Lomustine medac

Lomustine medac has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:

Brain tumors - both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.

Hodgkin's disease - secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

The recommended dose of Lomustine medac in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m² as a single oral dose every 6 weeks (see PATIENT INFORMATION and HOW SUPPLIED: Directions to the Pharmacist). In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m² every 6 weeks. When Lomustine medac is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:

A repeat course of Lomustine medac should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³; leukocytes above 4000/mm³), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

Lomustine medac should not be given to individuals who have demonstrated a previous hypersensitivity to it.

WARNINGS

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of Lomustine medac should not be given more frequently than every 6 weeks.

The bone marrow toxicity of Lomustine medac is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).

Pulmonary toxicity from Lomustine medac appears to be dose related (see ADVERSE REACTIONS).

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 REACTIONS).

Pregnancy Category D

Lomustine medac can cause fetal harm when administered to a pregnant woman. Lomustine medac is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. 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.

PRECAUTIONS

General

In all instances where the use of Lomustine medac is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Lomustine medac therapy should be carried out with caution and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Laboratory Tests

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 medac may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.

Renal function tests should also be monitored periodically.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lomustine medac 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 in humans (see ADVERSE REACTIONS). Lomustine medac also affects fertility in male rats at doses somewhat higher than the human dose.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

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 medac, 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.

Pediatric Use

See ADVERSE REACTIONS: Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION.

Geriatric Use

No data from clinical studies of Lomustine medac 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.

Hematologic Toxicity

The most frequent and most serious toxicity of Lomustine medac is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Lomustine medac and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m² develop white blood counts below 5000 wbc/mm³. Thirty-six percent developed white blood counts below 3000 wbc/mm³. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.

Lomustine medac 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 medac. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Lomustine medac usually greater than 1100 mg/m². There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.

Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1-16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.

Gastrointestinal Toxicity

Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Lomustine medac is administered to fasting patients.

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 medac.

Nephrotoxicity

Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Lomustine medac. Kidney damage has also been reported occasionally in patients receiving lower total doses.

Other Toxicities

Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.

Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Lomustine medac. However, the relationship to medication in these patients is unclear.

Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.

No proven antidotes have been established for Lomustine medac overdosage. In case of overdose, appropriate supportive measures should be taken.