Pharmacology
It is generally agreed that lomustine acts as an alkylating agent but, as with other nitrosoureas, it may also inhibit several key enzymatic processes.
Lomustine may be given orally. Following oral administration of radioactive lomustine at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted within 24 hours. The serum half-life of the drug and/or metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after i.v. administration.
Because of the high lipid solubility and the relative lack of ionization at physiological pH, lomustine crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma.
Indications
Adjuvant therapy to surgery and radiotherapy or in combination therapy with other chemotherapeutic agents in the following:
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Brain tumors: both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
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Lung cancer: squamous cell, anaplastic large cell, and adenocarcinoma. Lomustine has been used alone and in combination with other appropriate antineoplastic drugs, such as cyclophosphamide.
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Malignant melanoma: alone or in combination with other active drugs, such as vincristine.
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Hodgkin's disease: alone or in combination with other active drugs.
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Breast carcinoma: in advanced disease after conventional therapy has failed.
Lomustine has been used in renal cell carcinoma although the response rate is low in this resistant cancer. Responses have also been observed with non-Hodgkin's lymphoma, ovarian and pancreatic carcinoma but data are insufficient to make a definite recommendation.
Precautions
Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.
Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly at risk.
Since lomustine may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.
Renal function tests should also be monitored periodically.
Supplied
Each capsule with a white cap and body, imprinted with “BRISTOL” over “3030” on the cap and with “10 MG” on the body, contains: lomustine 10 mg. Nonmedicinal ingredients: mannitol and magnesium stearate; capsule shell: gelatin, printing ink and titanium dioxide. A desiccant packet is enclosed in each bottle of capsules. Bottles of 20.
Each capsule with a white cap and moss green body, imprinted with “BRISTOL” over “3031” on the cap and with “40 MG” on the body, contains: lomustine 40 mg. Nonmedicinal ingredients: mannitol and magnesium stearate; capsule shell: FD&C blue No. 2, gelatin, printing ink, titanium dioxide and yellow iron oxide. A desiccant packet is enclosed in each bottle of capsules. Bottles of 20.
Each capsule with a moss green cap and body, imprinted with “BRISTOL” over “3032” on the cap and with “100 MG” on the body, contains: lomustine 100 mg. Nonmedicinal ingredients: mannitol and magnesium stearate; capsule shell: FD&C blue No. 2, gelatin, printing ink, titanium dioxide and yellow iron oxide. A desiccant packet is enclosed in each bottle of capsules. Bottles of 20.
Unopened bottles of lomustine capsules are stable for 36 months at room temperature. Protect from light. Avoid excessive heat (over 40°C).
Contraindications
Known hypersensitivity to lomustine. Severe leukopenia and/or thrombocytopenia.
Warnings
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lomustine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically.
Nitrosourea therapy does have carcinogenic potential. The occurrence of acute leukemia and bone marrow dysplasias has been reported in patients following nitrosourea therapy.
Lomustine also affects fertility in male rats at doses somewhat higher than the human dose.
Safe use in pregnancy has not been established. Lomustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Adverse Effects
Renal abnormalities consisting of decrease in kidney size, progressive azotemia and renal failure have been reported in patients who receive large cumulative doses after prolonged therapy with lomustine and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually lasts less than 24 hours. The frequency and duration may be reduced by the use of antiemetics prior to dosing and by the administration of lomustine to fasting patients.
Stomatitis, alopecia, anemia have been reported infrequently.
Neurological reactions such as disorientation, lethargy, ataxia and dysarthria have been noted in some patients receiving lomustine. However, the relationship to medication in these patients is unclear.
The most frequent and most serious toxicity of lomustine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks post-administration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of lomustine and persists for 1 to 2 weeks.
Approximately 65% of patients receiving 130 mg/m2 develop white blood cell counts below 5000/mm3. Thirty-six percent developed white blood cell counts below 3000/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
Lomustine 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.
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 lomustine.
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with lomustine. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative dose of lomustine usually greater than 1100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600 mg.
Delayed onset pulmonary fibrosis occurring up to 15 years after treatment has been reported in patients with intracranial tumors who received related nitrosoureas during their childhood and early adolescence.
Overdose
In case of overdosage, treat the patient symptomatically.
Dosage
The recommended dose of lomustine in adults and children is 130 mg/m2 as a single dose by mouth every 6 weeks.
In individuals with compromised bone marrow function, reduce the dose to 100 mg/m2 every 6 weeks.
A repeat course of lomustine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100 000/mm3; leukocytes above 4000/mm3). Monitor blood counts weekly and do not give repeat courses before 6 weeks because the hematologic toxicity is delayed and cumulative.
Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The schedule in Table 1 is suggested as a guide to dosage adjustments.
Table 1: CeeNUDosage Adjustment Guide | Nadir After Prior Dose | Percentage of
Prior Dose to be Given |
| Leukocytes | Platelets |
| >4000 | >100 000 | 100% |
| 3000–3999 | 75 000–99 999 | 100% |
| 2000–2999 | 25 000–74 999 | 70% |
| <2000 | <25 000 | 50% |
When lomustine is used in combination with myelosuppressive drugs, the doses should be adjusted accordingly.
Handing and Disposal: Preparation of lomustine should be done in a vertical laminar flow hood (Biological Safety Cabinet-class II). Lomustine capsules should not be placed in automated counting machines. The counting and pouring of lomustine should be done carefully and the equipment used should be rinsed with water and then thoroughly cleaned with detergent and water. Personnel handing lomustine should wear gloves, safety glasses, a mask and disposable protective clothing. Vials and other materials which have come in contact with lomustine should be segregated and incinerated at 1000°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. Personnel regularly involved in the preparation and handling of lomustine should have bi-anual blood examinations.
