Lomustine

Lomustine is a highly lipophilic nitrosourea. In the body it is hydrolysed and metabolised, rapidly and completely and mainly in the liver, into reactive metabolites with alkylating activity. These damage the DNA and RNA of tumour cells and stop them from dividing.

Mechanism of Action

• Alkylation and cross-linking: the metabolites alkylate and cross-link DNA (at the O6 position of guanine-containing bases) and RNA, which causes cytotoxicity.
• Further effects: the SmPC describes the mechanism as partly alkylating and partly the inhibition of several steps of nucleic acid synthesis and of the repair of strand breaks in DNA. Highly reactive isocyanates are also formed, but their role in the drug’s activity has not been clarified.
• Resistance: cross-resistance with other nitrosoureas is usual, whereas cross-resistance with conventional alkylating agents is less common.

Pharmacokinetics

• Absorption: lomustine is absorbed rapidly from the gastrointestinal tract and then fully metabolised on first pass; no unchanged lomustine was found after an oral radiolabelled dose. Peak plasma concentrations of the active metabolites occur 3–4 hours after an oral dose. The SmPC notes that the pharmacokinetics have not been fully determined.
• Distribution: about 50% bound to plasma proteins (DrugBank). Radiolabelled breakdown products cross the blood–brain barrier after oral dosing, and roughly 15–30% of the radioactivity measured in plasma can be detected in the cerebrospinal fluid.
• Metabolism: first-pass metabolism produces monohydroxylated metabolites with alkylating activity, trans-4-hydroxy-CCNU and cis-4-hydroxy-CCNU.
• Elimination: these metabolites are cleared mainly by the kidneys, with a plasma half-life of about 2 hours but large differences between individuals. After a radiolabelled dose of 30–100 mg/m², the labelled breakdown products peaked about 3 hours after the dose; a metabolite containing the chloroethyl group had a half-life of 72 hours and one containing the cyclohexyl group a terminal half-life of 50 hours. About half of the radioactivity given was excreted in the urine within 24 hours (DrugBank).
• Special populations: the SmPC gives no pharmacokinetic data for kidney or liver impairment; safety and efficacy in these patients have not been established.

The indications follow the SmPC of Lomustine Medac 40 mg capsules (France). Lomustine is nationally authorised, so wording may differ in other member states.

Lomustine is used for palliative or adjunctive treatment of the following conditions, usually in combination with radiotherapy and/or surgery as part of combination chemotherapy:

• Brain tumours, primary or metastatic.
• Small-cell lung cancer.
• Hodgkin’s disease that is resistant to conventional combination chemotherapy.
• Malignant melanoma, metastatic.
• Non-Hodgkin lymphoma.

• Hypersensitivity to lomustine, to other nitrosoureas or to any of the excipients.
• A tumour that did not respond to previous treatment with other nitrosoureas.
• Severe bone-marrow depression.
• Severe renal impairment.
• Pregnancy and breastfeeding.
• Allergy to wheat.
• Concomitant yellow fever vaccine or other live vaccines in immunocompromised patients.

Bone-marrow toxicity and gastrointestinal symptoms are the most frequent and most relevant side effects of lomustine.

Very common (≥1/10): myelosuppression, pancytopenia, thrombocytopenia, leukopenia, neutropenia, anaemia; nausea, vomiting, decreased appetite.

Common (≥1/100 to <1/10): infection, including opportunistic infection such as herpes zoster; abnormal coordination, disorientation, lethargy, dysarthria, ataxia; stomatitis, diarrhoea; abnormal liver function; raised liver enzymes (AST, ALT, LDH and alkaline phosphatase).

Uncommon (≥1/1,000 to <1/100): apathy, confusional state, stuttering (dysphemia); renal failure, renal injury.

Rare (≥1/10,000 to <1/1,000): interstitial pneumonia, pulmonary fibrosis; cholestatic jaundice; alopecia; abnormal spermatogenesis, ovulation disorder.

