INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CeeNU 10 mg CAPSULES
CeeNU 40 mg CAPSULES

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CeeNU 10 mg CAPSULES
CeeNU 40 mg CAPSULES

COMPOSITION:
Capsules containing 10 mg and 40 mg lomustine respectively.

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents.

PHARMACOLOGICAL ACTION:
CeeNU [1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea] is one of a group of nitrosoureas. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular mass of 233,71. It is soluble in water, saline and alcohol and highly lipid soluble. It is relatively unionized at a physiological pH. The structural formula is: {Structure here}



It is generally agreed that CeeNU acts as an alkylating agent but, as with other nitrosoureas, it may also inhibit several key enzymatic processes. CeeNU is given orally. Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted within 24 hours. The serum half-life of the drug and/or metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes after intravenous administration. Because of the high lipid solubility and the relative lack of ionization at a physiological pH, CeeNU crosses the blood brain barrier quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma.

INDICATIONS:
CeeNU (lomustine) is indicated as adjuvant therapy to surgery and radiotherapy or in combination therapy with other chemotherapeutic agents in the following clinical situations:

Brain tumours - both primary and metastatic in patients who have already received appropriate surgical and/or radio therapeutic procedures.

Hodgkin’s Disease - as a secondary therapy. [Alone or in combination with other active drugs].

CONTRA-INDICATIONS:
CeeNU should not be given to individuals who have demonstrated a previous hypersensitivity to it.

WARNINGS:
SAFE USE IN PREGNANCY AND DURING LACTATION HAS NOT BEEN ESTABLISHED.

CeeNU is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. CeeNU also affects fertility in male rats at doses somewhat higher than the human dose. CeeNU 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.

DOSAGE AND DIRECTIONS FOR USE:
The recommended dose of CeeNU in adults and children is 130 mg/m² as a single dose by mouth every 6 weeks.

N.B.: THE CAPSULE MUST BE SWALLOWED WHOLE.

In individuals with compromised bone-marrow function, the dose should be reduced to 100 mg/m² every 6 weeks. A repeat course of CeeNU should not be given until circulating blood elements have returned to acceptable and sustained levels (platelets above 100 000/mm3, leukocytes above 4000/mm3). Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the haematologic 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 following schedule is suggested as a guide to dosage adjustment.

NADIR AFTER PRIOR DOSE		PERCENTAGE OF PRIOR DOSE TO BE GIVEN
Leukocytes	Platelets
> 4 000	> 100 000	100%
3 000 - 3 999	75 000 - 99 999	100%
2 000 - 2 999	25 000 - 74 999	70%
< 2 000	< 25 000	50%

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

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Gastrointestinal:
Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. The frequency and duration may be reduced by the use of anti-emetics prior to dosing and by the administration of CeeNU to tasting patients.

Haematologic Toxicity:
The most frequent and most serious toxicity of CeeNU is delayed myelosuppression. It usually occurs four to six weeks after drug administration and is dose related. Thrombocytopenia occurs at about four weeks post-administration and persists for one to two weeks. Leukopenia occurs at five to six weeks after a dose of CeeNU and persists for one to two weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5 000 wbc/mm3. Thirty-six percent developed white blood cell counts below 3000/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
CeeNU produces cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.
The occurrence of acute leukaemia and bone marrow dysplasia have been reported in patients following long-term nitrosourea therapy.
Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.

Pulmonary Toxicity:
Pulmonary toxicity characterised by pulmonary infiltrates and/or fibrosis have been rarely reported with CeeNU. Onset of toxicity has occurred after an interval of six months or longer from the start of therapy with cumulative doses of CeeNU ranging from 600 to 1 240 mg/m2.
Delayed onset pulmonary fibrosis occurring up to 15 years after treatment has been reported in patients with intracranial tumours who received related nitrosoureas during their childhood and early adolescence.

Other Toxicities:
Stomatitis, alopecia, anemia have been reported infrequently.

Neurological reactions such as disorientation, lethargy, ataxia and dysarthria have been noted in some patients receiving CeeNU. However, the relationship to medication in these patients is unclear.

Nephrotoxicity:
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 CeeNU and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.

Hepatotoxicity:
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase and bilirubin levels, has been reported in a small percentage of patients receiving CeeNU.

Special Precautions:
CeeNU should be administered by individuals experienced in the use of antineoplastic therapy.

Delayed bone marrow suppression, notably thrombocytopenia and leukopenia which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of CeeNU.

Blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of CeeNU should not be given more frequently than every 6 weeks.

The bone marrow toxicity of CeeNU 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 Directions for Use).

Caution should be used in administering CeeNU to patients with decreased circulating platelets, leukocytes, or erythrocytes (See Dosage and direction for ruse).

Pulmonary toxicity from CeeNU appears to be dose related. Baseline pulmonary function tests 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.

Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.

IDENTIFICATION:
10 mg capsules (white/white) imprinted BRISTOL 3030
40 mg capsules (white/green) imprinted BRISTOL 3031

PRESENTATION:
Amber glass bottles containing 20 capsules.

DIRECTION TO THE PHARMACIST:
The capsules are to provide enough medication for a single dose. The total dose prescribed by the physician can be obtained (to within 10 mg) by determining the appropriate combination of capsule strengths. The appropriate number of capsules of each size should be placed in a single vial and the patient provided with information explaining the differences in the appearances of the capsules.

STORAGE INSTRUCTIONS:
CeeNU capsules are stable for at least 2 years when stored at room temperature in well closed containers. Avoid excessive heat (over 40°C).

REGISTRATION NUMBERS:
10 mg L/26/81
40 mg L/26/82

NAME AND BUSINESS ADDRESS OF APPLICANT:
Bristol-Myers Squibb (Pty) Ltd
AMR Park - 1 Concorde Rd East
Bedfordview
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
October 1991

* Authorised user of the TM CeeNU.
290049 06/92 SE
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