TEMODAR (temozolomide)

CAPSULES

DESCRIPTION

1. TEMODAR Capsules for oral administration contain temozolomide, an imidazotetrazine

2. derivative. The chemical name of temozolomide is

3. 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula

4. is:

CONH2

N

N N

N N

CH3 O

1. The material is a white to light tan/light pink powder with a molecular formula of C6H6N6O2 and

2. a molecular weight of 194.15. The molecule is stable at acidic pH (<5), and labile at pH>7,

3. hence can be administered orally. The prodrug, temozolomide, is rapidly hydrolysed to the

4. active 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at neutral and alkaline pH

5. values, with hydrolysis taking place even faster at alkaline pH.

1. Each capsule contains 5 mg, 20 mg, 100 mg, or 250 mg of temozolomide. The inactive

2. ingredients for TEMODAR CAPSULES are lactose anhydrous, colloidal silicon dioxide, sodium

3. starch glycolate, tartaric acid, and stearic acid. Gelatin capsule shells contain titanium dioxide.

4. The capsules are imprinted with pharmaceutical ink.

5. TEMODAR 5 mg: green imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol,

6. isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, titanium dioxide,

7. yellow iron oxide and FD&C Blue #2 aluminum lake.

8. TEMODAR 20 mg: brown imprint also contains pharmaceutical grade shellac, anhydrous ethyl

9. alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium

10. hydroxide, potassium hydroxide, titanium dioxide, black iron oxide, yellow iron oxide, brown

11. iron oxide, and red iron oxide.

12. TEMODAR 100 mg: blue imprint contains pharmaceutical glaze (modified) in an ethanol/shellac

13. mixture, isopropyl alcohol, n-butyl alcohol, propylene glycol, titanium dioxide, and FD & C Blue

14. #2 aluminium lake.

15. TEMODAR 250 mg: black, imprint contains pharmaceutical grade shellac, anhydrous ethyl

16. alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium

17. hydroxide, potassium hydroxide, and black iron oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Temozolomide is not directly active but undergoes rapid non-enzymatic

conversion at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.

Pharmacokinetics:

Temozolomide is rapidly and completely absorbed after oral administration;

peak plasma concentrations occur in 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32 % and 9 %, respectively, and Tmax increased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a modified high fat breakfast. Temozolomide is rapidly eliminated with a mean elimination half- life of 1.8 hours and exhibits linear kinetics over the therapeutic dosing range. Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.

Metabolism and Elimination:

Temozolomide is spontaneously hydrolyzed at physiologic pH to

the active species, 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. About 38% of the administered temozolomide total radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is as unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m2.

Special Populations:

Age:

Population pharmacokinetic analysis indicates that age (range 19-78 years) has no

influence on the pharmacokinetics of temozolomide. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy than patients under 70 years of age. (See Precautions). In the entire safety database, however, there did not appear to be a higher incidence in patients 70 years of age or older. (See Adverse Reactions).

Gender:

Population pharmacokinetic analysis indicates that women have an approximately 5%

lower clearance (adjusted for body surface area) for temozolomide than men. Women have higher incidences of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than men. (See Adverse Reactions)

Race:

The effect of race on the pharmacokinetics of temozolomide has not been studied.

Tobacco Use

: Population pharmacokinetic analysis indicates that the oral clearance of

temozolomide is similar in smokers and non-smokers. Creatinine Clearance: Population pharmacokinetic analysis indicates that creatinine clearance over the range of 36-130 ml/min/m2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr < 36 ml/min/ m2). Caution should be exercised when TEMODAR is administered to patients with severe renal impairment. TEMODAR has not been studied in patients on dialysis.

Hepatically Impaired Patients:

In a pharmacokinetic study, the pharmacokinetics of temozolomide in patients with mild to moderate hepatic impairment (Child's-Pugh Class I - II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.

Pediatrics:

Pediatric patients (3 to 17 years of age) and adult patients have similar clearance and half-life values for temozolomide. There is no clinical experience with the use of TEMODAR in children under the age of 3 years.

