LOMUSTINE

1 INDICATIONS AND USAGE Lomustine Capsules are 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 Lomustine Capsules are indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures. 1.2 Hodgkin’s Lymphoma Lomustine Capsules are indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin’s lymphoma whose disease has progressed following initial chemotherapy.

1.1 Brain Tumors Lomustine Capsules are indicated for the treatment of patients with primary and metastatic brain tumors following appropriate surgical and/or radiotherapeutic procedures.

1.2 Hodgkin’s Lymphoma Lomustine Capsules are 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 5 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 Lomustine 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 Lomustine Capsules are 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) ]. Lomustine Capsules 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 Lomustine Capsules. Do not break Lomustine 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 Lomustine Capsules in adult and pediatric patients is 130 mg/m 2 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/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 Lomustine Capsules according to the hematologic response of the preceding dose as described in Table 1: Table 1. Dose Modifications for Lomustine Capsules 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%

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 Lomustine 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 Lomustine Capsules are 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) ]. Lomustine Capsules 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 Lomustine Capsules. Do not break Lomustine 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 Lomustine Capsules in adult and pediatric patients is 130 mg/m 2 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/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 …

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

4 CONTRAINDICATIONS None.

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 Lomustine Capsules 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 Carnegie Pharmaceuticals LLC at 1-732-783-7010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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, Lomustine Capsules can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data on Lomustine Capsules 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 Lomustine Capsules, advise women not to breastfeed during treatment with Lomustine Capsules 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, Lomustine Capsules 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 Lomustine Capsules's mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with Lomustine Capsules and for 3.5 months after the final dose [see Clinical Pharmacology (12.1) ]. Infertility Based on animal findings and its mechanism of action, Lomustine Capsules 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 Lomustine Capsules 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 ren …

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.

11 DESCRIPTION Lomustine Capsules, USP (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: Lomustine Capsules, USP are supplied as 10 mg, 40 mg, and 100 mg capsules and contain the following inactive ingredients: magnesium stearate NF and mannitol USP. The 10 mg capsule shells are composed of gelatin and titanium dioxide. The 40 mg and 100 mg capsule shells are composed of FD&C blue #1, gelatin, iron oxide black, iron oxide yellow, and titanium dioxide. The capsules are printed with black ink composed of iron oxide black, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. FDA approved dissolution method is not listed in the USP Monograph for Lomustine Capsules, USP, 10 mg, 40 mg, and 100 mg. image description

10 OVERDOSAGE Overdosage with Lomustine Capsules 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 Lomustine Capsules overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Lomustine Capsules, USP are 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 Hard gelatin capsule shell with light green opaque body and light green opaque cap, imprinted with black ink “CP116” on cap, containing white powder. 80005-116-02 40 mg Hard gelatin capsule shell with light green opaque body and bright white opaque cap, imprinted with black ink “CP115” on cap, containing white powder. 80005-115-02 10 mg Hard gelatin capsule shell with bright white opaque body and bright white opaque cap, imprinted with black ink “CP114” on cap, containing white powder. 80005-114-02 16.2 Storage and Handling Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Avoid temperatures over 40°C (104°F). Lomustine Capsules, USP 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 Lomustine Capsules, USP. Do not break Lomustine Capsules, USP; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.

16.1 How Supplied Lomustine Capsules, USP are 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 Hard gelatin capsule shell with light green opaque body and light green opaque cap, imprinted with black ink “CP116” on cap, containing white powder. 80005-116-02 40 mg Hard gelatin capsule shell with light green opaque body and bright white opaque cap, imprinted with black ink “CP115” on cap, containing white powder. 80005-115-02 10 mg Hard gelatin capsule shell with bright white opaque body and bright white opaque cap, imprinted with black ink “CP114” on cap, containing white powder. 80005-114-02

16.2 Storage and Handling Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Avoid temperatures over 40°C (104°F). Lomustine Capsules, USP 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 Lomustine Capsules, USP. Do not break Lomustine Capsules, USP; avoid exposure to broken capsules. If dermal contact occurs, wash areas of skin contact immediately and thoroughly.