Ceenu Information
Ceenu (Lomustine) Warnings
Ceenu (Lomustine)
(lomustine) should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents.
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 (Lomustine) (see and ).
Since
the major toxicity is delayed bone marrow suppression, blood counts should
be monitored weekly for at least 6 weeks after a dose (see ). At the recommended dosage, courses of Ceenu (Lomustine) should
not be given more frequently than every 6 weeks.
The
bone marrow toxicity of Ceenu (Lomustine) is cumulative and therefore dosage adjustment
must be considered on the basis of nadir blood counts from prior dose (see under ).
Ceenu (Lomustine) Description
Ceenu (Lomustine) (lomustine)
(CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic
diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow
powder with the empirical formula of CHClNO and
a molecular weight of 233.71. Ceenu (Lomustine) is soluble in 10% ethanol (0.05 mg per
mL) and in absolute alcohol (70 mg per mL). Ceenu (Lomustine) is relatively insoluble
in water (<0.05 mg per mL).
It is relatively un-ionized
at a physiological pH.
Inactive ingredients in Ceenu (Lomustine)
Capsules are magnesium stearate and mannitol.
The
structural formula is:
Ceenu (Lomustine) is available in
10 mg, 40 mg, and 100 mg capsules for oral administration.
Ceenu (Lomustine) Clinical Pharmacology
Although it is generally agreed that
Ceenu (Lomustine) alkylates DNA and RNA, it is not cross resistant with other alkylators.
As with other nitrosoureas, it may also inhibit several key enzymatic processes
by carbamoylation of amino acids in proteins.
Ceenu (Lomustine)
may be given orally. Following oral administration of radioactive Ceenu (Lomustine) at
doses ranging from 30 mg/m to 100 mg/m,
about half of the radioactivity given was excreted in the urine in the form
of degradation products within 24 hours.
The serum
half-life of the 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 physiological
pH, Ceenu (Lomustine) crosses the blood-brain barrier quite effectively. Levels of radioactivity
in the CSF are 50% or greater than those measured concurrently in plasma.
Ceenu (Lomustine) Indications And Usage
Ceenu (Lomustine) has been shown to be useful as
a single agent in addition to other treatment modalities, or in established
combination therapy with other approved chemotherapeutic agents in the following:
Ceenu (Lomustine) Contraindications
Ceenu (Lomustine) should not be given to individuals
who have demonstrated a previous hypersensitivity to it.
Ceenu (Lomustine) Warnings
Since the major toxicity is delayed bone marrow suppression, blood counts should
be monitored weekly for at least 6 weeks after a dose (see ). At the recommended dosage, courses of Ceenu (Lomustine) should
not be given more frequently than every 6 weeks.
The bone marrow toxicity of Ceenu (Lomustine) is cumulative and therefore dosage adjustment
must be considered on the basis of nadir blood counts from prior dose (see under ).
Pulmonary toxicity from Ceenu (Lomustine) appears to be dose related (see ).
Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary
malignancies.
Liver and renal function tests should be monitored periodically (see ).
Ceenu (Lomustine) Precautions
Due to delayed bone marrow suppression,
blood counts should be monitored weekly for at least 6 weeks after a dose.
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) are particularly at risk.
Since
Ceenu (Lomustine) may cause liver dysfunction, it is recommended that liver function tests
be monitored periodically.
Renal function tests should
also be monitored periodically.
No data from clinical studies of Ceenu (Lomustine)
are available for patients 65 years of age and over to determine whether they
respond differently than younger patients. Other reported clinical experience
has not identified differences in responses between elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.
Lomustine
and its metabolites are known to be substantially excreted by the kidney,
and the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and renal
function should be monitored.
Ceenu (Lomustine) Adverse Reactions
The most frequent and most serious toxicity
of Ceenu (Lomustine) is delayed myelosuppression. It usually occurs 4 to 6 weeks after
drug administration and is dose related. Thrombocytopenia occurs at about
4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs
at 5 to 6 weeks after a dose of Ceenu (Lomustine) and persists for 1 to 2 weeks. Approximately
65% of patients receiving 130 mg/m develop white
blood counts below 5000 wbc/mm. Thirty-six percent
developed white blood counts below 3000 wbc/mm.
Thrombocytopenia is generally more severe than leukopenia. However, both may
be dose-limiting toxicities.
Ceenu (Lomustine) may produce
cumulative myelosuppression, manifested by more depressed indices or longer
duration of suppression after repeated doses.
The
occurrence of acute leukemia and bone marrow dysplasias 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 characterized by pulmonary
infiltrates and/or fibrosis has been reported rarely with Ceenu (Lomustine) . Onset of
toxicity has occurred after an interval of 6 months or longer from the start
of therapy with cumulative doses of Ceenu (Lomustine) usually greater than 1100 mg/m.
There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
Delayed
onset pulmonary fibrosis occurring up to 17 years after treatment has been
reported in patients who received related nitrosoureas in childhood and early
adolescence (1-16 years) combined with cranial radiotherapy for intracranial
tumors. There appeared to be some late reduction of pulmonary function of
all long-term survivors. This form of lung fibrosis may be slowly progressive
and has resulted in death in some cases. In this long-term study of carmustine,
all those initially treated at less than 5 years of age died of delayed pulmonary
fibrosis.
Stomatitis, alopecia, optic atrophy,
and visual disturbances, such as blindness, have been reported infrequently.
Neurological
reactions, such as disorientation, lethargy, ataxia, and dysarthria have been
noted in some patients receiving Ceenu (Lomustine) . However, the relationship to medication
in these patients is unclear.
Ceenu (Lomustine) Overdosage
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.
No proven antidotes have been established for Ceenu (Lomustine) overdosage. In case of overdose, appropriate supportive measures should be taken.
Ceenu (Lomustine) Dosage And Administration
The recommended dose of Ceenu (Lomustine) in adult
and pediatric patients as a single agent in previously untreated patients
is 130 mg/m as a single oral dose every 6 weeks (see and ). In individuals with compromised bone marrow function, the dose should be reduced
to 100 mg/m every 6 weeks. When Ceenu (Lomustine) is used
in combination with other myelosuppressive drugs, the doses should be adjusted
accordingly.
Doses subsequent to the initial dose should
be adjusted according to the hematologic response of the patient to the preceding
dose. The following schedule is suggested as a guide to dosage adjustment:
Ceenu (Lomustine) How Supplied
Ceenu (Lomustine) Capsules are available in individual bottles of 20 capsules each.
The total dose prescribed by the physician
can be obtained (to within 10 mg) by determining the appropriate combination
of capsule strengths. Only the appropriate number of Ceenu (Lomustine) capsules required
for a single administration should be dispensed.
The
appropriate number of capsules of each size should be placed in a single vial.
Each color-coded capsule is imprinted with the dose in milligrams. In order
to provide the proper dose of Ceenu (Lomustine) , patients should be aware that there may
be 2 or more different types and colors of capsules in the container. Patients
should be told that Ceenu (Lomustine) is taken as a single oral dose and will not be repeated
for at least 6 weeks.
Caution should be exercised when
handling Ceenu (Lomustine) Capsules. Procedures for proper handling and disposal of anticancer
drugs should be utilized. Several guidelines on this subject have been published. To
minimize the risk of dermal exposure, always wear impervious gloves when handling
bottles containing Ceenu (Lomustine) Capsules. Ceenu (Lomustine) Capsules should not be broken. Personnel
should avoid exposure to broken capsules. If contact occurs, wash immediately
and thoroughly. More information is available in the references listed below.
Ceenu (Lomustine)
Ceenu (Lomustine)
