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Lomustine

Pronunciation

(loe MUS teen)

Index Terms

  • CCNU
  • CeeNU
  • Lomustinum

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

CeeNU: 10 mg [DSC], 40 mg [DSC], 100 mg [DSC]

Gleostine: 5 mg, 10 mg, 40 mg, 100 mg

Generic: 10 mg, 40 mg, 100 mg

Brand Names: U.S.

  • CeeNU [DSC]
  • Gleostine

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrosourea)

Pharmacology

Inhibits DNA and RNA synthesis via carbamylation of DNA polymerase, alkylation of DNA, and alteration of RNA, proteins, and enzymes

Distribution

Crosses blood-brain barrier; CNS concentrations are ≥50% of plasma concentrations

Metabolism

Hepatic to active metabolites (Perry 2012)

Excretion

Urine (~50%, as metabolites)

Time to Peak

Serum: ~3 hours (Perry 2012)

Half-Life Elimination

Metabolites: 16 to 48 hours

Use: Labeled Indications

Brain tumors: Treatment of primary and metastatic brain tumors (after appropriate surgical and/or radiotherapeutic procedures).

Hodgkin lymphoma: Treatment of relapsed or refractory Hodgkin lymphoma (secondary therapy) in combination with other chemotherapy agents; however, its use is limited in the management of Hodgkin lymphoma due to efficacy of other chemotherapy agents/regimens.

Contraindications

Hypersensitivity to lomustine or any component of the formulation

Dosage

Note: Dispense only enough capsules for a single dose; do not dispense more than one dose at a time (ISMP, 2014). Repeat courses should only be administered after adequate recovery of leukocytes to >4000/mm3 and platelets to >100,000/mm3. Doses should be rounded to the nearest 10 mg. Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011).

Brain tumors: Pediatrics and Adults: Manufacturer’s labeling: Oral: 130 mg/m2 as a single dose once every 6 weeks; reduce dose to 100 mg/m2 as a single dose once every 6 weeks in patients with compromised bone marrow function (dosage reductions may be recommended for combination chemotherapy regimens).

Anaplastic oligodendroglioma: PCV regimen (off-label combination): Adults: Oral: 130 mg/m2 on day 1 every 6 weeks for up to 4 cycles prior to radiation therapy (in combination with procarbazine and vincristine) (Cairncross, 2006; Cairncross, 2013).

Astrocytoma, high grade: POC regimen (off-label dosing): Children ≥18 months, Adolescents, and Adults ≤21 years: Oral: 100 mg/m2 on day 1 every 6 weeks for 8 cycles (in combination with vincristine and prednisone) (Finlay, 1995).

Glioblastoma, recurrent: Adults:

PCV regimen (off-label dosing): Oral: 110 mg/m2 on day 1 every 6 weeks for 7 cycles (in combination with procarbazine and vincristine) (Levin, 2000)

Single-agent therapy: Oral: 100 to 130 mg/m2 every 6 weeks until disease progression or unacceptable toxicity (Wick, 2010).

Medulloblastoma (off-label dosing): Children ≥3 years, Adolescents, and Adults ≤21 years: Oral: 75 mg/m2 once every 6 weeks for 8 cycles (in combination with cisplatin and vincristine) (Packer, 2006; Packer, 1999).

Hodgkin lymphoma: Pediatrics and Adults: Manufacturer’s labeling: Oral: 130 mg/m2 as a single dose once every 6 weeks; reduce dose to 100 mg/m2 as a single dose once every 6 weeks in patients with compromised bone marrow function (dosage reductions may be recommended for combination chemotherapy regimens)

Dosing adjustment (based on nadir) for subsequent cycles:

Leukocytes ≥3,000/mm3, platelets ≥75,000/mm3: No dosage adjustment required

Leukocytes 2,000 to 2,999/mm3, platelets 25,000 to 74,999/mm3: Administer 70% of prior dose

Leukocytes <2,000/mm3, platelets <25,000/mm3: Administer 50% of prior dose

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling. The following adjustments have been recommended:

Aronoff, 2007: Adults:

CrCl 10 to 50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 25% to 50% of dose

Hemodialysis: Supplemental dose is not necessary

Continuous ambulatory peritoneal dialysis (CAPD): Administer 25% to 50% of dose

Kintzel, 1995:

CrCl 46 to 60 mL/minute: Administer 75% of normal dose

CrCl 31 to 45 mL/minute: Administer 70% of normal dose

CrCl ≤30 mL/minute: Avoid use

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling. However, lomustine is hepatically metabolized and caution should be used in patients with hepatic dysfunction.

Dosing in obesity: ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Administration

Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011).

Oral: Administer with fluids on an empty stomach; no food or drink for 2 hours after administration. Administering on an empty stomach will reduce the incidence of nausea and vomiting.

