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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 [DSC], 40 mg [DSC], 100 mg [DSC]

Brand Names: U.S.

  • CeeNU [DSC]
  • Gleostine

Pharmacologic Category

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

Pharmacology

Inhibits DNA, RNA, and protein synthesis via alkylation and carbamylation of DNA and RNA; lomustine is cell cycle non-specific (Perry 2012)

Distribution

Crosses blood-brain barrier; CNS concentrations are high (Perry 2012)

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 (in combination with other chemotherapy agents) of Hodgkin lymphoma which has progressed following initial chemotherapy; however, the use of lomustine in the management of Hodgkin lymphoma is limited due to efficacy of other chemotherapy agents/regimens.

Contraindications

US labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to lomustine or any component of the formulation; severe leukopenia and/or thrombocytopenia.

Dosing: Adult

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 >4,000/mm3 and platelets to >100,000/mm3. Doses should be rounded to the nearest 5 mg. Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Brain tumors: 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): 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 2013; Cairncross 2006).

Astrocytoma, high grade: POC regimen (off-label dosing): 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:

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): 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: 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). Note: The use of lomustine in the management of Hodgkin lymphoma is limited due to efficacy of other chemotherapy agents/regimens.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 >4,000/mm3 and platelets to >100,000/mm3. Doses should be rounded to the nearest 5 mg. Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Brain tumors: 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)

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

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

Hodgkin lymphoma: 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). Note: The use of lomustine in the management of Hodgkin lymphoma is limited due to efficacy of other chemotherapy agents/regimens.

Dosing: 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: Reduce dose to 75% of normal dose

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

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

Kintzel 1995:

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

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

CrCl ≤30 mL/minute: Avoid use

Hemodialysis: Due to its lipophilic nature, lomustine is not dialyzable (Canadian labeling). Supplemental dose is not necessary (Aronoff 2007).

Dosing: 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: Adjustment for Toxicity

Hematologic toxicity: 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: Reduce dose to 70% of prior dose

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

Nonhematologic toxicity: Pulmonary fibrosis: Discontinue permanently.

Dosing: 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: Administering on an empty stomach may 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). If contact with skin occurs, immediately wash area (thoroughly). Avoid exposure to broken capsules.

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Avoid temperatures over 40°C (104°F).

Drug Interactions

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

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

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

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

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 to 6 hours after oral administration; duration: <24 hours)

Hematologic & oncologic: Leukopenia (65%; nadir: 5 to 6 weeks; recovery 6 to 8 weeks), bone marrow depression (dose-limiting, delayed, cumulative), thrombocytopenia (nadir: 4 weeks; recovery 5 to 6 weeks)

Frequency not defined:

Central nervous system: Ataxia, disorientation, dysarthria, lethargy

Dermatologic: Alopecia

Gastrointestinal: Stomatitis

Genitourinary: Azotemia (progressive), drug-induced nephrotoxicity, nephron atrophy

Hematologic & oncologic: Acute leukemia, anemia, bone marrow dysplasia

Hepatic: Hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases

Ophthalmic: Blindness, optic atrophy, visual disturbance

Renal: Renal failure

Respiratory: Pulmonary fibrosis, pulmonary infiltrates

ALERT: U.S. Boxed Warning

Bone marrow suppression:

Lomustine causes myelosuppression, including fatal myelosuppression. Myelosuppression is delayed, dose-related, and cumulative, occurring 4 to 6 weeks after drug administration and persisting for 1 to 2 weeks. Thrombocytopenia is generally more severe than leukopenia. Cumulative myelosuppression from lomustine is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give lomustine more frequently than every 6 weeks.

Medication error prevention:

Prescribe, dispense, and administer only enough capsules for one dose. Fatal toxicity occurs with overdosage of lomustine. Both health care provider and pharmacist should emphasize to the patient that only one dose of lomustine is taken every 6 weeks.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Lomustine causes bone marrow suppression, including fatal myelosuppression. Hematologic toxicity is dose-related, cumulative, and delayed (occurring 4 to 6 weeks after drug administration and persisting for 1 to 2 weeks). Thrombocytopenia is generally more severe than leukopenia. Cumulative myelosuppression from lomustine is manifested by greater severity and longer duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not administer lomustine more frequently than once every 6 weeks. Dose adjustments should be based on nadir counts from prior dose. The Canadian labeling contraindicates use in patients with severe leukopenia and/or thrombocytopenia.

• Gastrointestinal toxicity: Lomustine is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011). Stomatitis has also been reported.

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

• Pulmonary toxicity: May cause pulmonary toxicity (infiltrates and/or fibrosis). Pulmonary toxicity is usually related to cumulative doses >1,100 mg/m2. May be delayed 6 months or longer after treatment initiation. Patients with baseline below 70% of predicted forced vital capacity or carbon monoxide diffusing capacity are at increased risk. Patients treated at a younger age may also be at increased risk for pulmonary toxicity. Monitor pulmonary function tests at baseline and frequently during treatment. Discontinue lomustine permanently in patients diagnosed with pulmonary fibrosis.

• Renal toxicity: Progressive renal failure with a decrease in kidney size has been reported. Use with caution in patients with renal impairment; may require dosage adjustment. Monitor renal function.

• Secondary malignancies: Long-term use of nitrosoureas is associated with the development of secondary malignancies, including acute leukemia and myelodysplasia.

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]). Wear gloves when handling the bottle/capsules; if contact with skin occurs, immediately wash area (thoroughly).

Other warnings/precautions:

• Immunizations: Avoid immunization with live viral vaccines; may result in severe infection or lack of vaccine response.

• Medication error prevention: [US Boxed Warning]: Lomustine should only be prescribed and dispensed as a single dose once every 6 weeks. Serious and fatal adverse events have occurred with overdosage (when lomustine was inadvertently administered daily). Health care providers, including pharmacists, should emphasize to the patient that only one dose of lomustine is taken every 6 weeks. 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).

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 Considerations

Adverse effects have been observed in animal reproduction studies. Based on the mechanism of action, lomustine may cause fetal harm when administered to a pregnant woman. Women of reproductive potential should use effective contraception during treatment and for 2 weeks after the final lomustine dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3.5 months (US labeling) or 6 months (Canadian labeling) after the final lomustine dose.

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, vomiting, or nausea. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), illogical thinking, loss of strength and energy, change in balance, swelling of arms or legs, difficulty speaking, mouth sores, vision changes, blindness, or signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse) (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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