Lomustine (CeeNU)
Lomustine is an antitumour agent, cancer chemotherapeutic agent, cytotoxic agent and alkylating agent. Chemically, lomustine is similar to the other nitrosoureas carmustine (BiCNU) and semustine (methyl CCNU) and, as well, to Streptozotocin. Biologically, lomustine has some comparability to the alkylating agents. The chemical name for Lomustine is 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with the structural formula: Molecular Formula: C9H16N3O2Cl Molecular Weight: 233.69 Lomustine is a yellow powder, very slightly soluble in water (0.5mg/mL); slightly soluble in propylene glycol (0.7mg/mL) and polysorbate 80 (2.5mg/mL); soluble in absolute alcohol (70mg/mL).
Pharmacokinetics
Lomustine rapidly decomposes under physiological conditions and no intact drug has been detected in serum after oral administration in humans. Pharmacokinetic studies have used radioactively labelled (C14) lomustine, with the label in either the chloroethyl, carboxyl or cyclohexyl groups.
Absorption
Average peak plasma levels occur at 4 hours, 1 hour and 3 hours respectively for the chloroethyl, carboxyl and cyclohexyl C14-labelled moieties. The extent of absorption was difficult to assess but approximately 60% of the radioactivity administered was recovered in the urine by 48 hours. No data are available on the site or mechanism of absorption, or the effect of blood, other drugs or excipients in the formulation, on absorption of lomustine.
Bioavailability
Bioavailability is difficult to define as lomustine is labile and undergoes rapid decomposition. Furthermore the active moiety is unknown.
Distribution
The volume of distribution, organ accumulation etc for this drug is unknown. CSF levels of the labelled chloroethyl moiety have been studied. Peak CSF levels coincide with peak plasma levels. CSF levels were about 30% of plasma levels and the half-life in CSF was 6 hours. No intact drug was detected in the CSF.
Protein-binding
Radiolabelled metabolites bind to proteins. There is no specific information on binding to plasma proteins, strength of binding and displacement by other drugs.
Metabolism
Lomustine decomposes under physiological conditions (half-life of 53 minutes in phosphate buffer, pH 7.4, 37oC). The in vivo site of decomposition (bowel, lumen, plasma, liver etc) is not known. Decomposition products include cyclohexylamine, cyclohexylisocyanate and N, N' -dicyclohexylurea. The disappearance of radioactivity from plasma for the chloroethyl-labelled moiety followed a single phase half-life of 72 hours. The cyclohexyl and carboxyl moieties had two-fold plasma disappearance half-lives of 4 and 5 hours respectively and 50 and 27 hours respectively. Prolonged plasma half-lives are thought to reflect a combination of protein binding and enterohepatic circulation of metabolites.
Excretion
Approximately 60% of the radioactivity administered was recovered in the urine by 48 hours and excretion of radioactivity was virtually complete within 72 hours. About 50 to 60% of radioactivity excreted was recovered during the first 12 hours. No intact drug was detected in the urine. In animals, less than 5% of the drug was excreted in the faeces.
Clinical Implications of Pharmacokinetic Data
The predominantly renal excretion of the drug metabolites suggests that severe renal insufficiency could predispose to increased toxicity. The high lipid solubility and the relative lack of ionisation at a physiological pH enables lomustine to cross the blood-brain barrier effectively. This is the rationale for its use in brain tumours. The prolonged half-life of the radioactively labelled metabolites may be an explanation for the delayed onset of myelosuppression.
Pharmacodynamics
Systemic screening of synthetic components at the National Cancer Institute in the US was carried out in the fifties, using animal tumours (Sarcoma 181, Carcinoma 755 and Leukaemia L1210). Activity against leukaemia L1210 was demonstrated for 1-methyl-1-nitroso-3-guanidine (MNNG) in 1959. Following this, structurally related compounds were evaluated, including the nitrosourea class. 1-methyl-1-nitrosourea (MNU) was found to be more effective than MNNG. It was also found to be lipid soluble, making it effective against L1210 in the CNS.
Site and mode of action
A single definitive molecular mechanism of action for lomustine is not apparent. It may act by the following possible mechanisms:
Alkylation of nucleic acids.
Carbamoylation of proteins.
Interference with enzyme activation (histidine metabolism, forminotransferase, DNA polymerase, NAD-ase).
Lomustine is labile and after oral administration no intact drug is detectable in plasma. Highly reactive intermediates, which bind to macromolecules, are formed rapidly. How the nature and selectivity of these intermediates relate to antitumour activity and toxicity is poorly understood. The overall result is thought to be the inhibition of both DNA and RNA synthesis. Cross resistance between lomustine and carmustine has occurred.