Drug-Drug Interactions: In a multiple-dose study, administration of TEMODAR with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC. Population analysis indicates that administration of valproic acid decreases the clearance of temozolomide by about 5% (See Precautions). Population analysis failed to demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.

Clinical Studies:

A single arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Median age of this subgroup of 54 patients was 42 years (19-76). Sixty-five percent were male. Seventy-

two percent of patients had a KPS of $80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2-75.4). TEMODAR was given for the first 5 consecutive days of a 28 day cycle at a starting dose of 150 mg/m2/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was $1.5 x 109/L (1,500/FL) and the nadir and day 29, Day 1 of next cycle, platelet count was >100 x 109/L (100,000/FL), the TEMODAR dose was increased to 200 mg/m2/day for the first 5 consecutive days of a 28 day cycle. In the refractory anaplastic astrocytoma population the overall tumor response rate (CR + PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range of 16 to 114 weeks) and the median duration of complete responses was 64 weeks ( range of 52 to 114 weeks). In this population, progression- free survival at 6 months was 45% (95% confidence interval 31-58%) and progression-free survival at 12 months was 29% (95% confidence interval 16-42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% confidence interval 62- 86%) and 12 month overall survival was 65% (95% confidence interval 52-78%). Median overall survival was 15.9 months.

CONTRAINDICATIONS

TEMODAR (temozolomide) Capsules are contraindicated in patients who have a history of hypersensitivity reaction to any of its components. TEMODAR is also contraindicated in patients who have a history of hypersensitivity to DTIC, since both drugs are metabolized to MTIC.

WARNINGS

Patients treated with TEMODAR may experience myelosuppression. Prior to dosing patients must have an absolute neutrophil count (ANC) 31.5 x 109/L and a platelet count 3100 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 the ANC is above 1.5 x 109/L and platelet count exceeds 100 x 109/L. In the clinical trials, if the ANC fell to <1.0 x 109/L or the platelet count was <50 x 109/L during any cycle, the next cycle was reduced by 50 mg/m2, but not below 100 mg/m2. Patients who do not tolerate 100 mg/m2 should not receive TEMODAR. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Myelosuppression generally occurred late in the treatment cycle. The median nadirs occurred at 26 days for platelets [range 21-40 days] and 28 days for neutrophils [range 1-44 days]. Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir which may have delayed the start of the next cycle. Neutrophil and platelet counts returned to normal, on average, within 14 days of nadir counts (see Precautions). Pregnancy. Temozolomide may cause fetal harm when administered to a pregnant woman. Five consecutive days of oral administration of 75 mg/m2/day in rats and 150 mg/m2/day in rabbits during the period of organogenesis (3/8 and 3/4 the maximum recommended human dose, respectively) caused numerous malformations of the external organs, soft tissues and skeleton in both species. Doses of 150 mg/m2/day in rats and rabbits also caused embryolethality as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TEMODAR.

PRECAUTIONS

Information for Patients:

In clinical trials, the most frequently occurring adverse effects were nausea and vomiting. These were usually either self-limiting or readily controlled with standard anti-emetic therapy. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. The medication should be kept away from children and pets.

Drug Interaction: .

Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known

Patients with Severe Hepatic or Renal Impairment:

Caution should be exercised when TEMODAR is administered to patients with severe hepatic or renal impairment. (See Special Populations).

Geriatrics:

Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should be exercised when treating elderly patients.

