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.^a

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.¹⁰⁰

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.^{101 111 112 101 102 109 110 114 115}

Hodgkin’s Disease

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed Hodgkin’s disease.¹⁰⁰

Combination regimens containing other agents currently are preferred for treatment of this cancer.¹⁰¹

Lomustine Dosage and Administration

General

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

Administration

Oral Administration

Administer orally as a single dose.^a

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

Dosage

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

Pediatric Patients

Cancer (General)

Oral

130 mg/m² as a single dose; administer at intervals of at least 6 weeks.¹⁰⁰

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.¹⁰⁰

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁰

Adults

Cancer (General)

Oral

130 mg/m² as a single dose; administer at intervals of at least 6 weeks.¹⁰⁰

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.¹⁰⁰

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁰

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.¹⁰⁰

Bone marrow toxicity is cumulative; adjust subsequent dosages based on nadir blood counts from previous dose.¹⁰⁰

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.^b

Cautions for Lomustine

Contraindications

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

Warnings/Precautions

Warnings

Hematologic Effects

Risk of myelosuppression (e.g., thrombocytopenia, leukopenia); effects are delayed and cumulative.¹⁰⁰ (See Boxed Warning.) Thrombocytopenia generally more severe than leukopenia but both considered dose-limiting toxicities.¹⁰⁰ Anemia reported less frequently and is less severe.¹⁰⁰

Following oral administration, thrombocytopenia and leukopenia occur at approximately 4 and 5–6 weeks, respectively, and persist for 1–2 weeks.¹⁰⁰

Repeated dosing associated with more severe and more prolonged myelosuppression.¹⁰⁰

Pulmonary Effects

Risk of dose-related, sometimes fatal, pulmonary toxicity (characterized by pulmonary infiltrates and/or fibrosis).¹⁰⁰ Risk factors include prolonged therapy (with cumulative doses >1100 mg/m²).¹⁰⁰

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.¹⁰⁰ (See Pediatric Use under Cautions.)

Perform pulmonary function tests prior to initiation of and frequently during therapy.¹⁰⁵ Patients with baseline forced vital capacity (FVC) or pulmonary diffusion capacity for carbon monoxide (DL_CO) <70% of predicted value are particularly at risk.¹⁰⁰

Secondary Malignancies

Risk of secondary malignancies following long-term use of nitrosoureas.¹⁰⁰

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; teratogenicity and embryotoxicity demonstrated in animals.¹⁰⁰ Avoid pregnancy during therapy.¹⁰⁰ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹⁰⁰

Major Toxicities

GI Effects

Dose-related nausea and vomiting reported within 3–6 hours following dose; may persist for 24 hours.¹⁰⁰ Premedication with antiemetics may diminish or prevent.¹⁰⁰

Hepatic Effects

Reversible increases in serum transaminase, alkaline phosphatase, and bilirubin concentrations reported.¹⁰⁰ Possible hepatic dysfunction.¹⁰⁰ Monitor hepatic function periodically.¹⁰⁰

Renal Effects

After prolonged oral therapy (with large cumulative doses), progressive azotemia, decrease in kidney size, and renal failure reported.¹⁰⁰ Kidney damage reported occasionally in patients receiving lower total doses.¹⁰⁰ Monitor renal function periodically.¹⁰⁰

Nervous System Effects

Disorientation, lethargy, ataxia, and dysarthria reported.¹⁰⁰

Ocular Effects

Optic atrophy and visual disturbances (e.g., blindness) reported.¹⁰⁰

General Precautions

Therapy Monitoring

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

Specific Populations

Pregnancy

Category D.¹⁰⁰ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether lomustine is distributed into milk.¹⁰⁰ Discontinue nursing because of potential risk to nursing infants.¹⁰⁰

Pediatric Use

Fatal pulmonary fibrosis reported; onset is delayed, occurring up to 17 years following treatment of brain tumors during childhood or adolescence.¹⁰⁰ 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.¹⁰⁰

Geriatric Use

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

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

Common Adverse Effects

Pulmonary infiltrates and/or fibrosis, thrombocytopenia, leukopenia, anemia, nausea, vomiting, hepatic and renal toxicity.^a (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.^b

Distribution

Extent

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

Not known whether lomustine is distributed into milk.¹⁰⁰

Elimination

Metabolism

Rapidly and extensively metabolized within 1 hour after oral administration.^b

Elimination Route

Excreted principally in urine as metabolites.^b

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

Half-life

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

Stability

Storage

Oral

Capsules

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

Actions

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

Advice to Patients

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

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

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

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

• 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.^a Advise pregnant women of risk to the fetus.^a

• Importance of informing patients of other important precautionary information.^a (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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