CeeNU may be used for the treatment of:
Brain tumours (primary and secondary).
Hodgkin' s disease (as secondary therapy).
Lomustine is used in addition to appropriate surgical and/or radiotherapeutic procedures or as a component of various chemotherapeutic regimens in the palliative treatment of primary and metastatic brain tumours. CeeNU containing combinations should be used as alternative therapy in the treatment of disseminated Hodgkin' s disease in patients refractory to other established treatment regimens.
Hypersensitivity
CeeNU should not be given to patients who have demonstrated a previous hypersensitivity to it.
Severe myelosuppression
CeeNU is contraindicated in patients with marked myelosuppression.
CeeNU should be used in approved institutions and be administered by individuals experienced in the use of antineoplastic therapy.
Delayed haematological toxicity
Since the major toxicity is delayed bone marrow suppression, notably thrombocytopenia and leucopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, blood counts should be monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of CeeNU should not be given more frequently than 6 weekly.
Myelosuppression
Caution should be used in administering CeeNU to patients with decreased circulating platelets, leucocytes or erythrocytes (see DOSAGE AND ADMINISTRATION, ADULTS).
Pulmonary fibrosis
Respiratory symptoms indicative of pulmonary fibrosis may not appear for several months following initiation of treatment with CeeNU. Withdrawal of the drug does not arrest fibrotic degeneration, and a number of deaths from acute respiratory failure have occurred. Pulmonary toxicty appears to be dose related.
Secondary malignancies
Long-term use of nitrosourea has been reported to be possibly associated with the development of secondary malignancies.
Bone marrow toxicity
The bone marrow toxicity of lomustine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).
Liver function
Animal studies revealed delayed liver damage evidenced by the sudden marked elevation of transaminase, alkaline phosphatase and BSP values. The reversibility of such toxicity has not been demonstrated and regular liver function tests should be carried out during therapy.
Renal toxicity
Evidence of renal toxicity has been observed in dogs and monkeys manifested by elevated BUN. Chronic renal failure has been reported with lomustine administration (see ADVERSE REACTIONS). Renal function tests should be monitored periodically.
Carcinogenesis
Lomustine is carcinogenic in rats and mice, producing a marked increase in tumour incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential. The occurrence of acute leukaemia and bone marrow dysplasias has been reported in patients following nitrosourea therapy.
Pulmonary Function
Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLco) are particularly at risk.
Fertility
CeeNU affects fertility in male rats at doses somewhat higher than the human dose. Dispense only a single dose to patient.
Pregnancy Category (Category D)
Safety in pregnancy has not been established. Lomustine has been shown to be carcinogenic, embryotoxic and teratogenic in animal studies. Lomustine must also be regarded as a potential mutagen. Therefore, the drug should not be used in pregnant women, or those likely to become pregnant, unless the expected benefit outweighs any potential risk.
Some lomustine metabolites are excreted in breast milk and may be harmful in young children (see USE IN PREGNANCY). Therefore it should not be given to nursing mothers.
Food
It is reported that administration of lomustine on an empty stomach reduces the incidence of nausea and vomiting.
More Common Reactions:
Gastrointestinal
Nausea and vomiting occur in 45 to 100% of patients within 45 minutes to 6 hours after ingestion of an oral dose of lomustine. Although these symptoms are not severe and usually abate within 24 hours, they may persist up to 36 hours and are often followed by 2 to 3 days of anorexia. The frequency and duration of these effects can be reduced by fasting or by administration of antiemetics. Clinical pharmacological studies indicated that the nausea and vomiting occur after drug absorption has taken place. It appears to be a CNS mediated effect of lomustine.
Haematological
Myelosuppression. The major and dose limiting side effect of lomustine is delayed haematological toxicity. Leucopenia occurs at about 6 weeks after a dose of lomustine and persists for 1 to 2 weeks. Approximately 65% of patients develop white blood counts below 5,000 wbc/mm3 and 36% develop white blood counts below 3,000 wbc/mm3. Thrombocytopenia occurs at about 4 weeks after a dose of lomustine and persists for 1 to 2 weeks. Lomustine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose- limiting toxicities. The occurrence of acute leukaemia and bone marrow dysplasias have been reported in patients following long term nitrosourea therapy. Anaemia also occurs, but is less frequent and less severe than thrombocytopenia or leucopenia.
Less Common Reactions:
Biochemical abnormalities
Elevation of liver function test results. Dermatological Alopecia. Gastrointestinal Stomatitis. Anaemia General Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as possible haemorrhagic complications.
