Action And Clinical 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/mto 100 mg/m 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 And Clinical Uses: Adjuvant therapy to surgery and radiotherapy or in combination therapy with other chemotherapeutic agents in the following: 1. Brain tumors: both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. 2. 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. 3. Malignant melanoma: alone or in combination with other active drugs, such as vincristine. 4. Hodgkin’s disease: alone or in combination with other active drugs. 5. 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.
Contra-Indications: Known hypersensitivity to lomustine. Severe leukopenia and/or thrombocytopenia.
Manufacturers’ Warnings In Clinical States: Caution: Lomustine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts as well as renal and hepatic function tests should be taken regularly. Discontinue the drug if abnormal depression of bone marrow is seen.
Lomustine should be administered by individuals experienced in the use of antineoplastic therapy.
Delayed bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of lomustine.
Blood counts should be monitored weekly for at least 6 weeks after a dose (see Adverse Effects). At the recommended dosage, courses of lomustine should not be given more frequently than every 6 weeks.
The bone marrow toxicity of lomustine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see Table I).
Caution should be used in administering lomustine to patients with decreased circulating platelets, leukocytes or erythrocytes (see Dosage).
Pulmonary toxicity from lomustine appears to be dose related (see Adverse Effects).
Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
Liver and renal function tests should be monitored periodically (see Adverse Effects).
Pregnancy: 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.
Lactation: 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.
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.
Adverse Reactions: Gastrointestinal: 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.
Hematologic Toxicity: 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/mdevelop white blood cell counts below 5 000 wbc/mm Thirty-six percent developed white blood cell counts below 3 000 wbc/mm 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.
Pulmonary Toxicity: 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 1 100 mg/m 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.
Other Toxicities: 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.
Nephrotoxicity: 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.
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 lomustine.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In case of overdosage, treat the patient symptomatically.
Dosage And Administration: The recommended dose of lomustine in adults and children is 130 mg/mas a single dose by mouth every 6 weeks.
In individuals with compromised bone marrow function, reduce the dose to 100 mg/mevery 6 weeks.
A repeat course of lomustine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100 000/mm leukocytes above 4 000/mm. 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.
When lomustine is used in combination with myelosuppressive drugs, the doses should be adjusted accordingly.
Availability And Storage: 10 mg: Each capsule 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.
40 mg: Each capsule 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.
100 mg: Each capsule 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 24 months at room temperature. Protect from light and excessive heat (over 40°C). (Shown in Product Recognition Section)
CeeNU® Bristol Lomustine Antineoplastic Agent