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Lomustine

Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 13010-47-4
Brands: CeeNU, CeeNU DosePak

Warning(s)

  • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.a

  • Risk of bone marrow suppression (e.g., thrombocytopenia, leukopenia), resulting in bleeding and infection.a Bone marrow toxicity is delayed and cumulative.a Monitor CBCs weekly during and for at least 6 weeks following each dose; do not administer more frequently than every 6 weeks.a Adjust subsequent dosages based on nadir blood counts from previous dose.a (See Dosage Modification for Toxicity under Dosage and Administration.)

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

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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

Table 1. Dosage Adjustments for Hematologic Toxicities Based on Nadir After Prior Dose (manufacturer’s recommendations)

Leukocytes (cells/mm3)

Platelets (cells/mm3)

Percentage of Prior Dose to be Given

>4000

>100,000

100%

3000–3999

75,000–99,999

100%

2000–2999

25,000–74,999

70%

<2000

<25,000

50%

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 (DLCO) <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.

Lomustine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

10 mg

CeeNU

Bristol-Myers Squibb

40 mg

CeeNU

Bristol-Myers Squibb

100 mg

CeeNU

Bristol-Myers Squibb

Kit

2 Capsules Lomustine 10 mg

2 Capsules Lomustine 40 mg

2 Capsules Lomustine 100 mg

CeeNUDose Pack

Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

CeeNU 10MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 30/$315.99 or 90/$929.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Bristol Myers Squibb. CeeNU (lomustine) capsules prescribing information. Princeton, NJ; 1998 Jun.

101. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

102. Levin VA, Silver P, Hannigan J et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990; 18:321-4. [PubMed 2154418]

103. DeAngelis LM. Brain tumors. N Engl J Med. 2001; 344:114-23. [PubMed 11150363]

104. Galanis E, Buckner J. Chemotherapy for high-grade gliomas. Br J Cancer. 2000; 82:1371-80. [PubMed 10780513]

105. Fine HA, Dear KB, Loeffler JS et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993; 71:2585-97. [IDIS 313362] [PubMed 8453582]

106. Medical Research Council. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001; 19:509-18. [IDIS 460628] [PubMed 11208845]

107. Prados MD, Scott C, Curran WJ et al. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol. 1999; 17:3389-95. [IDIS 437721] [PubMed 10550132]

108. Trojanowski T, Peszynski J, Turowski K et al. Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas. J Neurooncol. 1988; 6:285-91. [PubMed 3066856]

109. Sposto R, Ertel IJ, Jenkin RD et al. The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol. 1989; 7:165-77. [PubMed 2550594]

110. Childhood cerebral astrocytoma. From CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 May.

111. Packer RJ, Sutton LN, Elterman R et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg. 1994; 81:690-8. [PubMed 7931615]

112. Evans AE, Jenkin RD, Sposto R et al. The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg. 1990; 72:572-82. [PubMed 2319316]

113. Childhood medulloblastoma. From CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.

114. Cairncross G, Macdonald D, Ludwin S et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994; 12:2013-21. [IDIS 337224] [PubMed 7931469]

115. Olson JD, Riedel E, DeAngelis LM. Long-term outcome of low-grade oligodendroglioma and mixed glioma. Neurology. 2000; 54:1442-8. [IDIS 446653] [PubMed 10751254]

116. Food and Drug Administration. Prescription drug advertising; content and format for labeling of human prescription drugs. Fed Regist. 1979; 44:37434-67.

a. Bristol Myers Squibb. CeeNu (lomustine) capsules prescribing information. Princeton, NJ; 2006 Feb.

b. AHFS drug information 2005. McEvoy GK, ed. Lomustine. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2005:1094-6.

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