Compendium November 1999
PHARM PROFILE
CYCLOPHOSPHAMIDE
Ravinder S. Dhaliwal, DVM
All Care Animal Referral Center,
Fountain Valley, California
Barbara E. Kitchell, DVM, PhD
University of Illinois
C
yclophosphamide (CTX) is
an alkylating agent that is of-
ten used by veterinarians for
neoplastic and nonneoplastic (au-
toimmune) diseases in dogs and cats.
The systemic anticancer effects of
alkylating agents were first identified
during World War II.1 Several alky-
lating agents are used in veterinary
medicine today, of which CTX, chlor-
ambucil, and melphalan are the most
common.
PHARMACOLOGY
Cyclophosphamide acts by dissoci-
ating a positively charged, electro-
philic alkyl group capable of attacking
negatively charged, electron-rich, nu-
cleophilic centers on DNA, protein,
and such small molecules as gluta-
thione.2 The most common site of
DNA alkylation is the N-7 position
of the nucleotide guanine. Alkylating
agents are cell-cycle dependent but
not cell-cycle phase specific.2 They
damage both proliferating and resting
cells, but cycling cells are more sensi-
tive than those that are resting.2 CTX
is a prodrug that is converted by hep-
atic microsomal enzymes to 4-hy-
droxycyclophosphamide (4-HC).2,3
Pharm Profile introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like
Pharm Profile to cover a particular agent, please contact column editor GiGi Davidson, BS, RPh, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email gigi_davidson@ncsu.edu.
20TH ANNIVERSARY
Spontaneous breakdown of 4-HC re-
sults in production of phosphoramide
mustard and acrolein, both of which
damage DNA (Figure 1). The cyto-
toxic action of CTX is thought to re-
sult from phosphoramide mustard–
induced DNA crosslinking.3 Acrolein
is capable of depleting glutathione.2
DNA alkylation occurs when these
CTX metabolites crosslink DNA.
The clinical efficacy of CTX in
treating immune-mediated hemolytic
anemia (IMHA) is based on subjec-
tive evaluation. The exact mecha-
nisms by which CTX is immunosup-
pressive are not completely defined.
Leukocyte numbers and antibody
production are generally decreased.
CTX is considered more effective in
treating aberrant humoral immune
responses than in suppressing cell-me-
diated immune responses.4 Antibody
production by B lymphocytes is sup-
pressed in a dose- and antigen-specific
manner. Because of the cell-cycle
phase nonspecific nature of CTX cy-
totoxicity, CTX is capable of affecting
immune response either before or af-
ter antigenic challenge.4
Cyclophosphamide can be admin-
istered either orally or intravenously
Small Animal/Exotics
(IV). Metabolism is similar in dogs
and humans. Bioavailability is greater
than 75% after oral administration.
Up to 90% of the parent drug and
metabolites are excreted in urine with
IV administration. Although elevated
plasma levels of CTX have been ob-
served in humans with renal failure,
increased toxicity in such patients has
not been demonstrated. The plasma
half-life of CTX is 2.5 to 5.5 hours.3
INDICATIONS
Lymphocytes appear to be highly
sensitive to the cytotoxic effect of
CTX, and thus CTX is commonly
used to treat neoplasms of lymphoid
origin (lymphosarcoma). Table One
lists the neoplastic and nonneoplastic
pathologic conditions for which CTX
is recommended and has been ad-
ministered. In general, IMHA is a re-
generative anemia; nonregenerative
forms of IMHA or pure red-cell apla-
sia can also be treated with CTX, but
careful monitoring of the thrombon
and leukon is required. Because pan-
cytopenia associated with IMHA is
usually caused by other myeloid dis-
orders, further marrow suppression
by CTX should be avoided. If pancy-
Small Animal/Exotics
CTX
Hepatic
activation
4-HC
4-HC reenters the
circulation to enter the
peripheral and tumor tissues
Phosphoramide Acrolein
mustard
Figure 1—The mechanism of action
of cyclophosphamide (CTX). After con-
version to 4-hydroxycyclophospha-
mide (4-HC) in the hepatic cells, CTX
reenters the circulation and finally is
taken up by the peripheral and tumor
tissues, where it decomposes to phos-
phoramide mustard and acrolein.
topenia is noted, other causes for mar-
row suppression should be investigat-
ed. To the best of our knowledge, no
studies strongly suggest that CTX is
useful in treating IMHA.
CAUTIONS
Because CTX is activated in the
liver and is excreted renally, caution
should be practiced when using this
drug in patients with compromised
renal and/or hepatic function. CTX
is contraindicated in patients with cys-
titis, urinary bladder neoplasia, and
myelosuppression.
