Lomustine (Monograph)

Brand names: CeeNU, CeeNU DosePak
Drug class: Antineoplastic Agents
- Alkylating Agents
VA class: AN100
CAS number: 13010-47-4

Introduction

Antineoplastic agent; a nitrosourea-derivative alkylating agent.

Uses for Lomustine

Brain Tumors

Used as a component of combination chemotherapy in addition to appropriate surgical and/or radiotherapeutic procedures for the palliative treatment of primary and metastatic brain tumors.

Used in combination regimens that typically include lomustine and vincristine with another antineoplastic agent, such as procarbazine or cisplatin, or a corticosteroid (prednisone) as adjuvant therapy following surgical resection and radiation therapy for the treatment of astrocytic tumors (e.g., glioblastoma multiforme, anaplastic astrocytoma), medulloblastoma, and anaplastic oligodendroglioma.

Hodgkin’s Disease

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed Hodgkin’s disease.

Combination regimens containing other agents currently are preferred for treatment of this cancer.

Lomustine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

Oral Administration

Administer orally as a single dose.

Handle cautiously; use protective equipment (e.g., latex gloves) and wash hands after removal of the latex gloves.

Dosage

Consult published protocols for the dosage of lomustine and other chemotherapeutic agents and the method and sequence of administration.

Pediatric Patients

Cancer (General)

Oral

130 mg/m² as a single dose; administer at intervals of at least 6 weeks.

100 mg/m² as a single dose is recommended if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

Adults

Cancer (General)

Oral

130 mg/m² as a single dose; administer at intervals of at least 6 weeks.

100 mg/m² as a single dose is recommended if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

Dosage Modification for Toxicity

Do not administer repeat courses until leukocyte count >4000/mm³, platelet count >100,000/mm³, and an adequate number of neutrophils is present on peripheral blood smear.

Bone marrow toxicity is cumulative; adjust subsequent dosages based on nadir blood counts from previous dose.

Alternatively, to avoid potential overdosage associated with manufacturer’s suggested modifications, some clinicians recommend reducing subsequent dosage by 25% when platelet nadirs are 50,000–74,999/mm³; by 50% for nadirs of 25,000–49,999/mm³; and by 75% for nadirs <25,000/mm³.

Related/similar drugs

Keytruda, cyclophosphamide, pembrolizumab, cisplatin, doxorubicin, vincristine, etoposide

Cautions for Lomustine

Contraindications

• Known hypersensitivity to lomustine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hematologic Effects

Risk of myelosuppression (e.g., thrombocytopenia, leukopenia); effects are delayed and cumulative. (See Boxed Warning.) Thrombocytopenia generally more severe than leukopenia but both considered dose-limiting toxicities. Anemia reported less frequently and is less severe.

Following oral administration, thrombocytopenia and leukopenia occur at approximately 4 and 5–6 weeks, respectively, and persist for 1–2 weeks.

Repeated dosing associated with more severe and more prolonged myelosuppression.

Pulmonary Effects

Risk of dose-related, sometimes fatal, pulmonary toxicity (characterized by pulmonary infiltrates and/or fibrosis). Risk factors include prolonged therapy (with cumulative doses >1100 mg/m²).

Risk of delayed-onset pulmonary fibrosis (has occurred up to 17 years after treatment during childhood and early adolescence); possible reduction of pulmonary function or death. (See Pediatric Use under Cautions.)

Perform pulmonary function tests prior to initiation of and frequently during therapy. Patients with baseline forced vital capacity (FVC) or pulmonary diffusion capacity for carbon monoxide (DL_CO) <70% of predicted value are particularly at risk.

Secondary Malignancies

Risk of secondary malignancies following long-term use of nitrosoureas.

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; teratogenicity and embryotoxicity demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Major Toxicities

GI Effects

Dose-related nausea and vomiting reported within 3–6 hours following dose; may persist for 24 hours. Premedication with antiemetics may diminish or prevent.

Hepatic Effects

Reversible increases in serum transaminase, alkaline phosphatase, and bilirubin concentrations reported. Possible hepatic dysfunction. Monitor hepatic function periodically.

Renal Effects

After prolonged oral therapy (with large cumulative doses), progressive azotemia, decrease in kidney size, and renal failure reported. Kidney damage reported occasionally in patients receiving lower total doses. Monitor renal function periodically.

Nervous System Effects

Disorientation, lethargy, ataxia, and dysarthria reported.

Ocular Effects

Optic atrophy and visual disturbances (e.g., blindness) reported.

General Precautions

Therapy Monitoring

Monitor CBCs weekly during and for at least 6 weeks following each dose. Also monitor pulmonary, hepatic, and renal function tests periodically during treatment.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether lomustine is distributed into milk. Discontinue nursing because of potential risk to nursing infants.

Pediatric Use

Fatal pulmonary fibrosis reported; onset is delayed, occurring up to 17 years following treatment of brain tumors during childhood or adolescence. Extremely high risk of fatal pulmonary toxicity, particularly in children <5 years of age at initial treatment; carefully weigh benefits and risks of therapy in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Lomustine substantially eliminated by kidneys; monitor renal function periodically since geriatric patients are more likely to have decreased renal function.

Common Adverse Effects

Pulmonary infiltrates and/or fibrosis, thrombocytopenia, leukopenia, anemia, nausea, vomiting, hepatic and renal toxicity. (See Warnings/Precautions under Cautions.)

Lomustine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration usually attained within 1–6 hours; also absorbed following topical application.

Distribution

Extent

Widely distributed. Readily crosses the blood-brain barrier (due to high lipid solubility); concentrations of metabolites in CSF are ≥15–50% of concurrent plasma concentrations.

Not known whether lomustine is distributed into milk.

Elimination

Metabolism

Rapidly and extensively metabolized within 1 hour after oral administration.

Elimination Route

Excreted principally in urine as metabolites.

Following oral administration, about 50 or 75% of radioactivity excreted within 12 hours or 4 days, respectively.

Half-life

Biphasic; initial plasma half-life is 6 hours, the second-phase plasma half-life is 1–2 days.

Stability

Storage

Oral

Capsules

Tight containers, at 25°C (may be exposed to 15–30°C).

Actions

• Alkylates DNA and RNA. May inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. Overall result is thought to be the inhibition of both DNA and RNA synthesis.

Advice to Patients

• Risk of myelosuppression or pulmonary toxicity. Importance of adherence to laboratory appointment schedules. Notify clinician if fever, sore throat, or unusual bleeding or bruising occurs.

• Importance of understanding there may be 2 or more different types and colors of capsules in the dispensed container.

• Importance of understanding lomustine is administered as a single oral dose and will not be repeated for at least 6 weeks.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of women avoiding pregnancy during therapy. Advise pregnant women of risk to the fetus.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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