Usage
Lomustine is prescribed for the treatment of various types of cancers, including brain tumors (both primary and metastatic), Hodgkin’s lymphoma (as a second-line therapy after initial chemotherapy fails), and other cancers such as lung cancer, malignant melanoma, and cancers of the colon, breast, kidney, testis, ovary, cervix, and breast. It is classified as an alkylating agent, a type of chemotherapy.
Lomustine works by interfering with DNA and RNA synthesis in cancer cells. It alkylates DNA and RNA, which disrupts cell division and ultimately leads to cell death.
Alternate Names
Lomustine is also known as CCNU. Common brand names include Gleostine and CeeNU.
How It Works
Pharmacodynamics: Lomustine exerts its cytotoxic effects by alkylating DNA and RNA. This alkylation process disrupts nucleic acid function and inhibits DNA replication and RNA transcription, ultimately triggering cell death. The drug’s action is not cell cycle-specific, affecting cells in all phases of the cycle.
Pharmacokinetics: Lomustine is well-absorbed after oral administration. It undergoes extensive hepatic metabolism, forming active and inactive metabolites. Approximately 50% of the drug is bound to plasma proteins. Elimination is primarily through renal excretion of metabolites, with less than 10% excreted as carbon dioxide through the respiratory system. The terminal half-life ranges from 16 to 72 hours for lomustine and 31.2 to 48 hours for its active metabolite.
Mode of Action: Lomustine acts as a bifunctional alkylating agent. The drug forms interstrand cross-links in DNA, preventing DNA replication and RNA transcription.
Receptor Binding, Enzyme Inhibition or Neurotransmitter Modulation: Lomustine does not have a specific receptor target. Its primary mechanism involves direct interaction with DNA via alkylation. It is a major substrate of CYP2D6 and a weak inhibitor of both CYP2D6 and CYP3A4.
Elimination Pathways: Lomustine undergoes hepatic metabolism followed by renal excretion of the resulting metabolites. Some elimination occurs via respiratory excretion of carbon dioxide.
Dosage
Standard Dosage
Adults:
The standard dose is 130 mg/m² (body surface area) orally as a single dose every 6 weeks. The dose should be rounded to the nearest 5 mg.
Children:
The pediatric dosage is the same as the adult dosage, calculated based on body surface area (130 mg/m² every 6 weeks). Safety and efficacy in pediatric patients have not been fully established in all cancer types. Pediatric use should be guided by expert oncologists, especially for conditions other than brain tumors and Hodgkin’s lymphoma.
Special Cases:
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Elderly Patients: No specific dosage adjustments are explicitly defined for elderly patients. Caution is advised due to potential age-related decline in organ function (hepatic, renal, and cardiac). Dose modifications should be based on individual patient characteristics and close monitoring.
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Patients with Renal Impairment: Dose reduction is necessary in patients with renal impairment. For creatinine clearance between 10-50 mL/min, administer 75% of the regular dose. For creatinine clearance <10 mL/min, administer 25-50% of the regular dose. Some guidelines recommend discontinuing Lomustine if Creatinine clearance is <30mL/min. Monitor renal function closely.
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Patients with Hepatic Dysfunction: No specific dose adjustments are available for patients with hepatic impairment, however, the liver plays a significant role in Lomustine’s metabolism. Exercise caution and monitor liver function tests closely. Adjust dosage based on hematologic toxicity.
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Patients with Comorbid Conditions: Careful consideration is needed for patients with other health conditions. Monitor closely for pulmonary function, as pulmonary toxicity is a dose-related risk, especially with cumulative doses > 1100 mg/m².
Clinical Use Cases
Lomustine is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU care, or emergency situations. Its primary role is in cancer treatment, usually administered on an outpatient basis.
Dosage Adjustments
Dose reduction is required for patients with compromised bone marrow function (100 mg/m² every 6 weeks). Adjustments are also necessary when Lomustine is used in combination with other myelosuppressive drugs. Further modifications are determined by individual patient’s blood counts (leukocytes, platelets). Do not repeat a dose until leukocytes are >4000/mm³ and platelets are >100,000/mm³. Adjust subsequent doses based on the lowest blood cell counts (nadir) observed after the prior dose.
Side Effects
Common Side Effects
- Myelosuppression (decreased blood cell counts): This can lead to increased risk of infection (fever, chills, weakness), bleeding or bruising, and fatigue.
- Nausea and vomiting (often severe, lasting up to 24 hours)
- Loss of appetite (can last for several days)
- Diarrhea
- Mouth sores and ulcers
Rare but Serious Side Effects
- Pulmonary fibrosis (scarring of the lungs): Can develop months or even years after treatment.
- Secondary malignancies (e.g., leukemia)
- Renal toxicity (kidney damage)
- Hepatic toxicity (liver damage)
- Neurotoxicity (confusion, difficulty walking, difficulty speaking, loss of balance)
Long-Term Effects
- Pulmonary fibrosis
- Secondary cancers
- Infertility
Adverse Drug Reactions (ADR)
- Severe myelosuppression
- Pulmonary toxicity
- Renal or hepatic impairment
- Allergic reactions
Contraindications
- Hypersensitivity to lomustine or other nitrosoureas
- Severe bone marrow depression
- Severe renal impairment
- Pre-existing lung disease
- Pregnancy and breastfeeding
- Active infections (especially with live vaccines such as yellow fever vaccine)
- Celiac disease or wheat allergy (due to the presence of wheat starch in some formulations)
Drug Interactions
- CYP450 Interactions: Lomustine is a major CYP2D6 substrate and a weak inhibitor of CYP2D6 and CYP3A4. Co-administration with drugs that are metabolized by or inhibit these enzymes can alter lomustine levels or the levels of other drugs.
