Consumer medicine information

CeeNU

Lomustine

BRAND INFORMATION

Brand name

CeeNU

Active ingredient

Lomustine

Schedule

What is in this leaflet

This leaflet answers some common questions about CeeNU. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CeeNU against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CeeNU is used for

CeeNU is used to treat brain cancer. It may also be used to treat another type of cancer called Hodgkin's Disease.

CeeNU belongs to a group of medicines called cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

CeeNU works by killing cancer cells.

CeeNU is often used in combination with other medicines to treat your cancer.

Your doctor may have prescribed CeeNU for another reason. Ask your doctor if you have any questions about why CeeNU has been prescribed for you.

This medicine is available only with a doctor's prescription.

Safety and effectiveness in children have not been established.

Before you take CeeNU

Do not take CeeNU if you have a severe allergy to CeeNU or any of the ingredients listed at the end of this leaflet,

Symptoms of an allergic reaction may include:

shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
swelling of the face, lips, tongue or other parts of the body
rash, itching, hives or flushed, red skin
dizziness or light headedness

Do not take CeeNU if you have, or have had, any of the following medical conditions, unless you have discussed it with your doctor:

blood disorder with a reduced number of red or white blood cells
liver problems
kidney problems
lung disease (including asthma)
heart problems (including a heart attack)
any other cancer
lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer

Tell your doctor if you have allergies to:

any other medicines
any other substances, such as foods, preservatives or dyes

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

You should advise your doctor if you have had surgery recently.

Females: tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Like most cytotoxic medicines, CeeNU is not recommended for use during pregnancy. If there is any need to consider CeeNU during your pregnancy, your doctor will discuss with you the benefits and risks of using it. CeeNU may affect your developing baby if you take it during pregnancy.

Males: tell your doctor or pharmacist if your partner intends to become pregnant while you are taking CeeNU or shortly after you have stopped taking CeeNU.

You should use some kind of birth control while you are taking CeeNU and for at least 12 weeks after you stop using it. CeeNU may cause birth defects if either the male or female is using it at the time of conception.

Do not breastfeed while taking CeeNU. CeeNU passes into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and CeeNU may interfere with each other.

These medicines may be affected by CeeNU, or may affect how well it works. You may need different amounts of your medicine, or you may need to have different medicines. Your doctor or pharmacist will advise you.

CeeNU when used in combination with other drugs or radiation therapy may further depress your immune system. Your doctor or pharmacist may have more information on medicines to be careful with or avoid while having CeeNU.

If you are not sure whether you should start taking CeeNU or if you have not told your doctor about any of the above, you MUST tell them before you start taking CeeNU.

How to take CeeNU

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet. Your doctor or pharmacist will tell you how many capsules you will need to take, the time between doses and the length of time to take CeeNU. This depends on your condition and your weight and whether or not you are taking any other medicines.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many capsules you will need to take, the time between doses and the length of time to take CeeNU. This depends on your condition and your weight and whether or not you are taking any other medicines.

How to take it

Swallow CeeNU whole with a full glass of water. Do not chew the capsules. The capsules have a special coating to stop them dissolving until they have passed through the stomach into the intestines where they work. Chewing them destroys the coating.

When to take it

Take CeeNU on an empty stomach, for example, 1 hour before food or 2 hours after food. Food can interfere with the absorption of CeeNU.

How long to take it

Continue taking your medicine for as long as your doctor tells you. Your doctor will tell you when your treatment should be stopped.

CeeNU is given as a single oral dose. Another dose of CeeNU will not be repeated for at least six weeks. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

If you forget to take it

If you have forgotten to take a dose of CeeNU, contact your doctor.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much CeeNU. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using CeeNU

Things you must do

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have your follow-up doses of CeeNU at the appropriate times to get the best effects from your treatments.

If you forget a hospital appointment, immediately contact your doctor.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking CeeNU.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking CeeNU.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking CeeNU.

If you become pregnant while taking CeeNU, tell your doctor.