TOXICITY
Myelosuppression secondary to cy-
totoxic therapy is almost always re-
versible with routine medical man-
agement. A routine complete blood
count should be obtained. Patients
with neutrophil counts above 2000
cells/µl are usually afebrile and other-
wise asymptomatic. If the segmented
neutrophil count is below 1000 to
20TH ANNIVERSARY
1500 cells/µl, prophylactic oral anti-
biotic therapy can be initiated using
oral trimethoprim–sulfadiazine (15 mg/
kg twice daily). These patients should
be monitored closely for signs of sep-
sis (e.g., fever, lethargy, anorexia),
but life-threatening sepsis rarely oc-
curs with a neutrophil count above
1000 cells/µl. Neutropenia with signs
of sepsis must be treated as a medical
emergency. Blood and urine cultures
should be obtained along with cul-
tures of other probable sites of sepsis
that were discovered on careful physi-
cal examination.
Animals in septic shock should be
treated with IV fluid therapy and par-
enteral combination antibiotic thera-
py. The clinical management of sep-
tic shock is beyond the scope of this
column, and readers should seek an
appropriate reference for further in-
formation.
The other most frequent adverse
effect associated with CTX therapy
in humans is hemorrhagic cystitis,
which may progress to bladder fibro-
sis. Transitional cell carcinoma, squa-
mous cell carcinoma, adenocarcinoma,
and sarcomas of the urinary bladder
have all been associated with chronic
CTX therapy in humans.5,6 Hemor-
rhagic cystitis and transitional cell
carcinoma of the urinary bladder sec-
ondary to CTX therapy have also
been reported in dogs.1,5–9 In one re-
port, the rates of CTX-induced hem-
orrhagic cystitis were 23.95% and
3.75% in dogs and cats, respectively;
female dogs appeared to be at the
highest risk (18.75%) and male cats
at the least risk (1.25%).7
Hemorrhagic cystitis caused by
CTX therapy results from interac-
tions of acrolein in the bladder mu-
cosa. Acrolein causes mucosal ulcera-
tion, edema, and necrosis; of the
urinary system epithelia, the bladder
epithelium is most susceptible to
these effects.5,8 Because of the possi-
bility of CTX-induced hemorrhagic
cystitis and transitional cell carcino-
ma in veterinary patients, precautions
Compendium November 1999
should be taken even when CTX is being
administered intermittently. Acute
development of hemorrhagic cystitis
(within 24 hours) has been reported
in dogs after IV administration.5 Clini-
cal signs noted with CTX-induced
cystitis include macrohematuria,
stranguria, and pollakiuria.
Several measures can be used to de-
crease the frequency and severity of
CTX-induced cystitis. Concurrent
administration of prednisone may de-
crease the rate of hemorrhagic cystitis
because it induces diuresis and in-
hibits activation of CTX by hepatic
microsomal enzymes.6,8,9 Treatment
of CTX-induced cystitis should ini-
tially include discontinuing the drug
and using an alkylating agent (e.g.,
chlorambucil) instead. When CTX is
administered, diuresis should be en-
couraged. Bactericidal antibiotics
should be used in patients with gross
hematuria because of the associated
compromised bladder mucosa. In most
cases, hematuria will resolve after CTX
is discontinued. If hematuria persists,
such methods as intravesicular instil-
lation of N-acetylcysteine,9 which in-
activates acrolein, should be consid-
ered.
The free-radical scavenger sodium 2-
mercaptoethane sulfonate (MESNA)3
and prostaglandin E1 (PGE1; which
has shown significant protective effects
in rats) can also be helpful to treat
CTX-induced cystitis.7 Both MESNA
and PGE1 are commercially available,
but controlled veterinary clinical trials
are lacking. Intravesicular administra-
tion of 50% dimethyl sulfoxide has
been used in humans and dogs to
treat CTX-induced cystitis.5,8,9 Other
toxicities seen with CTX administra-
tion are myelosuppression, gastroen-
teritis, and delayed wound healing.1,9
DRUG INTERACTIONS
The rate of CTX activation from
prodrug increases when it is given
concurrently with such drugs as barbi-
turates, which induce microsomal en-
zyme activity.9 Thus, the dose of CTX
Compendium November 1999 20TH ANNIVERSARY Small Animal/Exotics

TABLE ONE
Clinical Indications for Cyclophosphamide
Diseases Dosage Remarks
Neoplastic
Lymphosarcoma, lymphocytic 50 mg/m2 PO every other day a Schedule depends on the combination
leukemia OR chemotherapy regimen used
200 mg/m2 IV once/wka
Acute nonlymphocytic 100 mg/m2 PO for 4 consecutive daysa Used in combination with doxorubicin
leukemia in dogs11