Very rare (<1/10,000): secondary tumours, including acute leukaemia and myelodysplastic syndrome; blindness after combined treatment with radiotherapy.

Not known: pulmonary infiltration; azotaemia, renal atrophy; raised blood bilirubin.

Bone-marrow suppression is delayed, dose-related and usually appears 4 to 6 weeks after a dose. Platelets fall at about 4 weeks and stay at roughly 80,000–100,000/mm³ for 1 or 2 weeks; white cells fall at 5 to 6 weeks and stay low for 1 or 2 weeks. After 130 mg/m², about 65% of patients had a white cell count below 5,000/mm³ and 36% below 3,000/mm³. Thrombocytopenia is generally more severe than leukopenia, and anaemia is less frequent and less severe. Nausea and vomiting begin 3 to 6 hours after an oral dose, usually last less than 24 hours and are followed by reduced appetite for 2 to 3 days; they are less troublesome when the 6-weekly dose is divided over the first 3 days, and antiemetics before the dose and taking lomustine on an empty stomach can reduce them. Lung toxicity (infiltration, interstitial pneumonia, fibrosis) is rare and usually appears 6 months or more after the start of treatment, at cumulative doses generally above 1,100 mg/m²; delayed fibrosis up to 17 years later has been reported in patients treated in childhood for intracranial tumours with related nitrosoureas. Reversible liver toxicity occurs in a small percentage of patients. Kidney abnormalities (smaller kidneys, progressive azotaemia, renal failure) have followed large cumulative doses above 1,500 mg/m² and, occasionally, lower total doses.

No interaction studies have been performed.

• Theophylline and cimetidine: given together with lomustine, theophylline or the H2 antihistamine cimetidine could potentiate its bone-marrow toxicity.
• Antiepileptic medicines: combining antiepileptics with chemotherapy, including lomustine, can lead to complications from pharmacokinetic interactions. For example, earlier treatment with phenobarbital can reduce the antitumour effect of lomustine because induction of liver microsomal enzymes speeds its elimination.
• Other cytostatic agents and radiotherapy: given at the same time, they can amplify the bone-marrow depression associated with lomustine.
• Yellow fever vaccine and other live vaccines: the risk of fatal generalised vaccine disease is increased with yellow fever vaccine. Live vaccines are contraindicated in immunocompromised patients.

Treatment must be given under the supervision of physicians experienced in cancer treatment. The capsules are taken by mouth, swallowed whole and never opened, preferably at bedtime or 3 hours after a meal.

Recommended Dose (Adults)

• Normal bone-marrow function, lomustine as the only chemotherapy: a single dose of 120–130 mg/m² every 6 to 8 weeks, or the same dose divided over 3 days (for example 40 mg/m² per day). The dose must not exceed 130 mg/m².
• Bone-marrow insufficiency: 100 mg/m² every 6 weeks.
• Dose reduction: the dose is reduced when lomustine is given as part of a treatment that depresses the bone marrow, and in leukopenia (white cells below 3,000/mm³) or thrombocytopenia (platelets below 75,000/mm³).
• Cumulative dose: the maximum cumulative dose of 1,000 mg/m² must not be exceeded, because of the risk of pulmonary fibrosis.

Dose Adjustment and Blood-Count Monitoring

• After the first dose, later doses are adjusted to the blood-count response to the previous dose. The SmPC table may be used as a guide, based on the lowest (nadir) counts after the previous dose:
  • leucocytes 4,000/mm³ or more and platelets 100,000/mm³ or more: 100% of the previous dose;
  • leucocytes 3,000–3,999/mm³ and platelets 75,000–99,999/mm³: 100% of the previous dose;
  • leucocytes 2,000–2,999/mm³ and platelets 24,000–74,999/mm³: 70% of the previous dose;
  • leucocytes below 2,000/mm³ and platelets below 25,000/mm³: 50% of the previous dose.
• Bone-marrow depression lasts longer than with nitrogen mustards, and white cell and platelet counts may not normalise for 6 weeks or more. The next dose waits until counts are back to 4,000/mm³ (white cells) and 100,000/mm³ (platelets).
• Blood counts are checked every week, and at least 6 weeks must pass before the next dose, because the haematological toxicity is delayed and cumulative.

