxicity

Segment I studies were not conducted with temozolomide. In pregnant rats and rabbits, temozolomide did not affect pregnancy maintenance. The results of the multiple-cycle studies indicate testicular toxicity: reduced absolute testes weights occured in rats at doses of 50 mg/m2 and syncytial cells were observed in the testes of both rats and dogs at doses of 125 mg/m2. These results suggest additional potential reproductive effects including infertility and possibly genetic damage to germ cells. Testing for reproductive toxicity was limited to dose range finding studies in rats and rabbits. No significant maternal toxicity was observed and pregnancy rates were not affected in either species. Dosing did not influence implantation rates or lengths of gestation. Resorptions and post implantation loss were increased at the 150 mg/m2/day dose level, compared to 5, 25 and 50 mg/m2/day dose levels. Fetal weights were reduced at 50 (slight) and 150 mg/m2/day. No external variations or malformations were observed in the rat study. In the rabbit study, 18 different types of malformations were observed in the fetuses of rabbits dosed with 125 mg/m2/day. Based on these results, the developmental NOEL is approximately 50 mg/m2/day. These data indicate that temozolomide, like other alkylating agents, has potential to produce embryolethality and malformations in rats and rabbits. Segment III studies of temozolomide were not conducted. Considering that temozolomide's therapeutic intent is to interfere with mitosis, postnatal growth and development of offspring may be adversely affected by exposure to temozolomide if present in mothers milk.

REFERENCES

1. Bower M, Newlands ES, Bleehen NM, Brada M, et al. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Canc Chemother Pharmacol 1997; 40: 484-488.

2. Brock CS, Matthews JC, Brown G, Newlands ES, et al. In vivo demonstration of 11C temozolomide uptake by human recurrent high grade astrocytomas. Br J Cancer 1997; 75 (8): 1241.

3. Devineni D, Klein-Szanto A, Gallo JM. Uptake of temozolomide in a rat glioma model in the presence and absence of the angiogenesis inhibitor TNP-470. Cancer Research 1996; 56:1983-1987.

4. Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Canc Treat Rev 1997; 23: 35-61.

5. Osoba D, Aaronson NK, Muller M, Sneeuw K, et al. Effect of neurological dysfunction on health-related quality of life in patients with high-grade glioma. J Neuro-Oncol 1997; 34: 263-278.

6. Tsang LLH, Quarterman CP, Gescher A, Slack JA. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4- carboxamide. Cancer Chemother Pharmacol 1991; 27: 342-346.

7. Stupp R, Mason WP, van den Bent MJ, Weller M, et al., Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 2005; 352:987-96.

PART III: CONSUMER INFORMATION

(r)

TEMODAL

temozolomide

This leaflet is part III of a three-part "Product Monograph" published when TEMODAL was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about TEMODAL. Contact your doctor or pharmacist if you have any questions about the drug.

Please read this leaflet carefully before you start to take your medicine. Keep this leaflet. You may want to read it again. Remember, this medicine is for you and must be used as prescribed by your doctor. Never give it to anyone else.

black iron oxide and sometimes potassium hydroxide. 5 mg capsule shells also contain FD & C blue no. 2 and yellow iron oxide. 20 mg capsule shells also contain yellow iron oxide. 100 mg also contains red iron oxide. 140 mg capsule shells also contain FD & C blue no. 2. 180 mg capsule shells also contain yellow and red iron oxides.

What dosage forms it comes in:

Each TEMODAL capsule contains 5 mg (opaque white body with opaque green cap), 20 mg (opaque white body with yellow cap), 100 mg (opaque white body with opaque pink

cap), 140 mg (opaque white body with blue cap), 180 mg

(opaque white body with opaque orange cap), or 250 mg (opaque white body with opaque white cap) temozolomide.

WARNINGS AND PRECAUTIONS

ABOUT THIS MEDICATION

What the medication is used for:

• TEMODAL capsules are used to treat newly diagnosed adult patients with a specific form of brain tumor (glioblastoma multiforme (GBM)) in a combination treatment with radiation.

