Gleostine

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.

4 CONTRAINDICATIONS None.

11 DESCRIPTION Gleostine (lomustine) is an alkylating drug for oral administration. The chemical name for lomustine is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C 9 H 16 ClN 3 O 2 . The molecular weight is 233.71. Lomustine is a yellow powder, which is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is insoluble in water (<0.05 mg per mL). The chemical structure is: Gleostine is supplied as 10 mg, 40 mg, and 100 mg capsules and contains the following inactive ingredients: magnesium stearate NF and mannitol USP. The capsule shells are composed of gelatin and coloring pigments, depending on the strength: titanium dioxide, and/or yellow iron oxide, and/or Indigotine – FD&C Blue2. Chemical Structure

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%

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.

10 OVERDOSAGE Overdosage with Gleostine has occurred, including fatal cases [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.2 )]. Overdosage causes severe myelosuppression, as well as abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath. No antidotes exist for Gleostine overdosage.

12 CLINICAL PHARMACOLOGY 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 Distribution Lomustine crosses the blood-brain barrier. Elimination The serum half-life of lomustine metabolites ranges from 16 hours to 48 hours. Metabolism Metabolic pathways involved in the elimination of lomustine have not been characterized. Excretion Following oral administration of radioactive lomustine at doses ranging from 30 mg/m 2 to 100 mg/m 2 , approximately half of the radioactivity administered was excreted in the urine in the form of degradation products within 24 hours. Specific Populations The impact of patient specific (e.g., age, sex, and race) or disease (e.g., renal or hepatic impairment) characteristics on the pharmacokinetics of lomustine is unknown.

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.

12.3 Pharmacokinetics Distribution Lomustine crosses the blood-brain barrier. Elimination The serum half-life of lomustine metabolites ranges from 16 hours to 48 hours. Metabolism Metabolic pathways involved in the elimination of lomustine have not been characterized. Excretion Following oral administration of radioactive lomustine at doses ranging from 30 mg/m 2 to 100 mg/m 2 , approximately half of the radioactivity administered was excreted in the urine in the form of degradation products within 24 hours. Specific Populations The impact of patient specific (e.g., age, sex, and race) or disease (e.g., renal or hepatic impairment) characteristics on the pharmacokinetics of lomustine is unknown.

20230329

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3 DOSAGE FORMS AND STRENGTHS Gleostine capsules are available in three strengths, distinguishable by the color of the capsules: 100 mg capsules (green/green) 40 mg capsules (white/green) 10 mg capsules (white/white) Capsules: 10 mg, 40 mg, and 100 mg ( 3 )

Gleostine lomustine MAGNESIUM STEARATE MANNITOL LOMUSTINE LOMUSTINE green white CAPSULE CPL;3031;40;mg Gleostine lomustine MAGNESIUM STEARATE MANNITOL LOMUSTINE LOMUSTINE white CAPSULE CPL;3030;10;mg Gleostine lomustine MAGNESIUM STEARATE MANNITOL LOMUSTINE LOMUSTINE green CAPSULE CPL;3032;100;mg

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.

13 NONCLINICAL TOXICOLOGY 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.

NDA017588

Gleostine

lomustine

58181-3040

HUMAN PRESCRIPTION DRUG

ORAL

Principal Display Panel - Carton Label NDC 58181-3040-5 5 capsules Gleostine ® (lomustine) Capsules 10 mg per capsule Caution: DO NOT DISPENSE ENTIRE CONTAINER. Dispense only enough capsules for one dose. Rx Only NEXTSOURCE Biotechnology 10 mg Carton

17 PATIENT COUNSELING INFORMATION 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 Logo

15 REFERENCES OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

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.

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

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.

8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed. ( 8.2 ) 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. 8.2 Lactation Risk Summary There is no information on the presence of lomustine or its metabolites in human milk, its effects on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Gleostine, advise women not to breastfeed during treatment with Gleostine and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Based on animal data and its mechanism of action, Gleostine can cause fetal harm [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose. Males Based on Gleostine's mechanism of action, 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 Clinical Pharmacology ( 12.1 )] . Infertility Based on animal findings and its mechanism of action, Gleostine may result in reduced fertility in males and females of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Gleostine is available in three strengths, distinguishable by the color of the capsules, in individual bottles of 5 capsules each: Strength Capsule Description NDC Code 100 mg Moss green cap and body, imprinted in black ink, with "CPL" over "3032" on the cap and "100 mg" on the body of the capsule. 58181-3042-5 40 mg White cap and a moss green body, imprinted in black ink, with "CPL" over "3031" on the cap and "40 mg" on the body of the capsule. 58181-3041-5 10 mg White cap and body, imprinted in black ink, with "CPL" over "3030" on the cap and "10 mg" on the body of the capsule 58181-3040-5 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.

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.

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 )