- Myelosuppressive Drugs: Concomitant use with other myelosuppressive agents (e.g., other chemotherapy drugs) can increase the risk of severe myelosuppression.
- Cimetidine & Theophylline: These medications may increase bone marrow depression.
- Phenytoin & Fosphenytoin: Monitor for altered phenytoin levels.
- Live Vaccines: Avoid concomitant administration due to the risk of serious infections in immunocompromised patients.
Pregnancy and Breastfeeding
Lomustine is contraindicated during pregnancy (Pregnancy Category D) and breastfeeding. It is embryotoxic and teratogenic in animals and poses a significant risk to the developing fetus. It is likely excreted in breast milk, potentially harming the nursing infant. Effective contraception is essential during and for at least 6 months after treatment.
Drug Profile Summary
- Mechanism of Action: Alkylating agent, disrupts DNA and RNA synthesis.
- Side Effects: Myelosuppression, nausea, vomiting, loss of appetite, pulmonary fibrosis, secondary cancers.
- Contraindications: Hypersensitivity, severe bone marrow or renal impairment, pregnancy, breastfeeding.
- Drug Interactions: CYP2D6 and CYP3A4 interactions, other myelosuppressive drugs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 130 mg/m² orally every 6 weeks. Adjustments based on bone marrow function, renal/hepatic impairment.
- Monitoring Parameters: CBC (complete blood count) weekly, pulmonary function tests, liver and renal function tests.
Popular Combinations
Lomustine may be used in combination with other chemotherapy drugs, particularly in the treatment of Hodgkin’s lymphoma or brain tumors. Specific combinations and regimens will vary depending on the cancer type and individual patient factors. Procarbazine and Vincristine are commonly used with Lomustine, particularly with adjuvant radiation therapy for treatment of certain brain tumors. In pediatric low-grade glioma, it may be used adjuvant to surgery in combination with thioguanine, procarbazine, and vincristine. For pediatric medulloblastoma, it may be used after surgery and radiation therapy in combination with other chemotherapeutic agents.
Precautions
- General Precautions: Baseline pulmonary function tests, renal and liver function tests, and complete blood counts are necessary. Careful monitoring of blood counts throughout treatment is essential.
- Specific Populations: Avoid in pregnancy and breastfeeding. Exercise caution in elderly patients and those with hepatic or renal impairment.
- Lifestyle Considerations: No specific lifestyle restrictions are universally associated with lomustine, however, patients experiencing side effects like fatigue may need to limit strenuous activities.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lomustine?
A: The standard adult dosage is 130 mg/m² orally every 6 weeks. Dosage adjustments are required for patients with renal or hepatic impairment, compromised bone marrow function, or when used in combination with other myelosuppressive therapies. Pediatric dosing is the same as adult dosing, based on body surface area.
Q2: What is the mechanism of action of Lomustine?
A: Lomustine is an alkylating agent that crosslinks DNA and RNA, disrupting nucleic acid function, inhibiting DNA and RNA synthesis, and ultimately inducing cell death.
Q3: What are the most common side effects of Lomustine?
A: Myelosuppression (low blood cell counts), nausea, vomiting, loss of appetite, mouth sores, and fatigue are common side effects.
A: Pulmonary fibrosis, secondary malignancies, severe myelosuppression, renal impairment, hepatic impairment, and allergic reactions are rare but serious side effects.
Q5: Can Lomustine be used during pregnancy or breastfeeding?
A: No, Lomustine is contraindicated during pregnancy and breastfeeding due to its potential for fetal harm and excretion in breast milk.
Q6: What are the key drug interactions with Lomustine?
A: Lomustine interacts with drugs metabolized by or inhibiting CYP2D6 and CYP3A4. Co-administration with other myelosuppressive agents can exacerbate bone marrow toxicity. Cimetidine and Theophylline can potentiate bone marrow suppression, and interactions with Phenytoin and Fosphenytoin require close monitoring.
Q7: What monitoring parameters are crucial during Lomustine treatment?
A: Complete blood counts (weekly), pulmonary function tests, liver function tests, and renal function tests are essential for monitoring patients on Lomustine.
Q8: How is Lomustine administered?
A: Lomustine is administered orally as a single dose every six weeks. It should be taken on an empty stomach to minimize nausea and vomiting. Capsules should be swallowed whole and not crushed, chewed, opened or dissolved.
Q9: Is there a maximum cumulative dose for Lomustine?
A: Some guidelines recommend a maximum cumulative dose of 1000 mg/m² due to the risk of pulmonary fibrosis.
Q10: How should Lomustine be handled?
A: When handling Lomustine capsules, wear protective gloves to prevent skin contact. Pregnant women should avoid handling the drug altogether due to the potential risk to the fetus.