• TEMODAL capsules are used to treat adult patients with recurrent brain tumours. A recurrent tumour is a tumour that has returned.

What it does:

TEMODAL is an antitumor agent. TEMODAL acts on cancer cells. Normal cells may also be affected which may lead to side effects (See Warnings and Precautions section).

When it should not be used:

This medicine should not be used:

• If you are allergic to TEMODAL (temozolomide) or to any of its ingredients.

• If you have had an allergic reaction to dacarbazine (DTIC), another drug used to treat cancer.

• If some components of your blood are severely reduced.

• If you are pregnant. TEMODAL should not be used by a woman who is pregnant or breast feeding a baby. Both male and female patients should use effective contraceptive precautions while taking TEMODAL and up to six months after stopping treatment (See Warnings and Precautions section).

What the medicinal ingredient is:

TEMODAL medicinal ingredient is temozolomide.

What the nonmedicinal ingredients are:

Non-medicinal ingredients: colloidal silicon dioxide, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid; capsule shells contain gelatin, sodium lauryl sulphate and titanium dioxide and are branded with black printing ink consisting of shellac, propylene glycol, ammonium hydroxide,

BEFORE you use TEMODAL talk to your doctor or pharmacist if:

• If you have anemia (low blood count) or blood clotting problems, your doctor will decide whether

any change in your treatment is needed.

If you vomit frequently.

In Male Patients: TEMODAL can have genotoxic effects which means that it may damage the genetic

material contained in your sperm and cause birth defects. Effective contraception should be used by

male patients taking TEMODAL. Men being treated

with TEMODAL are advised not to father a child during or up to 6 months after treatment and to seek advice on cryoconservation (this is a laboratory technique which involves freezing) of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with TEMODAL.

• Ask your doctor if it is safe for you to drive and operate machinery.

INTERACTIONS WITH THIS MEDICATION

To avoid the possibility of one drug affecting another drug, be sure to advise your doctor or pharmacist of any other medications you are taking. Valproic Acid is an example of such drug interaction.

PROPER USE OF THIS MEDICATION

INFORMATION NECESSARY BEFORE TAKING TEMODAL

IN CASE YOU HAVE ANY QUESTIONS ABOUT THIS MEDICINE IT IS IMPORTANT THAT YOU ASK THE ADVICE OF YOUR DOCTOR OR PHARMACIST.

EACH TIME YOU START A NEW CYCLE TREATMENT, BE SURE YOU UNDERSTAND EXACTLY HOW MANY CAPSULES OF EACH STRENGHT YOU NEED TO TAKE EACH DAY OF DOSING.

IMPORTANT

Note that before each new cycle of your treatment, your blood will be tested and your dose of medicine may change. In some cases, it may be necessary to stop treatment with TEMODAL. Sometime the dose or mix of capsules you need to take will be different from the last cycle.

TEMODAL comes in different strength capsules (shown on the outer label in mg). Each strength has a different colour cap. Depending on the dose of TEMODAL that your doctor prescribes, you may have to take several capsules on each dosing day of the treatment cycle (Day 1 through Day 5, followed by 23 days with no capsules).

Each time you start a new treatment be sure you understand exactly how many capsules of each strength you need to take each day of dosing.

Once you take the medicine home, if you are confused about how to take the dose, call for re-instructions before beginning your treatment cycle.

Be sure you know exactly which days are your dosing day.

Marking them down on a calendar will help you.

Be sure you review the dose with your healthcare provider each time you start a new cycle. ERRORS IN HOW YOU TAKE THE MEDICINE MAY HAVE SERIOUS HEALTH CONSEQUENCES.

Usual dose:

How to take TEMODAL?

Your doctor will determine the correct dose of TEMODAL for you to take, based on your size (height and weight) and whether you have had chemotherapy treatment. You may be

given other medication to take before and/or after TEMODAL

to avoid or control nausea.

