Lomustine (Gleostine) is an alkylating agent that is used in combination with other chemotherapeutic drugs to treat certain malignant conditions such as brain tumors and Hodgkin's lymphoma.

Lomustine Uses:

• Brain tumors:

  • It is used in the treatment of primary and metastatic brain tumors after appropriate surgery, radiotherapy, or chemotherapy if indicated.

• Hodgkin lymphoma:

  • It is used in treatment in combination with other chemotherapeutic agents of Hodgkin lymphoma which has relapsed or progressed following initial chemotherapy.
  • But, the use of lomustine in the management of Hodgkin lymphoma is limited due to the efficacy of other chemotherapy agents/regimens.

Lomustine Dose in Adults:

Note:

• Dispense only enough capsules for a single dose.
• It should not be dispensed more than one dose at a time.
• Repeat courses should only be administered after adequate recovery of TLC greater than 4,000/mm³ and platelet count to more than 100,000/mm³.
• The dose should be approximated to the nearest 10 mg.
• Lomustine is associated with moderate symptoms of nausea. Antiemetics are advised to prevent nausea and vomiting.

Lomustine Dose in the treatment of Brain tumors:

• It is given orally as 130 mg/m² as a single dose once every 6 weeks.
• Reduce the dose to 100 mg/m² as a single dose once every 6 weeks in patients with compromised bone marrow function.
• Further dose reductions are necessary when used alongside other chemotherapeutic agents.

Lomustine Dose in the treatment of Anaplastic oligodendroglioma:

• PCV regimen (off-label combination):

  • Oral: 130 mg/m² on day 1 every 6 weeks for up to 4 cycles before radiation therapy. It is given in combination with procarbazine and vincristine.

Lomustine Dose in the treatment of high-grade Astrocytoma:

• POC regimen (off-label dosing):

  • Adults ≤21 years:
    • Orally as 100 mg/m² on day 1 every 6 weeks for 8 cycles along with a combination of vincristine and prednisone.

Lomustine Dose in the treatment of Recurrent Glioblastoma:

• PCV regimen (off-label dosing):

  • Oral: it is given as 110 mg/m² on day 1 every 6 weeks for 7 cycles in combination with procarbazine and vincristine.

• Single-agent therapy:

  • Orally as 100 to 130 mg/m² every 6 weeks until disease progression or harmful toxicity.

Lomustine Dose in the treatment of Medulloblastoma (off-label dosing):

• Adults ≤21 years:

  • Orally given as 75 mg/m² once every 6 weeks for 8 cycles in combination with cisplatin and vincristine.

Lomustine Dose in the treatment of Hodgkin lymphoma:

• Orally it can be given as 130 mg/m² as a single dose once every 6 weeks.
• Decrease the dose to 100 mg/m² as a single dose once every 6 weeks in patients with compromised bone marrow function. Dose reductions are recommended for combination chemotherapeutic regimens.

Lomustine Dose in Childrens:

Note:

• At FDA approved dosages, lomustine should only be dispensed and administered as a single dose once every 6 weeks due to delayed bone marrow suppression.
• Serious errors have occurred when lomustine was inadvertently administered daily.
• Repeat courses should only be administered after adequate recovery of TLC to more than 4,000/mm³ and platelets to more than 100,000/mm³.
• Details concerning doses in combination regimes should also be consulted. The dose, frequency, number of doses, and start date may vary by protocol and treatment phase according to clinician judgment.

Lomustine Dose in the treatment of Brain tumors:

• General dosing: Manufacturer's labeling:

  • Infants, Children, and Adolescents:
    • Initially, it is given orally as 130 mg/m² as a single dose every 6 weeks.
    • The dose reductions are recommended for combination chemotherapy regimens.

• Compromised marrow function:

  • Reduce initial dose to 100 mg/m² as a single dose once every 6 weeks;
  • It is noteworthy that Subsequent doses may require adjustment after initial treatment according to platelet and leukocyte counts.

• Medulloblastoma:

  • Children ≥3 years and Adolescents:
    • Orally as 75 mg/m² on day 0 of each chemotherapy cycle in combination with cisplatin, vincristine, and radiotherapy.
    • However, limited data is available.

• Gliomas: Limited data available:

  • Low grade:

    • Infants, Children, and Adolescents:
      • Orally as 110 mg/m² on day 3 of a 6-week cycle in combination with thioguanine, vincristine, and procarbazine for up to 8 cycles for low grade, non-operable which are usually gliomas and astrocytomas.

  • High grade: Astrocytoma, glioblastoma:

    • Children ≥3 years and Adolescents:
      • Orally as 90 mg/m² on day 1 every 42 days or repeated when counts recovered as per physician's choice.
      • It is used in combination with temozolomide and following radiotherapy for a total of 6 cycles.
    • POC regimen: For Astrocytoma in Children ≥18 months and Adolescents:
      • It is given Orally as 100 mg/m² on day 1 every 6 weeks for 8 cycles in combination with vincristine and prednisone.

Lomustine Dose in the treatment of Hodgkin lymphoma:

• Infants, Children, and Adolescents:

  • Oral: Initially, it is given as 130 mg/m² as a single dose every 6 weeks. It is notable that subsequent doses may require adjustment after initial treatment according to platelet and leukocyte counts.
  • Compromised marrow function: The dose is reduced from the initial 100 mg/m² as a single dose once every 6 weeks

Lomustine Dosage adjustment based on toxicity:

• Infants, Children, and Adolescents:

  • Hematologic toxicity (nadir for subsequent cycles):

    • Leukocytes ≥3,000/mm³, platelets ≥75,000/mm³:
      • No adjustment required
    • Leukocytes 2,000 to 2,999/mm³, platelets 25,000 to 74,999/mm³:
      • Administer 70% of the prior dose
    • Leukocytes <2,000/mm³, platelets <25,000/mm³:
      • Administer 50% of the prior dose

  • Nonhematologic toxicity:

    • In the case of pulmonary fibrosis, discontinue lomustine.

