1.1 Brain Tumors

Gleostine is indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures.

1.2 Hodgkin's Lymphoma

Gleostine is indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin's lymphoma whose disease has progressed following initial chemotherapy.

2.1 Important Prescribing and Dispensing Information

PRESCRIBE ONLY ONE DOSE FOR EACH TREATMENT CYCLE. DO NOT DISPENSE ENTIRE CONTAINER. Dispense only a sufficient number of capsules for one dose.

Confirm the total dose prescribed by the physician and the appropriate combination of capsule strengths.

Dispense only the appropriate number of Gleostine capsules required for the administration of a single dose.

The prescribed dose may consist of two or more different strengths and colors of capsules.

Instruct patients that Gleostine is taken as a single oral dose and will not be repeated for at least 6 weeks. Taking more than the recommended dose causes toxicities, including fatal outcomes [see Warnings and Precautions ( 5.2) and Overdosage ( 10)] .

Gleostine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

2.2 Recommended Dose

The recommended dose of Gleostine in adult and pediatric patients is 130 mg/m 2 taken as a single oral dose every 6 weeks. Round doses to the nearest 10 mg. Give as a single oral dose and do not repeat for at least 6 weeks. Reduce dose to 100 mg/m 2 every 6 weeks in patients with compromised bone marrow function. Also reduce dose accordingly when using with other myelosuppressive drugs.

2.3 Dose Modifications

Perform weekly complete blood counts and withhold each subsequent dose for more than 6 weeks if needed until platelet counts recover to 100,000/mm 3 or greater and leukocytes recover to 4000/mm 3or greater [see Warnings and Precautions ( 5.1)] .

Modify each dose of Gleostine according to the hematologic response of the preceding dose as described in Table 1:

5.1 Delayed Myelosuppression

Gleostine causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Gleostine is delayed, dose-related, and cumulative. It usually occurs 4 to 6 weeks after drug administration and persists for 1 to 2 weeks. Thrombocytopenia is generally more severe than leukopenia. Cumulative myelosuppression from Gleostine is manifested by greater severity and longer duration of cytopenias.

Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose [see Dosage and Administration ( 2.3)].

5.2 Risk of Overdosage

Fatal toxicity occurs with overdosage of Gleostine. Dispensing or administering more than one dose can lead to fatal toxicity.

Prescribe only one dose at a time. Dispense only enough capsules for one dose. Both physician and pharmacist should emphasize to the patient that only one dose of Gleostine is taken every 6 weeks [see Dosage and Administration ( 2.1) and Overdosage ( 10)].

5.3 Pulmonary Toxicity

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Gleostine. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DL CO) are at increased risk. The onset of pulmonary toxicity occurs after an interval of 6 months or longer from the start of therapy, with cumulative doses of Gleostine usually greater than 1100 mg/m 2.

Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis.

5.4 Secondary Malignancies

Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use.

5.5 Hepatotoxicity

Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs with Gleostine.

Monitor liver function.

5.6 Nephrotoxicity

Progressive renal failure with a decrease in kidney size occurs with Gleostine.

Monitor renal function.

5.7 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats and rabbits receiving lomustine daily during organogenesis at doses approximately two to four times the total human dose of 130 mg/m 2 over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m 2) based on body surface area (BSA). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Gleostine and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gleostine and for 3.5 months after the final dose [see Use in Specific Populations ( 8.1, 8.3)] .

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Contraception

8.4 Pediatric Use

Pediatric use, including dose, is not based on adequate and well-controlled clinical studies.

8.5 Geriatric Use

No data in the clinical studies of Gleostine are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

12.1 Mechanism of Action

Lomustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

12.2 Pharmacodynamics

The pharmacodynamics of lomustine are unknown.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses lower than those employed clinically.

In female rats, daily intraperitoneal treatment with lomustine for 2 weeks prior to mating with untreated males resulted in dose dependent decreases in number of corpora lutea and resorption rates with no live births at a dose of 3 mg/kg (approximately 0.14 times the recommended clinical dose of 130 mg/m 2 based on body surface area (BSA), or approximately twice the total clinical dose of lomustine over 6 weeks) and decreased pup survival during the first 4 postnatal days at doses greater than or equal to 1.5 mg/kg (a daily dose of approximately 0.06 times the recommended clinical dose of 130 mg/m 2 based on BSA or approximately equal to the total clinical dose of lomustine over 6 weeks). Gleostine may also result in decreased male fertility. Intraperitoneal injection of lomustine resulted in decreased fertility in male rats mated to untreated females based on decreased implantations and decreased fetal body weight at weekly doses greater than or equal to 5 mg/kg (approximately 0.23 times the single clinical dose of 130 mg/m 2 based on BSA, or approximately equal to the total clinical dose of lomustine over 6 weeks), and increased resorptions at doses greater than or equal to 2.5 mg/kg/week.

16.1 How Supplied

Gleostine is available in three strengths, distinguishable by the color of the capsules, in individual bottles of 5 capsules each:

16.2 Storage and Handling

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid temperatures over 40°C (104°F).

Gleostine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

Myelosuppression

Advise patients that periodic assessment of their blood counts are required. Advise patients to contact their healthcare provider for new onset of bleeding or fever or symptoms of infection [see Warnings and Precautions ( 5.1)].

Overdosage

Advise patients that toxicity including fatal toxicity occurs with Gleostine overdosage [see Warnings and Precautions ( 5.2), Overdosage ( 10), Dosage and Administration ( 2.1)].

Advise patients to take Gleostine as directed:

•

Gleostine is taken as a single oral dose that will not be repeated for at least 6 weeks.

•

Use of the recommended dose at less than 6 week intervals leads to toxicities including fatal toxicities.

•

Each dose may consist of 2 or more different strengths and colors of capsules.

Pulmonary Fibrosis

Advise patients to contact their healthcare provider for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions ( 5.3)] .

Hepatotoxicity

Inform patients that Gleostine can cause hepatotoxicity and that liver function monitoring during treatment is necessary [see Warnings and Precautions ( 5.5)].

Nephrotoxicity

Inform patients that Gleostine can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary [see Warnings and Precautions ( 5.6)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.7), Use in Specific Populations ( 8.1)] .

Advise females of reproductive potential to use effective contraception during treatment with Gleostine and for at least 2 weeks after the final dose [see Use in Specific Populations ( 8.3)].

Advise male patients with female partners of reproductive potential to use condoms during treatment with Gleostine and for 3.5 months after the final dose [see Use in Specific Populations ( 8.3)] .

Lactation

Advise women not to breastfeed during treatment with Gleostine and for 2 weeks after the final dose [see Use in Specific Populations ( 8.2)].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from Gleostine [see Use in Specific Populations ( 8.3) and Nonclinical Toxicology ( 13.1)].

Manufactured by Corden Pharma Latina S.p.A., Sermoneta (LT), Italy for:
NextSource Biotechnology, LLC
Miami, FL 33130 USA