In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, p=.31 and 2/10; 20%, p=.09, respectively) in the first cycle of therapy than patients under 70 years of age. (See Adverse Reactions). Laboratory Tests: A complete blood count should be obtained on day 22 (21 days after the first dose). Blood counts should be performed weekly until recovery if the ANC falls below 1.5 x 109/L and the platelet count falls below 100 x 109/L. Carcinogenesis, Mutagenesis and Impairment of Fertility: Standard carcinogenicity studies were not conducted with temozolomide. In rats treated with 200 mg/m2 temozolomide (equivalent to the maximum recommended daily human dose) on 5 consecutive days every 28 days for 3 cycles, mammary carcinomas were found in both males and females. With 6 cycles of treatment at 25, 50 and 125 mg/m2 (about 1/8 - 1/2 the maximum recommended daily human dose), mammary carcinomas were observed at all doses and fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus and prostate; carcinoma of the seminal vesicles, schwannoma of the heart, optic nerve and harderian gland; and adenomas of the skin, lung, pituitary and thyroid were observed at at the high dose. Temozolomide was mutagenic in vitro in bacteria (Ames assay) and clastogenic in mammalian cells (human peripheral blood lymphocyte assays). Reproductive function studies have not been conducted with temozolomide. However, multi- cycle toxicology studies in rats and dogs have demonstrated testicular toxicity (syncytial cells/immature sperm, testicular atrophy) at doses of 50 mg/m2 in rats and 125 mg/m2 in dogs (1/4 and 5/8 respectively of the maximum recommended human dose on a body surface area basis).

Pregnancy Category D. See Warnings Section.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TEMODAR, patients receiving TEMODAR should discontinue nursing.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

OVERDOSAGE

a: Change from grade 0-2 at baseline to grade 3 or 4 during treatment.

Doses of 500, 750, 1,000 and 1,250 mg/m2 (total dose per cycle over five days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported at 1,000 mg/m2 and at 1,250 mg/m2. Up to 1,000 mg/m2 has been taken as a single dose, with only the expected effects of neutropenia and thrombocytopenia resulting. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.

DOSAGE AND ADMINISTRATION

Dosage of TEMODAR must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and neutrophil and platelet counts at the time of initiating the next cycle. The initial dose is 150 mg/m2 orally once daily for 5 consecutive days per 28 day treatment cycle. If both the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are >1.5 x 109/L (1,500/mL) and both the nadir and day 29, Day 1 of next cycle platelet counts are >100 x 109 /L (100,000/mL), the TEMODAR dose may be increased to 200 mg/m2/day for 5 consecutive days per 28 day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1,500/mL) and the platelet count exceeds 100 x 109/L (100,000/mL). The next cycle of TEMODAR should not be started until the ANC and platelet count, exceed these levels. If the ANC falls to <1.0 x 109/L (1,000/mL) or the platelet count is <50 x 109/L (50,000/mL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 3). (See Warnings). TEMODAR therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years; but the optimum duration of therapy is not known. For TEMODAR dosage calculations based on body surface area (BSA), see table 4. For suggested capsule combinations based on daily dose, see table 5.

Table 3 Dosing Modification

150 mg/m5/d x 5d (Starting Dose) or 200 mg/m5/d x 5d Measure Day 22 ANC and platelets Measure ANC and platelets on Day 29 (Day 1 of next cycle) Based on lowest counts at either Day 22 or Day 29

9 9 9

ANC <1,000/FL or platelets <50,000/FL ANC 1,000/FL-1,500/FL or platelets 50,000/FL-100,000/FL ANC >1,500/FL and platelets >100,000/FL

9 9 9

Postpone therapy until ANC >1,500/FL and platelets >100,000/FL; reduce dose by 50 mg/m5/d for subsequent cycle Postpone therapy until ANC >1,500/FL and platelets >100,000/FL; maintain initial dose Increase dose to, or maintain dose at, 200/mg/m5/d x 5d for subsequent cycle Table 4. Daily Dose Calculations by Body Surface Area (BSA) for 5 consecutive days per 28 day treatment cycle for the initial chemotherapy cycle (150 mg/m2) and for subsequent chemotherapy cycles (200 mg/m2) for patients whose nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count (ANC) is >1.5 x 109/L (1,500/FL) and whose nadir and day 29, Day 1 of next cycle platelet count is >100 x 109/L (100,000/FL).

