Cyclophosphamide

Drug Name │Mechanism of Action & Pharmacokinetics │ Indications & Status │ Adverse Effects │ Dosing │ Administration Guidelines │
Special Precautions │ Interactions │ Recommended Clinical Monitoring │ References

A DRUG NAME: CYCLOPHOSPHAMIDE

SYNONYM(S): Cyclo, CPA, CPM, CTX, CYC, CYT

COMMON TRADE NAME(S): Procytox® (Baxter), Cytoxan® (Bristol), Neosar® (USA)

B MECHANISM OF ACTION AND PHARMACOKINETICS

Cyclophosphamide is an inactive cyclic phosphamide ester of mechlorethamine. It is

transformed via hepatic and intracellular enzymes to active alkylating metabolites, 4-
hydroxycyclophophosphamide, aldophosphamide, acrolein and phosphoramide mustard.
Cyclophosphamide causes prevention of cell division primarily by cross-linking DNA and RNA
strands. It is considered to be cell cycle phase-nonspecific.

Oral Absorption Yes, bioavailability 75-100%. Also absorbed when applied topically.
Oral administration results in increased alkylating activity.

Distribution Most tissues, crosses placenta, present in breast milk, present in

ascites
Cross blood brain barrier? Yes, including metabolites
Vd 0.34-1.2 L/kg, 11-16.4 L/m2
PPB 12-14%, metabolites 39-67%

Metabolism Mainly activated by hepatic microsomal enzyme oxidation system

(CYP 450), some activation peripherally; great interpatient variability
in metabolism. CYP 2B6 (highest activity), 2A6, 3A4, 3A5, 2C9,
2C18, and 2C19 are involved in bioactivation. Potent inducer of 2C8,
2C9, 3A4, 2B6 leading to autoinduction.
Active metabolite(s) Phosphoramide mustard / acrolein
/ 4-hydroxy cyclophosphamide
Inactive metabolite(s) Yes

Excretion Drug and metabolites excreted by kidney, tubular reabsorption occurs

Urine 37-82% (20% unchanged)
t½ 6.5 hours

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 Cyclophosphamide

C INDICATIONS AND STATUS

∗ Acute lymphoblastic leukemia Other uses include:
∗ Acute myelogenous leukemia Brain tumours, pediatric
∗ Breast cancer Endometrial cancer
∗ Burkitt's Lymphoma Germ cell tumours
∗ Chronic lymphocytic leukemia Testicular cancer
∗ Chronic granulocytic leukemia Ewing's sarcoma
∗ Hodgkin's disease Osteogenic sarcoma
∗ Lung cancer (SCLC and NSCLC) Rhabdomyosarcoma
∗ Multiple myeloma Soft tissue sarcoma
∗ Mycosis fungoides *Ovarian cancer
∗ Neuroblastoma
∗ Non-Hodgkin's lymphoma
∗ Retinoblastoma

∗ Health Canada approved indication

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D
ADVERSE EFFECTS

ORGAN SITE SIDE EFFECT ONSET

Cardiovascular
E
Thromboembolism (rare)

Hemorrhagic myocarditis, pericarditis

(high dose)

Congestive heart failure (with prior

anthracyclines) E

Dermatologic Alopecia (severe 5-30%, some degree

100%) E

Facial flushing (during IV administration) I

Hyperpigmentation (skin and fingernails) E

Hand foot syndrome (rare)
Rash (rare, may be severe) I E

Radiation recall reaction (rare) I

Extravasation hazard None

(refer to Appendix 2 )

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D
ADVERSE EFFECTS (continued)

ORGAN SITE SIDE EFFECT ONSET

Gastrointestinal Nausea and vomiting (moderate to

severe in 50%) I

Abdominal Pain E

Stomatitis (less common) E

Diarrhea (less common) E

Constipation E

Pancreatitis (rare) E

Hemorrhagic colitis (rare) E

Anorexia (common) E

Hematologic Myelosuppression (common)

Nadir 8-15 days, recovery 17-28 days E

Disseminated intravascular coagulation

(rare)

Immunosuppression
E

Hypersensitivity Type I (anaphylactoid, rare, may be

fatal, may be cross-sensitivity with other I
alkylating agents)

Injection site Chemical phlebitis I

Neoplastic Second malignancies, including bladder L

and myelodysplasia

Pulmonary Acute interstitial pneumonitis (rare) E D

Chronic pulmonary fibrosis (rare, with

high doses/prolonged exposure) D L
General Fever, fatigue E

Rhabdomyolysis (rare) E

Hepatic Elevated LFT’s (rare) E D

Veno-occlusive disease (rare, high dose
only, esp with busulfan)
E

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 Cyclophosphamide

D ADVERSE EFFECTS (continued)

ORGAN SITE SIDE EFFECT ONSET

Renal/metabolic Hemorrhagic cystitis (10%, BMT > 40%) I E D

Non-hemorrhagic cystitis, bladder

fibrosis E

Hemolytic-uremic syndrome (rare) E

Hyperuricemia (during periods of active

cell lysis) E

Nephrotoxicity (rare) E

SIADH (syndrome of inappropriate

secretion of ADH, rare) I E

Reproductive Amenorrhea (+ ovarian failure) E D

Azospermia (+ sterility) E D

Neurologic Blurred vision/myopia E

Headache I

Dizziness I

Dose-limiting side effects are underlined.

I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)

Myelosuppression is the major dose limiting toxicity.

