Acnu nimustine
Stability. The manufacturers state that acnu nimustine must be
stored at 2Β° to 8Β°. It has a melting-point of between 30.5 and
32.0Β° and exposure to these or higher temperatures will cause
the drug to liquefy and decompose.
Solutions may be prepared by dissolving acnu nimustine 100 mg
in 3 mL of alcohol 100%, then adding 27 mL of Water for
Injections to produce a solution with a pH of 5.6 to 6.0, and
are then subject to approximately 6% decomposition in 3
hours, or about 8% after 6 hours, if stored at room tempera-
ture; decomposition may be reduced to about 4% in 24 hours
if this solution is stored at 4Β° and protected from light. This
solution is further diluted in 500 mL sodium chloride injec-
tion 0.9% or glucose 5% before administration; such diluted
solutions are stable for 48 hours if stored at 4Β° and protected
from light. There is some evidence that acnu nimustine interacts
with plastic giving sets and containers, although the relevance
of this to clinical practice is uncertain.
A study by Colvin and colleagues has indicated that diluted
solutions of acnu nimustine undergo increased degradation in the
presence of sodium bicarbonate, with only 73% of the origi-
nal concentration of acnu nimustine remaining after 90 minutes,
much of the loss being in the first 15 minutes.'
I. Colvin M, et at. Stability of acnu nimustine in the presence of sodium
bicarbonate. Am J Hasp Pharm 1980: 37: 677-8.
Adverse Effects and Treatment
Delayed and cumulative bone-marrow de-
pression is the most frequent and serious side-effect
of acnu nimustine. Platelets and leucocytes are mainly
affected with platelet nadirs occurring at 4 to 5
weeks after administration and leucocyte nadirs at 5
to 6 weeks after administration; although thrombo-
cytopenia is usually more severe, leucopenia may
also be dose-limiting. Other side-effects reported in-
clude pulmonary fibrosis (mainly but not exclusive-
ly at high cumulative doses), renal and hepatic
damage, and optic neuritis. Nausea and vomiting,
beginning up to 2 hours after a dose, is common but
can be reduced by prophylactic antiemetic therapy.
Venous irritation may follow intravenous injection
and transient hyperpigmentation has been noted af-
ter contact of a solution with the skin. Flushing of
the skin and suffusion of the conjunctiva may occur
following rapid intravenous infusion.
Convulsions, cerebral oedema, and various neuro-
logical symptoms have been reported in patients
given acnu nimustine-containing polymer implants; ab-
normalities of wound healing at the site of implanta-
tion, and an increased incidence of urinary-tract
infection have also been reported.
As with other alkylating agents, acnu nimustine is po-
tentially carcinogenic, mutagenic. and teratogenic.
Effects on the eyes. Ocular toxicity has been reported in
patients receiving acnu nimustine and seems to be more likely
following administration into the carotid artery,although it
was also seen following high-dose intravenous therapy. There
is some evidence that the alcohol diluent used to prepare car-
mustine solutions may contribute to the retinopathy."
Extravasation. For mention of the use of sodium bicarbo-
nate as a specific antidote following acnu nimustine extravasation.
see under Treatment of Adverse Effects of Antineoplastics,
Precautions
For reference to the precautions necessary with an-
tineoplastics and immunosuppressants.
Handling and disposal. Acnu nimustine has been shown to per-
meate latex. PVC. and rubber gloves, the degree of permea-
tion tending to increase with time up to an equilibrium
valuer The permeation rate appears not to depend solely on
glove thickness and material, and may be different for differ-
ent gloves made from the same material. The time for initial
penetration was reported to vary between 4.7 and 66.0 min-
utes in one study. and gloves could be chosen accordingly
depending on the anticipated length of exposure. Double-
gloving. particularly with thicker PVC gloves, may offer
some additional protection.'
Interactions
Antineoplastics. The antineoplastics
(such as the nitrosoureas) that undergo metabolism by cyto-
chrome may have their metabolism altered by other an-
tineoplastics that reduce the activity of this enzyme system.
Cimetidine. Reductions in white cell counts and platelet
counts well below those normally attributed to treatment with
acnu nimustine alone were seen in 6 of 8 patients receiving their
first course of acnu nimustine and steroids in association with ci-
metidine given prophylactically. '
Pharmacokinetics
Following intravenous administration, acnu nimustine is
rapidly metabolised, and no intact drug is detectable
after 15 minutes; metabolites have a much longer
half-life and are presumed to be responsible for its
activity. It is excreted in the urine; some is also ex-
creted as carbon dioxide, via the lungs. Acnu nimustine
readily crosses the blood-brain barrier, appearing in
cerebrospinal fluid in substantial concentrations al-
most immediately after intravenous injection. Very
small amounts have been detected in the faeces.