CeeNU can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
Avoid contact sports or other situations where you may bruise or get injured.

Things you must not do

Do not give CeeNU to anyone else, even if they have the same condition as you.

Do not take CeeNU to treat any other complaints unless your doctor or pharmacist tells you to.

Do not open the capsules. If a capsule is damaged, avoid contact with your skin and eyes. If you accidentally touch or inhale the powder, carefully wash the affected area with water. Avoid inhaling the powder.

Do not drink alcohol while taking CeeNU. You may feel flushed or get headaches.

Do not take more than your doctor has prescribed. High doses of CeeNU may be associated with a serious blood disorder.

Do not take CeeNU after the expiry date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take CeeNU if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Things to be careful of

Be careful driving or operating machinery until you know how CeeNU affects you. As with other anticancer medicines, CeeNU may cause nausea, disorientation or tiredness in some people. Make sure you know how you react to CeeNU before you drive a car, operate machinery, or do anything else that could be dangerous if you are disorientated or tired. If this occurs do not drive. If you drink alcohol, disorientation or tiredness may be worse.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking CeeNU. Like other medicines that treat cancer, CeeNU may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you.

These are the more common side effects of CeeNU.

nausea, vomiting, loss of appetite, sore mouth
dry cough
swelling of feet or lower legs
confusion
unusual hair loss or hair thinning
dizziness; light-headedness
feeling tired or drowsy

Tell your doctor or nurse as soon as possible if you notice any of the following.

These may be serious side effects. You may need medical attention.

infections, fever, severe chills, sore throat or mouth ulcers
bleeding or bruising more easily than normal, bleeding gums or nose bleeds, rash of small reddish-purple spots on your skin), blood in your stool or urine
tiredness, headaches, short of breath when exercising, dizziness, looking pale, fast heart rate
shortness of breath or change in breathing, cough, unusual tiredness
passing little or no urine, drowsiness, nausea, vomiting, headache and breathlessness
liver disease with symptoms such as weakness, tiredness, confusion, yellowing of the eyes and skin, loss of appetite, weight loss and stomach pain
lack of coordination or unsteady when walking, difficulty speaking

Other side effects not listed above may occur in some patients. Tell your doctor, nurse or pharmacist if you notice anything that is making you fell unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using CeeNU

The benefits and side effects of CeeNU may take some time to occur. Therefore even after you have finished your CeeNU treatment you should tell your doctor immediately if you notice any of the side effects listed.

Storage

Keep your capsules in the bottle until it is time to take them. If you take the tablets out of the pack they will not keep as well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store CeeNU or any other medicine in the bathroom or near a sink.

Do not leave it on a window sill or in the car on hot days. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicine.

Product description

What it looks like

Capsule 10 mg: - white, marked CPL3030/10mg

Capsule 40 mg: - white/dark green, marked CPL3031/40mg

Ingredients

Active ingredient:

lomustine

Other ingredients:

mannitol
magnesium stearate

Registration Numbers

10 mg capsules AUST R 19252

40 mg capsules AUST R 19249

Date of Preparation: November 2020

AU_CMI_CeeNU_V5.0_Nov20.docx

Published by MIMS January 2021

BRAND INFORMATION

Brand name

CeeNU

Active ingredient

Lomustine

Schedule

1 Name of Medicine

Lomustine.

2 Qualitative and Quantitative Composition

Capsules containing 10 mg and 40 mg of lomustine.
Lomustine (CeeNU) is an antitumour agent, cancer chemotherapeutic agent, cytotoxic agent and alkylating agent. Lomustine is a yellow powder, very slightly soluble in water (0.5 mg/mL); slightly soluble in propylene glycol (0.7 mg/mL) and polysorbate 80 (2.5 mg/mL); soluble in absolute alcohol (70 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Capsule containing 10 mg lomustine are white, marked CPL 3030/10 mg.
Capsule containing 40 mg lomustine are white/dark green, marked CPL 3031/40 mg.