Special Populations

• Children: the dose is the same as in adults.
• Renal impairment: safety and efficacy have not been established; renal function should be checked periodically.
• Hepatic impairment: safety and efficacy have not been established; liver function should be checked periodically.

Missed Dose

The SmPC gives no separate missed-dose rule. It does state that the dose is a single oral dose (or divided over three days) that must not be repeated for at least 6 weeks, and that patients must be told strictly never to take more than the doctor recommended.

Bone-Marrow Suppression

Delayed bone-marrow aplasia, especially thrombocytopenia and leukopenia, is the most frequent and most severe toxic effect of lomustine; it can favour bleeding and serious infections in a patient who is already weakened. Blood counts must be checked before treatment and at close intervals during it, preferably every week for at least 6 weeks after each dose. Treatment and dose decisions are guided mainly by haemoglobin, white cell count and platelet count. The toxicity is cumulative, so each dose is adjusted to the nadir after the previous one, and the interval between doses must never be shorter than 6 weeks.

Lung Toxicity

Lung toxicity appears to be dose-related. Lung function tests should be done before treatment and repeated frequently during it. Patients whose forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLco) is below 70% of the predicted value at the start are at particular risk.

Liver and Kidney Function

Lomustine can cause liver dysfunction, so liver function should be checked periodically. Kidney function should also be monitored periodically. The cumulative dose must not exceed 1,000 mg/m².

Secondary Malignancies

A possible association has been reported between long-term use of nitrosoureas and secondary malignant tumours.

Handling Anticancer Medicines

Anticancer medicines must be handled with care. Exposure should be avoided with suitable protective equipment such as gloves, and hands should be washed with soap and water after handling.

Vaccines

Live vaccines should be given no sooner than 3 months after the end of lomustine treatment. Yellow fever vaccine and other live vaccines are contraindicated in immunocompromised patients.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy: contraindicated. Safety in pregnancy has not been established and animal studies showed reproductive toxicity. A patient who takes lomustine during pregnancy, or becomes pregnant while taking it, must be told of the potential risk to the foetus. Women of childbearing potential should avoid pregnancy.
• Contraception: because lomustine is potentially genotoxic, women of childbearing potential must use effective contraception during treatment and for 7 months after it ends. Men are advised to use effective contraception and not to father a child during treatment and for 4 months after it ends.
• Breastfeeding: contraindicated; as lomustine is lipophilic it is probably excreted in breast milk.
• Fertility: lomustine may be mutagenic. Genetic counselling is recommended for patients who want children after treatment, and men should seek advice on sperm preservation before starting because treatment may cause irreversible infertility.

Lactose and Wheat Starch

The capsules contain lactose; patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not use them. They also contain wheat starch, with no more than 4 micrograms of gluten per capsule; they are considered gluten-free and unlikely to cause problems in coeliac disease, but patients allergic to wheat must not take them.

Effect on Driving

The effect on the ability to drive and use machines has not been studied. Lomustine could impair it, for example through nausea and vomiting.

Store in the original package, protected from light and moisture, at a temperature not exceeding 25 °C. The capsules are supplied in plastic safety bottles of 5 or 20 capsules; not all pack sizes may be marketed. Keep out of the sight and reach of children.

3 years.

Prescription only (Rx). Treatment is given under the supervision of physicians experienced in cancer treatment. The capsules are taken by mouth as a single dose repeated no sooner than every 6 weeks, so they are supplied to the patient or to the treating clinic on prescription.