Table 5. Suggested Capsule Combinations Based on Daily Dose Number of Daily Capsules by Strength (mg)

405 0 4 0 1 410 0 4 0 2 415 0 4 0 3 420 0 4 1 0 425 0 4 1 1 430 1 1 4 0 435 0 4 1 3 440 0 4 2 0 445 0 4 2 1 450 1 2 0 0 455 1 2 0 1 460 1 2 0 2 465 1 2 0 3 470 1 2 1 0 475 1 2 1 1 480 1 2 1 2 485 1 2 1 3 490 1 2 2 0 495 1 2 2 1 500 2 0 0 0 In the clinical trial, TEMODAR was administered under both fasting and non-fasting conditions; however, absorption is affected by food (see CLINICAL PHARMACOLOGY) and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide. To reduce nausea and vomiting, temozolomide should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of TEMODAR. TEMODAR (temozolomide) CAPSULES should not be opened or chewed. They should be swallowed whole with a glass of water. Handling and Disposal: Temozolomide causes the rapid appearance of malignant tumors in rats. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. Procedures for proper handling and disposal of anticancer drugs should be considered1-7. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How Supplied:

TEMODAR (temozolomide) Capsules are supplied in amber glass bottles with child-resistant polypropylene caps containing the following capsule strengths: TEMODAR (temozolomide) Capsules 5 mg: 5 and 20 capsule bottles. 5 count - NDC# 0085-1248-01 20 count - NDC# 0085-1248-02 TEMODAR (temozolomide) Capsules 20 mg: 5 and 20 capsule bottles. 5 count - NDC# 0085-1244-01 20 count - NDC# 0085-1244-02 TEMODAR (temozolomide) Capsules 100 mg: 5 and 20 capsule bottles. 5 count - NDC# 0085-1259-01 20 count - NDC# 0085-1259-02 TEMODAR (temozolomide) Capsules 250 mg: 5 and 20 capsule bottles. 5 count - NDC# 0085-1252-01 20 count - NDC# 0085-1252-02

Store at 25o (77oF); excursions to 15-30oC (59-86oF)

[See USP Controlled Room Temperature]

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing office, Washington, DC 20402.

2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 2.53(11):1590-1592.

3. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.

5. Jones RB, et al: Safe Handling Of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm, 1990; 47:1033--1049.

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines), Am J Health-Syst Pharm, 1996; 53:1669-1685.

Patient Package Insert

TEMODAR (temozolomide) Capsules

What is TEMODAR?

TEMODAR is used to treat certain cancerous tumors in the brain of adult patients for whom this tumor has recurred. Your doctor has prescribed TEMODAR (temozolomide) as part of your cancer treatment. TEMODAR is a drug you take by mouth that interferes with cell growth, especially in cells that are growing rapidly, such as cancerous cells. TEMODAR has been shown to help slow the growth of certain cancerous tumors. When given to patients with brain cancer, TEMODAR has been shown to reduce the size of the tumor in some patients.

Who should not take TEMODAR?

You should not take TEMODAR if you have had an allergic reaction to DTIC-Dome (dacarbazine), a different treatment for cancer. If you have had an allergic reaction before to drugs such as DTIC-Dome, be sure to tell your doctor before taking TEMODAR. If you are allergic to drugs similar to TEMODAR you may also have an allergic reaction to TEMODAR.

How should I take TEMODAR?

Take each day's dose of capsules at one time, with a full glass of water. DO NOT open or split the capsules. If the capsules are accidentally opened or damaged, you should be extremely careful to avoid inhaling the powder in the capsules or getting it on your skin or mucous membranes (in nose or mouth). The medication should be kept away from children and pets. They should be swallowed whole and NEVER CHEWED. The medicine is used best by your body if you take it at the same time every day in relation to a meal. To reduce nausea, try to take TEMODAR on an empty stomach or at bedtime. Your doctor may also have prescribed anti- nausea or other medications to relieve the side effects associated with TEMODAR. Anti-nausea medications should be taken as directed by your doctor. It is important that you continue to see your doctor regularly to check your progress. Your doctor can uncover side effects of treatment that you might not notice. Your pharmacist has carefully packaged the TEMODAR capsules for each day of treatment in five separate packets or vials, labeled "Day 1", "Day 2", "Day 3", "Day 4", and "Day 5". On the first day of treatment, you should take all the capsules in the package labeled "Day 1" (as a single dose), on the second day, take all the capsules in the package labeled Day 2 as a single dose, and so on. Don't worry that the capsules that you take on a given day are different sizes or colors. Your doctor and pharmacist have made sure that you will be taking the correct dose on each of the five days of the treatment cycle. If you think your medication has been packaged incorrectly, contact your physician or pharmacist immediately. Because TEMODAR is a drug you take by mouth, you can take it at home. TEMODAR is usually taken for five days in a row over a 28-day period. This period is called a treatment cycle. That means you will take TEMODAR for five days, have a break from therapy for 23 days, and then take the drug for another five days. The number of treatment cycles will depend on how you respond to and tolerate this treatment. Your doctor may have prescribed a treatment regimen that is different from the one discussed in this information sheet. If so, make sure you follow the specific instructions given to you by your doctor. You should talk to your doctor about what to do if you miss a day. If you take more than the prescribed amount of medicine, contact your doctor right away.

