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A - Drug Name

lomustine

SYNONYM(S):   CCNU

COMMON TRADE NAME(S):   CeeNU®

 
B - Mechanism of Action and Pharmacokinetics

Lomustine is a highly lipophilic nitrosourea compound, which undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross-linking of DNA. Other biologic effects include inhibition of DNA and RNA synthesis. Nitrosoureas generally lack cross-resistance with other alkylating agents; however, cross-resistance between lomustine and carmustine has been described.



Absorption
Bioavailability Oral : Rapidly and completely absorbed (in 30-60 minutes)

Distribution

Highly lipid soluble, rapid and extensive tissue distribution.

Cross blood brain barrier? CSF achieves ≥ 50% of plasma levels
PPB

No information found

Metabolism

Actively metabolized by hepatic microsomal enzyme oxidation system (P450)

Active metabolites Several
Inactive metabolites Yes
Elimination

Predominantly renal;  < 5% in feces.

Urine 75% within 4 days, primarily as metabolites.
Half-life

16-48 hours

 
C - Indications and Status
Health Canada Approvals:

  • Brain tumours
  • Hodgkin's disease


Other Uses:

  • Advanced breast cancer
  • Lung cancer (squamous cell, anaplastic large cell, adenocarcinoma)
  • Malignant melanoma
 
D - Adverse Effects

Emetogenic Potential:  

Moderate – Consider prophylaxis daily

Extravasation Potential:   Not applicable

ORGAN SITE SIDE EFFECT* (%) ONSET**
Dermatological Alopecia (rare) E
Gastrointestinal Mucositis (rare) E
Nausea (or vomiting - 45-100%) I
Vomiting I
General Fatigue E
Hematological Myelosuppression (65%) D
Hepatobiliary ↑ LFTs (transient, unusual) E
Neoplastic Leukemia (secondary) L
MDS L
Nervous System Ataxia (rare) E
Confusion (disorientation - rare) E
Dysarthria (rare) E
Ophthalmic Blurred vision (blindness - rare) E
Optic nerve disorder (optic atrophy - rare) E
Renal Nephrotoxicity L
Reproductive and breast disorders Infertility L
Respiratory Lung infiltrate (rare, dose-related) D
Pulmonary fibrosis (rare, dose-related) D


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

Myelosuppression is the principal dose limiting toxicity, may be delayed in onset (4-6 weeks) and is cumulative.

Nausea and vomiting is very common. Nausea may be minimized by giving the dose on an empty stomach; antiemetics should be used prophylactically.

Pulmonary toxicity with infiltrates and pulmonary fibrosis have been reported at cumulative doses usually greater than 1,100 mg/m2. The onset of toxicity has varied from 6 months after initiation of therapy, to as late as 15 years after. Patients with FVC or DLCO < 70% of normal are particularly at risk and should be monitored closely.

 
E - Dosing

Refer to protocol by which patient is being treated.  Numerous dosing schedules exist and depend on disease, response and concomitant therapy.  Guidelines for dosing also include consideration of white blood cell count.  Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxics/radiation therapy.  If the patient vomits after 30-45 minutes, do not repeat the dose.  Dose should be calculated to the nearest 10 mg to accommodate capsule sizes.



Adults:

Normal marrow function:
Oral: 130 mg/m² Every 6 weeks

Compromised marrow function:
Oral: 100 mg/m² Every 6 weeks

In combination:  Reduced dosing has been used.  Refer to specific protocol.
 



Dosage with Toxicity:

Dosage with myelosuppression: 

  • Do not retreat until leukocytes > 4 x 109/L and platelets > 100 x 109/L. 
  • Reduce next dose according to nadir counts as follows:

Nadir after prior dose

 

Leukocytes (x 109/L)

Platelets (x 109/L)

Lomustine (% previous dose)
 

> 4

> 100

100 %

3 - 4

75 – 100

100 %

2 - <3

25 – <75

70 %

<2

< 25

50 %



Dosage with Hepatic Impairment:

No specific recommendations found.  Although the metabolites are mainly excreted by the kidney, the liver is involved in lomustine metabolism.  Monitor closely in patients with hepatic impairment and adjust dose based on hematologic toxicity.


Dosage with Renal Impairment:

Dose reduction required.  The following is suggested:

Creatinine clearance (mL/min)

Lomustine (% previous dose)

> 50

100 %

10 – 50

75 %

< 10

50 %



Dosage in the elderly:

No specific recommendations found.


 
F - Administration Guidelines

  • Oral self-administration; drug available by outpatient prescription.
  • Protect from light.


 
G - Special Precautions
Other:

Lomustine is contraindicated in patients with known hypersensitivity to the drug, and in patients with severe leukopenia and/or thrombocytopenia.

Secondary malignancies, including acute leukemia and bone marrow dysplasias, have been reported following nitrosoureas therapy. Lomustine is carcinogenic, embryotoxic, teratogenic and causes infertility.  Lomustine should not be used in pregnancy.  Adequate contraception must be used during lomustine treatment and for at least 6 months after treatment cessation.  Lomustine metabolites are present in breast milk; therefore, breast feeding is not recommended.

 
H - Interactions

AGENT EFFECT MECHANISM MANAGEMENT
Cimetidine Potentiates marrow toxicity of lomustine Possibly by ↓ metabolism of lomustine Do not use cimetidine; choose a different H2 blocker
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency
Pulmonary function tests, in at risk patients:  extreme caution in patients with FVC or DLCO < 70% Baseline
CBC Baseline and regular
Liver and renal function tests Baseline
Clinical pulmonary exam, including auscultation, pulmonary toxicity ratings Periodic

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



Suggested Clinical Monitoring

Monitor Type Monitor Frequency
Pulmonary function tests, especially with with prolonged (> 6 months) therapy or cumulative doses > than 1,100 mg/m2 Baseline and regular
 
J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

  • lomustine ()

 
K - References

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)

Product Monograph:  CeeNU® (lomustine).  Bristol-Myers Squibb Canada, February 20, 2009.

Lomustine:  Chemotherapy Drug Manual, Clin-eguide.

 


June 2019 Updated emetic risk category.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.