Prescription Drugs

CLINICAL PHARMACOLOGY 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. Pharmacodynamic The pharmacodynamics of lomustine are unknown. 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/m² to 100 mg/m², 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.

Find Lowest Prices on GLEOSTINE® (lomustine) Capsules 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, DOSAGE AND ADMINISTRATION]. 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, WARNINGS AND PRECAUTIONS, OVERDOSAGE]. DESCRIPTION Gleostine (lomustine) is an alkylating drug for oral administration. The chemical name for lomustine is 1-(2chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C9H16ClN3O2. 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 5 mg, 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.

INDICATIONS Brain Tumors Gleostine is indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures. 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. DOSAGE AND ADMINISTRATION 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 and OVERDOSAGE]. 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. Recommended Dose The recommended dose of Gleostine in adult and pediatric patients is 130 mg/m² taken as a single oral dose every 6 weeks. Round doses to the nearest 5 mg. Give as a single oral dose and do not repeat for at least 6 weeks. Reduce dose to 100 mg/m² every 6 weeks in patients with compromised bone marrow function. Also reduce dose accordingly when using with other myelosuppressive drugs. 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/mm³ or greater and leukocytes recover to 4000/mm³or greater [see WARNINGS AND PRECAUTIONS]. 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 (/mm³) Platelets (/mm³) ≥ 4000 ≥ 100,000 None 3000 - 3999 75,000 - 99,999 None 2000 - 2999 25,000 - 74,999 Reduce dose by 70% < 2000 < 25,000 Reduce dose by 50% HOW SUPPLIED Dosage Forms And Strengths Gleostine capsules are available in four strengths, distinguishable by the color of the capsules: 100 mg capsules (green/green) 40 mg capsules (white/green) 10 mg capsules (white/white) 5 mg capsules (yellow/yellow) Gleostine is available in four 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 5 mg Yellow cap and body, imprinted in black ink, with “CPL” over “3033” on the cap and “5 mg” on the body of the capsule. 58181-3043-5 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. REFERENCES OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. Manufactured by Corden Pharma Latina S.p.A., Sermoneta (LT), Italy for: NextSource Biotechnology, LLC Miami, FL 33155 USA. Revised: Jan 2016

PATIENT 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]. Overdosage Advise patients that toxicity including fatal toxicity occurs with Gleostine overdosage [see WARNINGS AND PRECAUTIONS, OVERDOSAGE, DOSAGE AND ADMINISTRATION]. 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]. Hepatotoxicity Inform patients that Gleostine can cause hepatotoxicity and that liver function monitoring during treatment is necessary [see WARNINGS AND PRECAUTIONS]. Nephrotoxicity Inform patients that Gleostine can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary [see WARNINGS AND PRECAUTIONS]. 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, Use In Specific Populations]. 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]. Advise male patients with female partners of reproductive potential to use condoms during treatment with Gleostine and for 4 months after the final dose [see Use in Specific Populations]. Lactation Advise women not to breastfeed during treatment with Gleostine and for 2 weeks after the final dose [see Use in Specific Populations]. Infertility Advise females and males of reproductive potential of the potential for reduced fertility from Gleostine [see Use in Specific Populations  and Nonclinical Toxicology].

OVERDOSE Overdosage with Gleostine has occurred, including fatal cases [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. 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. CONTRAINDICATIONS None.

SIDE EFFECTS Hematologic Toxicity The most frequent and most serious toxicity of Gleostine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Gleostine and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m² develop white blood counts below 5000 wbc/mm³. Thirty-six percent developed white blood counts below 3000 wbc/mm³. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities. Gleostine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses. The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy. Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia. Pulmonary Toxicity Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with Gleostine. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Gleostine usually greater than 1100 mg/m² . There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1–16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis. Gastrointestinal Toxicity Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Gleostine is administered to fasting patients. Hepatotoxicity A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving Gleostine. Nephrotoxicity Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Gleostine. Kidney damage has also been reported occasionally in patients receiving lower total doses. Other Toxicities Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently. Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Gleostine. However, the relationship to medication in these patients is unclear. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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]. 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 and OVERDOSAGE]. 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 (DLCO) 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/m². Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis. Secondary Malignancies Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use. Hepatotoxicity Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs with Gleostine. Monitor liver function. Nephrotoxicity Progressive renal failure with a decrease in kidney size occurs with Gleostine. Monitor renal function. 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/m² over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m²) 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]. Nonclinical Toxicology 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/m² 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/m² 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/m² 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. Use In Specific Populations 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]. 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/m² over 6 weeks (0.18 to 0.27 times the single human dose of 130 mg/m²) 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/m² based on BSA or approximately twice the total clinical dose of lomustine over 6 weeks). Malformations (omphalocele, ectepia 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/m² 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. 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. 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]. 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]. 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]. Pediatric Use Pediatric use, including dose, is not based on adequate and well-controlled clinical studies. 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. REFERENCES OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.