Lomustine Pregnancy Category: D

• Based on animal in-utero studies, Lomustine may cause harm to fetal health.
• Women of reproductive age are recommended to use effective contraceptives until 2 weeks after their last dose of lomustine.
• Other studies have shown that effective contraception should be used by both the male and female partners for at least 3.5 weeks following the last dose.

Use of lomustine while breastfeeding

• It is unknown if the drug will be excreted into breastmilk.
• It is not recommended to breastfeed until 2 weeks after your last dose of lomustine.

Lomustine Dose in Kidney Disease:

There are no dosage adjustments according to the manufacturer. The following adjustments have been recommended:

• Aronoff 2007:

  • CrCl 10 to 50 mL/minute:
    • Reduce dose to 75% of the 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 the 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).
    • A supplemental dose is not necessary.

Dose in Liver disease:

Although the manufacturer has not recommended any adjustments in the dose, since, the drug is metabolized in the liver, it should be used with caution in these patients.

Common Side Effects of Lomustine:

• Gastrointestinal:

  • Nausea and vomiting

• Hematologic & oncologic:

  • Leukopenia
  • Bone marrow depression
  • Thrombocytopenia

Less common Side effects of Lomustine:

• Central Nervous System:

  • Ataxia
  • Disorientation
  • Dysarthria
  • Lethargy

• Dermatologic:

  • Alopecia

• Gastrointestinal:

  • Stomatitis

• Genitourinary:

  • Azotemia (Progressive)
  • Nephron Atrophy
  • Nephrotoxicity

• 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

Contraindications to Lomustine:

US Labeling

• The manufacturer does not provide any specific contraindications.

Canadian labeling

• Hypersensitivity is a contraindication because it can lead to severe leukopenia or thrombocytopenia.

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • Myelosuppression can be fatal with Lomustine. 
  • Hematologic toxicities are dose-related, cumulative and delayed.
  • They can occur 4 to 6 weeks after drug administration, and last for up to 2 weeks.
  • Leukopenia is more severe than thrombocytopenia. 
  • Cumulative myelosuppression due to lomustine can cause cytopenias that are more severe and last longer. 
  • After each dose, monitor blood counts for at most 42 days.
  • Lomustine should not be taken more often than once every six weeks.
  • Dose adjustments should take into account the perception of cell count from previous doses. 
  • Canadian labeling prohibits the use of this medication in patients suffering from severe leukopenia or thrombocytopenia.

• Gastrointestinal toxicities:

  • Lomustine has a moderate emetic potency. To prevent nausea and vomiting, antiemetics should be used. Stomatitis was also observed.

• Hepatotoxicity

  • It is possible to see transminitis.
  • It is advisable to monitor LFTs.

• Toxicity in the lungs:

  • Could cause pulmonary Fibrosis.
  • Chronic doses of more than 1,100 mg/m2 are usually associated with pulmonary toxicity.
  • It is possible for it to take up to 6 months after treatment has begun.
  • Patients who have a baseline lower than 70% of their predicted forced vital capacity or carbon Monoxide diffusing ability are at greater risk.
  • Patients of younger ages are more susceptible to pulmonary toxicities.
  • Monitoring pulmonary function at baseline and during treatment.
  • Patients with pulmonary Fibrosis should be given lomustine for life.

• Toxicity in the renal system:

  • It has been reported that progressive renal failure can lead to a decrease of kidney size.
  • Patients with impaired renal function should be cautious. Dosage adjustment may be necessary.
  • Monitor your renal function.

• Secondary malignancies

  • The development of secondary malignancies is possible with long-term nitrosoureas use, such as acute leukemia or myelodysplasia.

Lomustine: Drug Interaction

Monitoring parameters:

• CBC with differential and platelet count. It should be done weekly for at least 6 weeks after a dose.
• Hepatic and renal function tests.
• Pulmonary function tests should be done on the baseline and then periodically.

How to administer Lomustine?

• It is administered orally during an empty stomach to reduce nausea and vomiting.
• You may need to use different strengths of capsules in order to get the right dose. 
• Only dispense one capsule per dose. Do not dispense more than one dose.
• Avoid tearing capsules. Contact with skin should be immediately washed off. Avoid contact with broken capsules.

Mechanism of action of Lomustine:

It inhibits the production of DNA, RNA and protein through alkylation and carbamylation. Lomustine is not cell-cycle specific.

Distribution:

• It crosses the blood-brain barrier and CNS concentrations are high.

Metabolism:

• Hepatic to active metabolites.

Half-life elimination:

• Metabolites: 16 to 48 hours

Time to peak, serum:

• ~3 hours

Excretion:

• Urine (~50%, as metabolites)

International Brand Names of Lomustine:

• Gleostine
• CeeNU
• Belustine
• C.N.U.
• CCNU
• Cecenu
• CEENU
• CeeNU
• Ceenu
• G-Lomustin
• Lomustine
• Lomustine ”Medac”
• Lomustinum
• Lucostin
• Lucostine
• Prava

Lomustine Brand Names in Pakistan:

No Brands Available in Pakistan.