Temozolomide

DESCRIPTION

TEMODAR Capsules for oral administration contain temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide.

The material is a white to light tan/light pink powder with a molecular formula of C₆H₆N₆O₂ and a molecular weight of 194.15. The molecule is stable at acidic pH < 5, and labile at pH> 7, hence can be administered orally. The prodrug, temozolomide, is rapidly hydrolysed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.

Each capsule contains 5 mg, 20 mg, 100 mg, or 250 mg of temozolomide. The inactive ingredients for TEMODAR CAPSULES are lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and stearic acid. Gelatin capsule shells contain titanium dioxide. The capsules are imprinted with pharmaceutical ink.

TEMODAR 5 mg: green imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, titanium dioxide, yellow iron oxide and FD&C Blue #2 aluminum lake.

TEMODAR 20 mg: brown imprint also contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, titanium dioxide, black iron oxide, yellow iron oxide, brown iron oxide, and red iron oxide.

TEMODAR 100 mg: blue imprint contains pharmaceutical glaze (modified) in an ethanol/shellac mixture, isopropyl alcohol, n-butyl alcohol, propylene glycol, titanium dioxide, and FD &C Blue #2 aluminium lake.

TEMODAR 250 mg: black, imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium 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 p.r.n. 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 ³80.Sixty-three percent of patients had surgery other than a biobsy 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 2 count was ³1.5 x 10⁹ /L (1,500/µL) and the nadir and day 29, Day 1 of next cycle, platlet count was >100 x 10⁹ /L (100,000/µL), 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.

INDICATIONS

TEMODAR (temozolomide) Capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine.

This indication is based on the response rate in the indicated population. No results are available from randomized controlled trials in recurrent anaplastic astrocytoma that demonstrate a clinical benefit resulting from treatment, such as improvement in disease- related symptoms, delayed disease progression, or improved survival.

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) ³1.5 x 10⁹ /L (1,500/µL) and both the nadir and day 29, Day 1 of the next cycle platelet counts are ³100 x 10⁹/L (100,000/µL), the TEMODAR dose may be increased to 200 mg/m²/day for 5 consecutive days per 28 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/µL) and the platelet count exceeds 100 x 10⁹/L (100,000/µL). The next cycle of TEMADOR should not be started until the ANC and the platelet count, exceeds these levels. If the ANC falls to > 1.0 x 10⁹ /L (1,000/µL) or the platelet count the TEMODAR dose may be increased to 200 mg/m²/day for 5 consecutive days per 28 day treatment cycle. If the ANC falls to <1.0 x 10⁹/L (1,000/µL) or the platelet count is < 50 x 10⁹/L (50,000/µL) 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 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/µL) and whose nadir and day 29, Day 1 of next cycle platelet count is >100 x 10⁹/L (100,000/µL).

Table 5. Suggested Capsule Combinations Based on Daily Dose

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.

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 25° (77° F); excursions to 15°-30° C (59°-86° F).

[See USP Controlled Room Temperature]

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 considered ^1-7. 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.

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.

SIDE EFFECTS

Tables 1 and 2 show the incidence of adverse events in the 158 patients in the Anaplastic Astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these events should be attributed to temozolomide or the patients' underlying conditions, but nausea, vomiting, fatigue and hematologic effects appear to be clearly drug-related. The most frequently occurring side effects were nausea, vomiting, headache and fatigue. The adverse events were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC grade 3 or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse event. It usually occurred within the first few cycles of therapy and was not cumulative.

Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. 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. (See WARNINGS). Less than 10% of patients required hospitalization, blood transfusion or discontinuation of therapy due to myelosuppression.

In clinical trial experience with 110-111 women and 169-174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC < 500 cells/µL) thrombocytopenia (< 20,000 cells/µL) in women than men in the first cycle of therapy: (12% versus 5% and 9% versus 3%, respectively).

In the entire Safety database for which hematologic data exist (N= 932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively.

DRUG INTERACTIONS

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

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 CLINICAL PHARMACOLOGY: 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, multicycle 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

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.