Haematological and reticuloendothelial
Decreases in haematocrit, mild anaemia. When lomustine therapy is continued for longer than 1 year, refractory anaemia and thrombocytopenia are common. Mild pancytopenia has also been reported after lomustine treatment.
Hepatic
Hepatic toxicity, manifested by transient elevation of transaminase, alkaline phosphatase and bilirubin levels, has been reported in a small percentage of patients receiving CeeNU.
Nervous System
Disorientation, lethargy, ataxia, dysarthria. Renal Renal abnormalities consisting of decrease in kidney size, progressive azotemia and renal failure have been reported in patients who receive large cumulative doses after prolonged therapy with lomustine and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Serious or Life-threatening Reactions:
Myelosuppression
The delayed onset of myelosuppression demands the utmost care by the prescriber in monitoring the patient' s haematology, selecting the appropriate interval between doses and deciding the actual dose to be administered. There is considerable risk of prolonged or fatal myelosuppression if such care is not taken.
Infection and haemorrhagic complications
As these complications are potentially fatal, the patient should be instructed to notify the physician if fever, sore throat, or unusual bleeding or bruising occurs.
Pulmonary toxicity
Pulmonary toxicity characterised by pulmonary infiltrates and/or fibrosis have been rarely reported with lomustine. Onset of toxicity has occurred after an interval of six months or longer from the start of therapy with cumulative doses of lomustine usually greater than 1100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600mg. Delayed onset pulmonary fibrosis accurring up to 17 years after treatment has been reported in patients with intracranial tumours who received related nitrosoureas during their childhood and early adolescence.
Adults
The recommended dose of CeeNU is 130mg/m2 as a single dose by mouth every 6 weeks. In individuals with compromised bone marrow function, the dose should be reduced to 100mg/m2 every six weeks. A repeat course of CeeNU should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3, leucocytes above 4,000/mm3). Blood counts should be monitored weekly and repeat courses should not be given before six weeks because the haematological toxicity is delayed and cumulative. Doses subsequent to the initial dose should be adjusted according to the haematologic response of the patient to the preceding dose. The hematologic response should be checked prior to the next dose and the dose adjusted accordingly. The following schedule is suggested by the manufacturer as a guide to dosage adjustment.
| Nadir After Prior Dose | Percentage of Dose to be Given | |
| Leukocytes (/mm 3 ) Platelets (/mm 3 ) | ||
| 4,000 | 100,000 | 100 percent |
| 3,000-3,999 | 75,000-99,999 | 100 percent |
| 2,000-2,999 | 25,000-74,999 | 70 percent |
| <2,000 | <25,000 | 50 percent |
When CeeNU is used in combination with myelosuppressive drugs, the doses should be adjusted accordingly.
As for adults.
No specific recommendations are made, but as excretion of CeeNU metabolites is predominantly renal, severely impaired renal function could predispose to increased toxicity.
The hepatic excretion of lomustine metabolites is minor and there are no clear indications that toxicity is altered in patients with impaired liver function.
The predominantly renal excretion of lomustine metabolites suggest that severe renal insufficiency could predispose to increased toxicity.
Only the appropriate number of CeeNU capsules required for a single administration should be dispensed. Patients should be told that CeeNU is taken as a single oral dose and will not be repeated for at least 6 weeks Procedures for proper handling and disposal of anticancer drugs should be followed, according to published guidelines. Care must be taken whenever handling cytostatic products. Always take steps to prevent exposure, This includes appropriate equipment, such as, wearing gloves, and washing hands with soap and water after handling such products.
Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath. There is no specific antidote for overdose with CeeNU. In case of overdose, appropriate supportive measures should be taken
Capsule, 10mg (white, marked BRISTOL 3030/10mg): 20' s, 40mg (white/dark green, marked BRISTOL 3031/40mg):20' s; 100mg (dark green, marked BRISTOL 3032/100mg):20' s.
Store below 25oC. Composition of Dosage Form In addition to the active ingredient each hard gelatin capsule contains mannitol and magnesium stearate as excipients.
In order to provide the proper dose of CeeNU, patients should be aware that there may be two or more different types and colours of capsules in the container dispensed by the pharmacist.
Patients should be told that CeeNU is given as a single oral dose and will not be repeated for at least six weeks. Capsules should be taken on an empty stomach.
Patients should be told that nausea and vomiting usually last less than 24 hours; it is extremely important to ensure that the capsules have not been vomited. Loss of appetite may last for several days.
If any of the following reactions occur, notify the physician: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion or yellowing of eyes and skin.
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