Lomustine

Lomustine 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 Lomustine 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 Lomustine is indicated as a component of combination chemotherapy for the treatment of patients with Hodgkin's lymphoma whose disease has progressed following initial chemotherapy.

Lomustine Capsules, USP 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 )

None.

Pulmonary toxicity : Pulmonary infiltrates and/or fibrosis occurs with lomustine. Perform pulmonary function tests prior to treatment and repeat frequently. Permanently discontinue lomustine 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. 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 causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from lomustine 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 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 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 lomustine. 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 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 lomustine. 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 usually greater than 1100 mg/m 2 . Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment. Permanently discontinue lomustine 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. Monitor liver function.

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

5.7 Embryo-Fetal Toxicity Based on animal data and its mechanism of action, lomustine 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 and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with lomustine and for 3.5 months after the final dose [see Use in Specific Populations (8.1, 8.3)] .

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 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 Wilshire Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lactation: Do not breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, lomustine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on lomustine 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, advise women not to breastfeed during treatment with lomustine 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 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’s mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with lomustine 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 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 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.

Lomustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.