What should I avoid while taking TEMODAR?

There are no limitations on what you may eat or drink while taking TEMODAR. However, to ease nausea, try to take TEMODAR on an empty stomach. There are no known interactions with other medications. TEMODAR may cause birth defects. Therefore, male or female patients who take TEMODAR should use effective birth control. Female patients should avoid becoming pregnant while receiving this drug. You should not breast feed an infant while taking TEMODAR. It is not known whether TEMODAR passes into breast milk. Because many drugs do pass into breast milk, there is the possibility of serious harm to nursing infants.

What are the possible or reasonably likely side effects of TEMODAR?

Nausea and vomiting are the most common side effects associated with TEMODAR. Your doctor can prescribe medicines that may help reduce some of these. Other common side effects include headache, feeling tired, and constipation. TEMODAR also can reduce the number of certain types of blood cells, which can have serious effects. Therefore, it is important that your doctor check your blood periodically while you are taking TEMODAR to see if these side effects are occurring. Patients, age 70 or older, women, and patients who have had chemotherapy or radiation therapy may be more likely to have their blood cells affected. There are other side effects associated with TEMODAR. They are included in a longer, more technical information leaflet written for health care providers that you can get from your doctor or pharmacist.

General information about the use of prescription drug products.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Package Insert. You should contact your health care professional regarding any concerns you may have about using TEMODAR. TEMODAR should not be used for a condition for which it was not prescribed, and it should not be given to other persons. Copyright (c) 1999, Schering Corporation, Kenilworth, NJ 07033. All rights reserved. TE0014/22420801

Pharmacist Information Sheet

IMPORTANT DISPENSING INFORMATION

For every patient, each day's dose of TEMODAR must be packaged separately so that, patients take the correct daily dose. Please see the dispensing instructions below for more information.

What is TEMODAR?

TEMODAR (temozolomide) is an oral alkylating agent for the treatment of refractory-anaplastic astrocytoma.

How is TEMODAR dosed?

The daily dose of TEMODAR for a given patient is calculated by the physician, based on the patient's body surface area (BSA). The initial daily dose of TEMODAR in milligrams is the BSA multiplied by 150 (150 mg/m2/day). The resulting dose is then rounded off to the nearest 5 mg. For example, the daily dose for a patient with a BSA of 1.84 is 1.84 x 150 = 276, or 275 mg/day. The dose for subsequent cycles may be adjusted according to nadir neutrophil and platelet counts in the previous cycle and at the time of initiating the next cycle.

How might the dose of TEMODAR be modified?

Dosage of TEMODAR must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and neutrophil and platelet counts at the time of initiating the next cycle. The initial dose is 150 mg/m2 orally once daily for 5 consecutive days per 28 day treatment cycle. If both the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are >1.5 x 109/L (1,500/mL) and both the nadir and day 29, Day 1 of next cycle platelet counts are >100 x 109 /L (100,000/mL), the TEMODAR dose may be increased to 200 mg/m2/day for 5 consecutive days per 28 day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1,500/mL) and the platelet count exceeds 100 x 109/L (100,000/mL). The next cycle of TEMODAR should not be started until the ANC and platelet count, exceed these levels. If the ANC falls to <1.0 x 109/L (1,000/mL) or the platelet count is <50 x 109/L (50,000/mL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see table below).