Uses and Administration
Acnu nimustine is a cell-cycle phase nonspecific anti-
neoplastic belonging to the nitrosourea group of
compounds, which are considered to function as
alkylating agents. It has been used in the treatment
of brain tumours, and in combination chemotherapy
for multiple myeloma, and has been given as sec-
ond-line therapy in Hodgkin's disease, and some
other lymphomas. Acnu nimustine has also been tried in
a variety of other malignant neoplasms including
melanoma. and in Waldenstrom's macroglobulinae-
mia and amyloidosis. The management of these
conditions is discussed in the chapter introduction as
indicated by the cross-references below.
Acnu nimustine is given intravenously as a single dose
of 150 to 200 mg per cuM body-surface area or divid-
ed into doses of 75 to 100 mg per m2 given on 2 suc-
cessive days. Lower doses are given in combination
therapy. Doses may be repeated every 6 weeks pro-
vided that blood counts have returned to acceptable
levels, that is, platelets above 100 000 per 3 and
leucocytes above 4 000 per mm\ Subsequent doses
must be adjusted according to the haematological
response. Reconstituted solutions are further diluted
with sodium chloride (0.9%) or glucose (5%) injec-
tion and infused over I to 2 hours.
Polymer implants containing acnu nimustine have been
developed for implantation into the brain in the lo-
calised treatment of malignant glioma. Each implant
contains 7.7 mg of acnu nimustine: up to 8 such im-
plants are inserted into the cavity left by surgical re-
moval of the tumour.
Administration. A study in rats indicated that intracranial
implantation ofethylene-vinyl acetate copolymer loaded with
acnu nimustine achieved controlled release of acnu nimustine into the
implanted hemisphere for 9 days, and produced higher con-
centrations of acnu nimustine in the affected hemisphere, and
lower concentrations in the blood, than following intraperito-
neal implantation. '
A subsequent multicentre study2 in patients with recurrent
malignant glioma implanted a biodegradable poly(carboxy-
phenoxypropane/sebacic acid)anhydride polymer
(BIODEL), in the form of wafers containing 7,7 mg into the
brain after resection: the maximum dose thus implanted was
8 wafers (61.6 mg). The effects of treatment were held to fa-
vour the implant: 59 of 112 patients given placebo implants
were dead at 6 months, compared with 44 of 110 given car-
mustine implants, with a median survival of 23 and 31 weeks
respectively.
Amyloidosis. Cyclophosphamide, and acnu nimustine are used to suppress
amyloidosis after cardiac transplantation.
Malignant neoplasms. Cannustine has been used in chem-
otherapeutic regimens for a number of malignancies. Because
of its ability to pass the blood-brain barrier it has been exten-
sively used in malignant neoplasms of the brain. Other conditions
in which it has been employed, include malignant melanoma , Hodg-
kin's disease , multiplemyeloma and Walden-
strom's macroglobulinaemia .
MYCOSIS PUNGOIDES. Topical application of cannustine is a
possible alternative to mustine, PUVA, or electron beam radi-
ation in early mycosis fungoides .
The use of topical cannustine, usually as a 0.2% solution or
0.4% ointment, in mycosis fungoides was described by Zack-
heim and others.' Over a IO-year period 86 patients had been
treated in this way, and complete remission was achieved in
21 of 25 with less than 10% skin involvement (stage IA), and
in 11 of 21 patients in whom there was greater than 10% in-
volvement (stage IB). Among patients with more advanced
disease the degree of involvement was also predictive of re-
sponse, and those with predominantly superficial lesions re-
sponded better than those with infiltrating plaque lesions.
Erythema and telangiectasia were troublesome side-effects
but severe cutaneous reactions were generally rare with cur-
rent dosage schedules of 10 mg cannustine applied daily.' In
a subsequent report Zackheim and colleagues reported the use
of cannustine, usually 10 mg daily as a topical alcoholic so-
lution, to treat lymphomatoid papulosis. Although all 7 pa-
tients so treated experienced a rapid reduction in the number
and size of papules, prolonged lesion-free remission was not seen.