Varying strengths of capsules may be required to obtain necessary dose. Dispense only enough capsules for a single dose; do not dispense more than one dose at a time (ISMP, 2014). Do not break capsules.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). NIOSH recommends single gloving for administration of intact capsules (NIOSH 2014). Avoid exposure to broken capsules.

Storage

Store at room temperature of 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Avoid excessive heat (over 40°C [104°F]). Keep container closed tightly.

Drug Interactions

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Gastrointestinal: Nausea and vomiting, (onset: 3-6 hours after oral administration; duration: <24 hours)

Hematologic: Myelosuppression (dose-limiting, delayed, cumulative); leukopenia (65%; nadir: 5-6 weeks; recovery 6-8 weeks); thrombocytopenia (nadir: 4 weeks; recovery 5-6 weeks)

Frequency not defined: Acute leukemia, alkaline phosphatase increased, alopecia, anemia, ataxia, azotemia (progressive), bilirubin increased, blindness, bone marrow dysplasia, disorientation, dysarthria, hepatotoxicity, kidney size decreased, lethargy, optic atrophy, pulmonary fibrosis, pulmonary infiltrates, renal damage, renal failure, stomatitis, transaminases increased, visual disturbances

ALERT: U.S. Boxed Warning

Experienced physician:

Administer lomustine under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression:

Bone marrow suppression, notably thrombocytopenia and leukopenia, may contribute to bleeding and overwhelming infections in an already compromised patient, and is the most common and severe of lomustine's toxic effects.

Because the major toxicity is delayed bone marrow suppression, monitor blood cell counts weekly for at least 6 weeks after a dose. At the recommended dosage, do not give courses of lomustine more frequently than every 6 weeks.

Bone marrow toxicity is cumulative. Consider dosage adjustments on the basis of nadir blood cell counts from prior dosage.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warnings]: Bone marrow suppression, particularly thrombocytopenia and leukopenia commonly occur and may be severe; may lead to bleeding and overwhelming infections in an already compromised patient. Hematologic toxicity may be delayed; monitor blood counts for at least 6 weeks after a dose. Do not administer courses more frequently than every 6 weeks due to delayed myelotoxicity. Because bone marrow toxicity is cumulative; dose adjustments should be based on nadir counts from prior dose. Bone marrow suppression is dose-related. The onset of hematologic toxicity is ~4 to 6 weeks after administration; thrombocytopenia occurs at ~4 weeks and leukopenia occurs at 5 to 6 weeks; both persist for 1 to 2 weeks. Anemia may also be observed. Use with caution in patients with depressed platelet, leukocyte or erythrocyte counts.

• Gastrointestinal toxicity: Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis, 2011). Nausea and omitting may occur 3 to 6 hours after administration and the duration is generally <24 hours; may be reduced if administered on an empty stomach. Stomatitis has also been reported.

• Hepatotoxicity: Reversible hepatotoxicity (transaminase, alkaline phosphatase and bilirubin elevations) has been reported; periodically monitor liver function tests.

• Pulmonary toxicity: May cause delayed pulmonary toxicity (infiltrates and/or fibrosis) which is rare and usually related to cumulative doses >1100 mg/m2. May be delayed (may occur 6 months or later after treatment and has been reported up to 17 years after childhood administration in combination with radiation therapy). Patients with baseline below 70% of predicted forced vital capacity or carbon monoxide diffusing capacity are in increased risk. Long-term survivors who received nitrosoureas may have late reduction in pulmonary function; this fibrosis may be slowly progressive and has been fatal in some patients. Monitor pulmonary function tests at baseline and frequently throughout treatment.

• Renal toxicity: Renal abnormalities, including azotemia (progressive), decreased kidney size, and renal failure have been reported with large cumulative doses and long-term use. Renal damage has also been observed with lower cumulative doses. Use with caution in patients with renal impairment; may require dosage adjustment. Monitor renal function periodically during treatment.

• Secondary malignancies: Long-term use of nitrosoureas may be associated with the development of secondary malignancies. Acute leukemias and bone marrow dysplasias have been reported follow chronic therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Medication error prevention: Lomustine should only be administered as a single dose once every 6 weeks; serious and fatal adverse events have occurred when lomustine was inadvertently administered daily. The Institute for Safe Medication Practices (ISMP) recommends that prescribers only prescribe one dose at a time and pharmacies dispense only enough capsules for a single dose; in addition, patients should receive both verbal counseling and written instructions regarding proper dose and administration (ISMP, 2014).

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC with differential and platelet count (weekly for at least 6 weeks after a dose), hepatic and renal function tests (periodic), pulmonary function tests (baseline and periodic)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. May cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy during treatment with lomustine.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite or nausea. Have patient report immediately to prescriber signs of infection, signs of hemorrhaging, signs of renal impairment, signs of hepatic impairment, illogical thinking, considerable asthenia, change in balance, edema of extremities, difficulty speaking, stomatitis, vision changes, blindness, or signs of pulmonary disorder (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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