Mast-cell tumor 50 mg/m2 PO on days 3, 4, 5, and 6a,b Used in combination with doxorubicin
and vincristine in dogs and cats
Mammary carcinoma 50 mg/m2 PO on days 3, 4, 5, and 6 a,b Used in combination with doxorubicin
and 5-fluorouracil in dogs
Hemangiosarcoma 100–150 mg/m2 IV on day 1,b 50 mg/m2 Used in combination with doxorubicin
PO on days 3, 4, 5, and 6a,b and vincristine in dogs12,13
Malignant histiocytosis 50 mg/m2 PO every other daya Used in combination with prednisone
and vincristine in dogs14
Lymphomatoid granulomatosis 2 mg/kg PO at 4 days/wka Used in combination with prednisone
and vincristine in dogs15
Tonsillar squamous cell 50 mg/m2 PO on days 3, 4, 5, and 6 a,b Used in combination with doxorubicin
carcinoma in dogs16

Nonneoplastic
Immune-mediated hemolytic Initially at 2 mg/kg/day IV or PO for 4 Prednisone and other supportive
anemia days, no treatment for 3 days, and then measures (e.g., fluid therapy, blood
repeat cyclea transfusion) should be used
concurrently
Immune-mediated 50 mg/m2 PO 3–4 days/wka May give initial dose IV; after 1–4
thrombocytopenia wk, taper dose and discontinue if
platelet count >100,000/L
Systemic lupus erythematosus 1.5–2.5 mg/kg/day or 50 mg/m2 IV CTX should be reserved for acute
or PO until the disease is controlled episodes only; clinicians must
OR try immunosuppression with
2 mg/kg/day IV or PO for 4 days, no corticosteroids and azathioprine
treatment for 3 days, until the disease first17,18
is controlled
Pemphigus vulgaris 0.45 mg/kg or 50 mg/m2 PO for 4 Used in combination with prednisone;
consecutive days each wk for 14–21 CTX should not be the first approach—
days clinicians must try corticosteroids and
azathioprine first19
Rheumatoid arthritis 2.5 mg/kg if <10 kg, 2 mg/kg if
10–35 kg, 1.5 mg/kg if >35 kg PO in the
morning for 4 consecutive days each wk;
discontinue 1 mo after remission
a
Duration of treatment varies.
b
Days refer to days of the combination therapy schedule.
CTX = cyclophosphamide; IV = intravenously; PO = orally.
Small Animal/Exotics 20TH ANNIVERSARY Compendium November 1999

tablet is $1.69 and $2.79, respective-

Client Counseling Information ly, for the 25- and 50-mg tablets.
■ Cyclophosphamide (CTX) is used to treat cancer in dogs and cats. Neosar® injectable costs $3.46 per
Procedures for proper handling of anticancer drugs must be followed. 100 mg. Tablets should not be split
CTX can be very toxic to humans if improperly handled. Clients or crushed, but an oral solution can
handling tablets at home should wear gloves when administering pills be compounded from the injectable
as well as when cleaning up any animal waste for 48 hours after the last form using aromatic elixir as the dil-
dose is given. Your veterinarian may also choose to administer the drug uent; at a concentration of 25 mg/ml,
intravenously or may recommend that pills be given in a small amount this solution is stable for 14 days in
of food. the refrigerator.a
■ Do not handle CTX if you are pregnant, breast-feeding, or trying to
conceive.
STORAGE AND HANDLING
■ Because CTX interacts with many drugs, your veterinarian must be
informed of all medications your pet is currently taking. Reconstituted lyophilized CTX for
■ CTX suppresses the immune system. If your animal shows any signs of injection is clinically and physically
lethargy, fever, or infection, contact your veterinarian immediately. stable for 24 hours at room tempera-
■ Keep CTX out of the reach of children and other pets. ture or for 6 days in the refrigerator.
Storage below 77˚F (25˚C) is recom-
mended for tablets, with a shelf life
should be tapered in patients being form.a When fractions of the 25- or of 3 years.
treated concurrently with phenobar- 50-mg tablet are required for the ac-
REFERENCES
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thereby decreasing CTX metabo- doses as high as 65 mg/m2. When us- in drug therapy. JAVMA 188:1319–1322,
lism.6,9 Review of human medical lit- ing doses higher than 50 mg/m2, we 1986.
2. Berger NA: Alkylating agents: Anticancer
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ABOUT THE AUTHORS
Dr. Dhaliwal is affiliated with the All Care Animal
Referral Center, Fountain Valley, California, and Dr.
Kitchell is affiliated with the Department of Veterinary
Clinical Medicine, College of Veterinary Medicine,
University of Illinois, Urbana, Illinois. Both authors are
Diplomates of the American College of Veterinary
Internal Medicine (Dhaliwal, Oncology; Kitchell,
Oncology and Internal Medicine).