Dosing Modification Table

150 mg/m5/d x 5d (Starting Dose) or 200 mg/m5/d x 5d Measure Day 22 ANC and platelets Measure ANC and platelets on Day 29 (Day 1 of next cycle) Based on lowest counts at either Day 22 or Day 29

9 9 9

ANC <1,000/FL or platelets <50,000/FL ANC 1,000/FL-1,500/FL or platelets 50,000/FL-100,000/FL ANC >1,500/FL and platelets >100,000/FL

9 9 9

Postpone therapy until ANC >1,500/FL and platelets >100,000/FL; reduce dose by 50 mg/m5/d for subsequent cycle Postpone therapy until ANC >1,500/FL and platelets >100,000/FL; maintain initial dose Increase dose to, or maintain dose at, 200/mg/m5/d x 5d for subsequent cycle

What is the TEMODAR treatment regimen?

TEMODAR is given for five consecutive days on a 28-day cycle. Patients should continue taking TEMODAR until their physician determines that their disease has progressed, up to 2 years, or until unacceptable side effects or toxicities occur. Physicians may alter the treatment regimen for a given patient.

How is TEMODAR taken?

Patients should take each day's dose with a full glass of water at the same time each day. Taking the medication on an empty stomach or at bedtime may help ease nausea. If patients are also taking anti-nausea or other medications to relieve the side effects associated with TEMODAR, they should be advised to take these medications 30 minutes before they take TEMODAR. Temozolomide causes the rapid appearance of malignant tumors in rats. Patients SHOULD NOT open or split the capsules. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. The medication should be kept away from children and pets. The TEMODAR capsules should be swallowed whole and NEVER CHEWED.

What should the patient avoid during treatment with TEMODAR

?

There are no dietary restrictions for patients taking TEMODAR. There are no known interactions with other medications. TEMODAR may affect testicular function so male patients should exercise adequate birth control measures. TEMODAR may cause birth defects. Female patients should avoid becoming pregnant while receiving this drug. Women who are nursing prior to receiving TEMODAR should discontinue nursing. It is not known whether TEMODAR is excreted into breast milk.

What are the side effects of TEMODAR?

Nausea and vomiting are the most common side effects associated with TEMODAR. Non- cumulative myelosuppression is the dose-limiting toxicity. Patients should be evaluated periodically by their physician to monitor blood counts.

Other commonly reported side effects reported by patients taking TEMODAR are

fatigue,constipation and headache

How is TEMODAR supplied?

TEMODAR capsules are available in 250mg, 100mg, 20mg, and 5mg strengths. The capsules are color coded according to strength. TEMODAR Capsule

Strength Color

5 mg Green 20 mg Brown 100 mg Blue 250 mg Black All capsule strengths are available in 5-count and 20-count packages.

How is TEMODAR dispensed?

For a given prescription, each day's dose of TEMODAR must be packaged separately so that, patients take the correct dose each day. Follow the instructions below: Determine the number of capsules of each strength needed to add up to the daily dose prescribed by the physician (eg, 275 mg/day = 1 x 250mg capsule, 1 x 20mg capsule and 1 x 5mg capsule). Place one day's supply of TEMODAR in each of five separate packets or vials. In the above prescription for 275 mg/day, each of the five packets or vials should contain 1 x 250mg capsule, 1 x 20mg capsule and 1 x 5mg capsule. Label the five packages as Day 1, Day 2, Day 3, Day 4, and Day 5, using the labels enclosed. Dispense to the patient, making sure that he or she understands that each day's dose of TEMODAR is packaged separately.

How can TEMODAR be ordered?

TEMODAR can be ordered from your wholesaler. Remember to order enough TEMODAR for a full five-day cycle. For example, a five-day course of 275 mg/day would require the following to be ordered: 1 5-count package of 250mg capsules 1 5-count package of 20mg capsules 1 5-count package of 5mg capsules

Copyright (c) 1999, Schering Corporation, Kenilworth, NJ 07033. All rights reserved. TE0011/22420402