Gleostine

1 INDICATIONS AND USAGE Gleostine is an alkylating drug indicated for the treatment of patients with: Brain tumors, primary and metastatic, following appropriate surgical and/or radiotherapeutic procedures. ( 1 ) Hodgkin's lymphoma in combination with other chemotherapies, following disease progression with initial chemotherapy. ( 1 ) 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 DOSAGE AND ADMINISTRATION Recommended dose in adult and pediatric patients is 130 mg/m 2 orally every 6 weeks. ( 2.1 ) Round dose to nearest 10 mg. Give as a single oral dose and do not repeat for at least 6 weeks. 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 3 or 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 : Table 1. Dose Modifications for Gleostine Nadir After Prior Dose Dose Adjustment Leukocytes (/mm 3 ) Platelets (/mm 3 ) ≥ 4000 ≥ 100,000 None 3000 – 3999 75,000 – 99,999 None 2000 – 2999 25,000 – 74,999 Reduce dose by 30% < 2000 < 25,000 Reduce dose by 50%

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS Pulmonary toxicity : Pulmonary infiltrates and/or fibrosis occurs with Gleostine. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis. ( 5.3 ) Secondary malignancies : Acute leukemia and myelodysplasia can occur with long-term use. ( 5.4 ) Hepatotoxicity : Increased levels of transaminases, alkaline phosphatase and bilirubin can occur with Gleostine. Monitor liver function. ( 5.5 ) Nephrotoxicity : Can cause renal failure. Monitor renal function. ( 5.6 ) Embryo-fetal toxicity : Can cause fetal harm. Advise males and females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 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)] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Delayed myelosuppression [see Warnings and Precautions ( 5.1 )] Risks of overdosage [see Warnings and Precautions ( 5.2 )] Pulmonary toxicity [see Warnings and Precautions ( 5.3 )] Secondary malignancies [see Warnings and Precautions ( 5.4 )] Hepatotoxicity [see Warnings and Precautions ( 5.5 )] Nephrotoxicity [see Warnings and Precautions ( 5.6 )] The following adverse reactions associated with the use of Gleostine were identified in clinical trials or postmarketing reports. Because these reactions were reported from a population of uncertain size, it is not possible to estimate their frequency, reliability, or establish a causal relationship to drug exposure. Gastrointestinal disorders: nausea, vomiting, and stomatitis Ocular disorders: optic atrophy, visual disturbances, and blindness Neurologic disorders: disorientation, lethargy, ataxia, and dysarthria Other: alopecia Common adverse reactions include delayed myelosupression, nausea, vomiting, stomatitis, and alopecia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Gleostine exposure in pregnant women. Lomustine was teratogenic in rats and embryotoxic in rabbits at total dose levels 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 BSA [see Data] . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Lomustine was administered by intraperitoneal injection daily to pregnant rats during the period of organogenesis at dose levels of 0, 2, 4, 6, and 8 mg/kg. Resorption rates and post-implantation loss occurred at doses greater than or equal to 4 mg/kg (approximately 0.18 times the clinical dose of 130 mg/m 2 based on BSA or approximately twice the total clinical dose of lomustine over 6 weeks). Malformations (omphalocele, ectopia cordis, scoliosis, syndactyly, hydrocephalus, microphthalmia, anophthalmia, anomalies of aortic arch, dextrocardia, malpositioning of the ovaries and testes, sternoschisis, and shortened/misshapen bone of the fore or hind limbs) and decreased fetal body weight occurred at all dose levels. In pregnant rabbits treated with lomustine at 3 mg/kg (approximately 0.27 times the 130 mg/m 2 clinical dose based on BSA or approximately four times the total clinical dose of lomustine over 6 weeks) during organogenesis, there were increases in abortions and decreases in surviving pup weight that persisted postnatally.