Take your prescribed dose of TEMODAL once a day for five days or once a day for 42 days with radiotherapy. Make sure you understand the schedule of dosing. Do not open or chew the capsules. Swallow the capsule(s) whole with a glass of water.

If a capsule is damaged, avoid contact 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.

Although TEMODAL is not affected by food, take your dose preferably before your first food of the day or at least one hour before or after you eat. This will help you lessen nausea or vomiting.

There are 2 dosing schedules.

Patients with a New Diagnosis of GBM:

One schedule with concomitant phase followed by a

maintenance phase. In the first part of your treatment during the concomitant phase, TEMODAL (temozolomide) is prescribed for 42 days (up to 49 days) with radiotherapy. In this phase you will complete your radiotherapy. Your blood will be tested weekly and your treatment maybe interrupted depending on how you tolerate the medicine. After 42 days period, your treatment will be interrupted for 4 weeks to give your body a chance to recover. You will also receive a treatment to prevent a certain kind of pneumonia during this phase.

Then, you will start the next phase of treatment ("maintenance phase") and your TEMODAL dose will change. In this phase, there are 6 treatment cycles (duration approximately 6 months). Each treatment cycle lasts 28 days. You will take your new dose of TEMODAL capsules once daily for the first five days ("dosing days") of each cycle, followed by 23 days without TEMODAL; 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 TEMODAL. Before each new treatment cycle begins, your blood will be tested to determine if the TEMODAL dose needs to be adjusted.

Other schedule for patients with recurrent disease:

In the other schedule a new treatment cycle will begin each 28 days. A treatment cycle with TEMODAL comprises 28 days. You will take the capsules once daily for the first five days

("dosing days") followed by 23 days without TEMODAL,

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 TEMODAL. The dose will depend upon your tolerance during the previous cycle and the results of your blood test.

Overdose

TEMODAL should be taken only as prescribed for you. If you take more capsules that you were told to, advise your doctor or pharmacists immediately. If you are not able to contact

them, go to the nearest hospital emergency department for

medical help. ERRORS IN HOW YOU TAKE THE MEDICINE MAY HAVE SERIOUS HEALTH CONSEQUENCES.

Missed Dose:

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 unless your doctor tells you to do so.

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

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, TEMODAL can have side effects.

Contact your doctor immediately if you have severe allergic reaction (which may include hives, wheezing or other breathing difficulty).

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

If you are taking TEMODAL for the 42 day regimen, in combination with radiation treatment, your doctor will also prescribe medicine to help prevent a serious form of pneumonia called Pneumocystis carinii pneumonia (PCP). There may be a higher occurrence of PCP when TEMODAL is administered during a longer dosing regimen. However, all patients receiving TEMODAL, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen.

The following side effects may occur and medical attention may be required: nausea (feeling sick), vomiting, tiredness, constipation, headache, loss of appetite or weight, diarrhea, sleepiness, fever, cough, rash, weakness, pain, confusion/memory impairment, convulsion, dizziness, blurred vision, dizziness, shortness of breath, upset stomach, hair loss, chills, itching, feeling unwell, change in taste, tingling sensation, and abnormal blood values.

In case of vomiting, ask your doctor about controlling the vomiting, and the best time to take TEMODAL until the vomiting is under control.

Very rare cases of rash with skin swelling, including on the palms of the hands and soles of the feet, have been observed. Tell your doctor if this occurs.

ADVISE YOUR DOCTOR OR PHARMACIST OF ANY UNDESIRABLE OR TROUBLESOME EFFECT NOT LISTED.

Store at room temperature between 15degC and 30degC. Protect from moisture.

Store out of the reach of children.

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

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Schering-Plough Canada Inc., at:

1-800-463-5442

This leaflet was prepared by Schering-Plough Canada Inc. Last revised: June 18, 2008

This is not a complete list of side effects. For any unexpected effects while taking TEMODAL, contact your doctor or pharmacist.

HOW TO STORE IT

Do not use this product after the expiration date on the package.