4 Clinical Particulars

4.1 Therapeutic Indications

CeeNU may be used for the treatment of:
1. Brain tumours (primary and secondary);
2. 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.

4.2 Dose and Method of Administration

Adults.

The recommended dose of CeeNU is 130 mg/m² as a single dose by mouth every 6 weeks.
In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/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.

When CeeNU is used in combination with myelosuppressive drugs, the doses should be adjusted accordingly.

Paediatric use.

As for adults.

Use in elderly.

No specific recommendations are made, but as excretion of CeeNU metabolites is predominantly renal, severely impaired renal function could predispose to increased toxicity.

Hepatic impairment.

The hepatic excretion of lomustine metabolites is minor and there are no clear indications that toxicity is altered in patients with impaired liver function.

Renal impairment.

The predominantly renal excretion of lomustine metabolites suggest that severe renal insufficiency could predispose to increased toxicity.

Information for the patient.

1. 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.
2. 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.
3. 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.
4. 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.

4.3 Contraindications

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.

4.4 Special Warnings and Precautions for Use

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 leucopoenia, 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 Section 4.8 Adverse Effects (Undesirable Effects)). At the recommended dosage, courses of CeeNU should not be given more frequently than 6 weekly.

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 toxicity appears to be dose related.

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 (DL_co) are particularly at risk.

Myelosuppression.

Caution should be used in administering CeeNU to patients with decreased circulating platelets, leucocytes or erythrocytes (see Section 4.2 Dose and Method of Administration, Adults).

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 Section 4.2 Dose and Method of Administration, Table 1 Guide to dosage adjustment,).

Live virus vaccines.

Concomitant use of CeeNU with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reaction of the vaccine virus because normal defence mechanisms may be suppressed by CeeNU. Vaccination with a live vaccine in a patient taking CeeNU may result in severe infection. Patient's antibody response to vaccines may be decreased. The use of live vaccines should be avoided and individual specialist advice sought.

Use in hepatic impairment.

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.

Use in renal impairment.

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 Section 4.8 Adverse Effects (Undesirable Effects)). Renal function tests should be monitored periodically.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There is increased risk of fatal systemic vaccine disease with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients (see Section 4.4 Special Warnings and Precautions for Use).

Food.

It is reported that administration of lomustine on an empty stomach reduces the incidence of nausea and vomiting.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

CeeNU affects fertility in male rats at doses somewhat higher than the human dose.
CeeNU can have a mutagenic effect. Men treated with CeeNU are therefore advised not to father children during treatment and for up to 6 months afterwards, and to seek advice regarding sperm conservation before the start of treatment given the possibility of irreversible infertility caused by CeeNU therapy.
Dispense only a single dose to patient.
(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 Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Therefore it should not be given to nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

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. Leucopoenia 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 leucopoenia.

Less common adverse effects.

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 azotaemia 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 adverse effects.

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 600 mg. Delayed onset pulmonary fibrosis occurring up to 20 years after treatment has been reported in patients with intracranial tumours who received related nitrosoureas during their childhood and early adolescence.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhoea, 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.
Because of the lipophilic nature of the drug, the product is not dialysable.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

A single definitive molecular mechanism of action for lomustine is not apparent. It may act by the following possible mechanisms.
1. Alkylation of nucleic acids.
2. Carbamoylation of proteins.
3. 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.

Clinical trials.

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.

Bioavailability.

Bioavailability is difficult to define as lomustine is labile and undergoes rapid decomposition. Furthermore the active moiety is unknown.

5.2 Pharmacokinetic Properties

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.

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.

Metabolism.

Lomustine decomposes under physiological conditions (half-life of 53 minutes in phosphate buffer, pH 7.4, 37°C). 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.

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.

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.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

CeeNu 10 mg and 40 mg are supplied in HDPE bottle with polypropylene child resistant cap containing 20 capsules.

6.6 Special Precautions for Disposal

Procedures for handling and disposal of anticancer drugs.

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. In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
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.

6.7 Physicochemical Properties

Chemical structure.

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.

CAS number.

13010-47-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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