LOMUSTINE: 1,614 Adverse Event Reports & Safety Profile

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

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.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Overdosage (10) ]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Overdosage (10) ]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. 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%

None.

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 .

AND PRECAUTIONS Pulmonary toxicity : Pulmonary infiltrates and/or fibrosis occurs with Lomustine Capsules. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue Lomustine Capsules 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 Lomustine Capsules. 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 Lomustine Capsules cause myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Lomustine Capsules 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 Lomustine Capsules is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Lomustine Capsules more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

5.2 Risk of Overdosage Fatal toxicity occurs with overdosage of Lomustine Capsules. 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 Lomustine Capsules is taken every 6 weeks <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Overdosage (10) ]</span>.

5.3 Pulmonary Toxicity Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Lomustine Capsules. 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 Lomustine Capsules usually greater than 1100 mg/m 2 . Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Lomustine Capsules 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 Lomustine Capsules. Monitor liver function.

5.6 Nephrotoxicity Progressive renal failure with a decrease in kidney size occurs with Lomustine Capsules. Monitor renal function.

5.7 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, Lomustine Capsules 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 Lomustine Capsules and for 2 weeks after the final dose. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.

5.1 Delayed Myelosuppression Lomustine Capsules cause myelosuppression that can result in fatal infections and bleeding. Myelosuppression from Lomustine Capsules 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 Lomustine Capsules is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Lomustine Capsules more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

5.2 Risk of Overdosage Fatal toxicity occurs with overdosage of Lomustine Capsules. 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 Lomustine Capsules is taken every 6 weeks <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Overdosage (10) ]</span>.

5.3 Pulmonary Toxicity Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Lomustine Capsules. 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 Lomustine Capsules usually greater than 1100 mg/m 2 . Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue Lomustine Capsules 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 Lomustine Capsules. Monitor liver function.

5.6 Nephrotoxicity Progressive renal failure with a decrease in kidney size occurs with Lomustine Capsules. Monitor renal function.

5.7 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, Lomustine Capsules 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 Lomustine Capsules and for 2 weeks after the final dose. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span>.