TEMOZOLOMIDE (Page 5 of 7)

14 CLINICAL STUDIES

14.1 Newly Diagnosed Glioblastoma

The efficacy of temozolomide was evaluated in MK-7365-051 (NCT00006353), a randomized (1:1), multicenter, open-label trial. Eligible patients were required to have newly diagnosed glioblastoma. Patients were randomized to receive either radiation therapy alone or concomitant temozolomide 75 mg/m2 once daily starting the first day of radiation therapy and continuing until the last day of radiation therapy for 42 days (with a maximum of 49 days), followed by temozolomide 150 mg/m2 or 200 mg/m2 once daily on Days 1 to 5 of each 28-day cycle, starting 4 weeks after the end of radiation therapy and continuing for 6 cycles. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions and included radiation to the tumor bed or resection site with a 2- to 3-cm margin. PCP prophylaxis was required during the concomitant phase regardless of lymphocyte count and continued until recovery of lymphocyte count to Grade 1 or less. The major efficacy outcome measure was overall survival.

A total of 573 patients were randomized, 287 to temozolomide and radiation therapy and 286 to radiation therapy alone. At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the radiation therapy alone arm and 62 patients of the 277 (22%) in the temozolomide and radiation therapy arm.

The addition of concomitant and maintenance temozolomide to radiation therapy for the treatment of patients with newly diagnosed glioblastoma showed a statistically significant improvement in overall survival compared to radiotherapy alone (Figure 1). The hazard ratio (HR) for overall survival was 0.63 (95% CI: 0.52, 0.75) with a log-rank P <0.0001 in favor of the temozolomide arm. The median overall survival was 14.6 months in the temozolomide arm and 12.1 months for radiation therapy alone arm.

FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population) in Patients with Newly Diagnosed Glioblastoma in MK-7365-051
temozolomide-figure-01
(click image for full-size original)

14.2 Anaplastic Astrocytoma

Newly Diagnosed Anaplastic Astrocytoma
The efficacy of temozolomide for the adjuvant treatment of newly diagnosed anaplastic astrocytoma was derived from studies of temozolomide in the published literature. Temozolomide was evaluated in CATNON (NCT00626990), a randomized, open-label, multicenter trial, where the major efficacy outcome measure was overall survival.

Refractory Anaplastic Astrocytoma

The efficacy of temozolomide was evaluated in Study MK-7365-006, a single-arm, multicenter trial. Eligible patients had anaplastic astrocytoma at first relapse and a baseline Karnofsky performance status (KPS) 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). Temozolomide capsules were given on Days 1 to 5 of each 28-day cycle at a starting dose of 150 mg/m2 /day. If ANC was ≥1.5 x 109 /L and platelet count was ≥100 x 109 /L at the nadir and on Day 1 of the next cycle, the temozolomide dose was increased to 200 mg/m2 /day. The major efficacy outcome measure was progression-free survival at 6 months and the additional efficacy outcome measures were overall survival and overall response rate.

In the refractory anaplastic astrocytoma population (n=54), the median age was 42 years (range: 19 to 76); 65% were male; and 72% 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 (range: 4.2 months to 6.3 years).

In the refractory anaplastic astrocytoma population, the overall response rate (CR+PR) was 22% (12 of 54 patients) and the complete response rate was 9% (5 of 54 patients). The median duration of all responses was 50 weeks (range: 16 to 114 weeks) and the median duration of complete responses was 64 weeks (range: 52 to 114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%, 58%) and progression-free survival at 12 months was 29% (95% CI: 16%, 42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%, 86%) and 12-month overall survival was 65% (95% CI: 52%, 78%). Median overall survival was 15.9 months.

15 REFERENCES

  1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/hazardous-drugs

16 HOW SUPPLIED/STORAGE AND HANDLING

Temozolomide is a hazardous drug. Follow applicable special handling and disposal procedures.1

Temozolomide Capsules, USP are supplied in HDPE plastic bottles with child-resistant polypropylene caps containing the following capsule strengths:

Temozolomide Capsules, USP 5 mg: have opaque white bodies with opaque light green caps. The capsule body is printed with “604” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-816-51
14 count: NDC 16571-816-41

20 count: NDC 16571-816-02

Temozolomide Capsules, USP 20 mg: have opaque white bodies with opaque rich yellow caps. The capsule body is printed with “605” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-817-51
14 count: NDC 16571-817-41

20 count: NDC 16571-817-02

Temozolomide Capsules, USP 100 mg: have opaque white bodies with opaque pink caps. The capsule body is printed with “606” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-818-51
14 count: NDC 16571-818-41

20 count: NDC 16571-818-02

Temozolomide Capsules, USP 140 mg: have opaque white bodies with opaque powder blue caps. The capsule body is printed with “607” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-819-51
14 count: NDC 16571-819-41

20 count: NDC 16571-819-02

Temozolomide Capsules, USP 180 mg: have opaque white bodies with opaque swedish orange caps. The capsule body is printed with “608” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-820-51
14 count: NDC 16571-820-41

20 count: NDC 16571-820-02

Temozolomide Capsules, USP 250 mg: have opaque white bodies with opaque white caps. The capsule body is printed with “609” in black ink and the cap is printed with “LP” in black ink. They are supplied as follows:

5 count: NDC 16571-821-51
20 count: NDC 16571-821-02

Store Temozolomide Capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression

Inform patients that temozolomide capsules can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)].

Hepatotoxicity

Advise patients of the increased risk of hepatotoxicity and to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity. Inform patients that they will have periodic liver enzyme tests during treatment and following the last dose of temozolomide capsules [see Warnings and Precautions (5.2)].

Pneumocystis Pneumonia

Advise patients of the increased risk of Pneumocystis pneumonia and to contact their healthcare provider immediately for new or worsening pulmonary symptoms. Inform patients that prophylaxis for Pneumocystis pneumonia may be needed [see Dosage and Administration (2.1), Warnings and Precautions (5.3)].

Secondary Malignancies
Advise patients of the increased risk of myelodysplastic syndrome and secondary malignancies [see Warnings and Precautions (5.4)].

Exposure to Opened Capsules
Advise patient to not open, chew, or dissolve the capsules. If capsules are accidentally opened or damaged, advise patients to take rigorous precautions with capsule contents to avoid inhalation or contact with the skin or mucous membranes [see Warnings and Precautions (5.6)]. In case of powder contact, wash the affected area with water immediately [see Dosage and Administration (2.4)].

Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Lactation

Advise women not to breastfeed during treatment with temozolomide and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males of reproductive potential that temozolomide may impair fertility [see U se in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Manufactured for:
Rising Pharma Holdings, Inc.
East Brunswick, NJ 08816
Made in India
Code No.: TS/DRUGS/24/2015
Revised: 03/2024
PIR82120-02

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