Gleostine

WARNING: DELAYED MYELOSUPPRESSION and RISK OF OVERDOSAGE DELAYED MYELOSUPPRESSION Gleostine causes myelosuppression including fatal myelosuppression. Myelosuppression is delayed, dose-related, and cumulative; occurring 4 to 6 weeks after drug administration and persisting 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 [see Warnings and Precautions ( 5.1 ), Dosage and Administration ( 2.2 , 2.3 )] . RISK OF OVERDOSAGE PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Gleostine. 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 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . WARNING: DELAYED MYELOSUPPRESSION and RISK OF OVERDOSAGE See full prescribing information for complete boxed warning. Delayed Myelosuppression Gleostine causes myelosuppression including fatal myelosuppression. Myelosuppression is delayed, dose-related, and cumulative. Thrombocytopenia is generally more severe than leukopenia. Monitor blood counts and do not give Gleostine more frequently than every 6 weeks. ( 2.2 , 2.3 , 5.1 ) Risk of Overdosage PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of Gleostine. Both physician and pharmacist should emphasize to patient that only one dose of Gleostine is taken every 6 weeks. ( 2.1 , 5.2 , 10 )

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 NextSource Biotechnology at 855- 672-2468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.