Dose-related chemical hemorrhagic cystitis occurs due to direct contact with bladder mucosa of active and
toxic metabolites which accumulate in concentrated urine. This occurs in 10% of patients (40% with high dose)
and may occur during or several months after treatment. Concurrent or previous radiation therapy to the pelvis
may increase the risk of this complication. Cystitis appears to result in chronic inflammation leading to fibrosis,
telangiectasis of the bladder epithelium and bladder cancer. Severe cases may be fatal. Prophylactic
measures to reduce the incidence of cystitis include catheter bladder drainage, bladder irrigation,
hyperhydration, forced diuresis and the administration of mesna. However, hyperhydration places the patient
at risk for fluid overload and electrolyte imbalance, particularly given the antidiuretic effect of
cyclophosphamide. It appears that mesna and hyperhydration are equally effective in preventing
cyclophosphamide-induced cystitis in the BMT population. Cyclophosphamide should be administered as early
in the day as possible to decrease the amount of drug remaining in the bladder overnight. The drug should be
promptly discontinued and not re-instituted if possible in patients developing this complication.

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 Cyclophosphamide

D ADVERSE EFFECTS (continued)

Mild cases can be controlled by simple measures such as bladder irrigation with water or normal saline.
Intravesical instillations of astringents (alum, silver nitrate) or systemic administration of antifibrinolytics
(aminocaproic acid, tranexamic acid) are also effective. For moderate bladder hemorrhage, cystoscopy
should be undertaken to evacuate the bladder of clots and continuous bladder irrigation instituted to prevent
recurrent clot formation. Treatment can then be attempted with astringents or antifibrinolytics. Intravesical
prostaglandins have also been recommended in addition to the above treatments. Following cystoscopy for
severe hematuria, treatment begins with intravesical formalin (the aqueous solution of formaldehyde), phenol
or intravesical prostaglandin and may proceed to surgical intervention. Electrocautery, cryosurgery, diversion
of urine flow, hypogastric artery ligation or cystectomy have been advocated.

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly
proliferative tumours of massive burden (e.g., some leukemias and lymphomas), can be minimized with
allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium
bicarbonate to the IV fluids, if tumour lysis is expected.

Interstitial pneumonitis and pulmonary fibrosis occur occasionally. This frequently fails to respond to
cyclophosphamide withdrawal and corticosteroid therapy and is often fatal. Lung biopsy is the only sure
method of diagnosis. The drug should be stopped at the first hint of pulmonary toxicity; all other possible
causes of pneumonitis should be ruled out. It is most frequently reported in patients with Hodgkin's and non-
Hodgkin's lymphomas. There does not appear to be a duration, route, dose, or schedule relationship.

Administration of cyclophosphamide in doses higher than 30-40 mg/kg has been associated with water
retention and dilutional hyponatremia. Decreased urine flow, decreased serum osmolarity and sodium and
increased urine osmolarity occur 4 to 12 hours after cyclophosphamide and resolve within 20 to 24 hours after
therapy. This is related to a direct toxic effect of alkylating metabolites on distal renal tubules and collecting
ducts. SIADH (syndrome of inappropriate secretion of ADH) may also be a contributing factor. The
condition is self-limiting although diuretic therapy may be helpful in the situation where the patient has stopped
urinating (especially if this occurs during the first 24 hours of cyclophosphamide therapy), in order to minimize
contact of the toxic metabolites with the bladder mucosa. Susceptible patients should be monitored for cardiac
decompensation. If weight gain is excessive (1.5-2 kg) during hydration, the volume of IV fluid should be
reduced.

Nasal stuffiness or facial discomfort can occur with rapid injection. If troublesome for the patient, slow the
infusion rate or give as an intermittent infusion rather than as an IV bolus.

Cardiac toxicity and acute cardiac failure (hemorrhagic necrosis) can occur, especially with high doses
used in preparing patients for marrow transplantation (>120 mg/kg) and concomitant doxorubicin or
daunorubicin therapy or with radiation to cardiac vessels or heart. Cardiac tamponade has been observed in
thalassemic patients given cyclophosphamide prior to bone marrow transplant. Special caution is advised for
patients with pre-existing cardiac disease and prior cardiac radiation.

Cyclophosphamide has the potential to enhance radiation injury to tissues. While often called radiation recall
reactions, the timing of the radiation may be before, concurrent with, or even after the administration of the
cyclophosphamide.

Secondary malignancies have developed in some treated patients, often several years after administration.
Neoplasms most frequently have been urinary bladder cancer, non-lymphocytic leukemia and non-Hodgkin's
lymphoma. Patients who develop bladder cancer usually have a history of hemorrhagic cystitis.

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CCO Formulary Revised June 2009

 Cyclophosphamide

E DOSING

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count.
Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation
therapy. Recommendations for hydration should be followed, with ample fluids and frequent voiding.

Adults:

Intravenous:
Q3W: 500 mg/m2 (ie. FEC regimen) to 1200mg/m2 (ie. VAC regimen)
Q1W: 300 mg/m2 (ie. CycloPred in myeloma)

Oral:
Daily: 50-200mg daily (ie. CycloPred in myeloma)
Q28D: 100mg/m2 daily for 14 days (ie. CMF PO)
Oral preparations may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir USP.

Bone Marrow Transplant: much higher doses are used for tumour ablation prior to marrow transplant than for
standard treatment regimens.

Compromised bone marrow: decrease dose by 30-50%

Dosage with Toxicity Consider dose reduction with after cystitis or infection

Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 (Dosage Modification for Myelosuppression).

Dosage with renal impairment: Renal failure may lead to the reduced excretion of metabolites and increased
toxicity. Significant falls in clearance (25-80%) with increased exposure have
been documented in patients with renal impairment. Dose reduction (25-
50%) should be considered in patients with mild to moderate renal impairment.
Patients with moderate renal impairment receiving high doses or severe
renally impaired patients (CrCl < 10 mL/min) are at particular risk and should
be treated at a reduced dose and with extreme caution.

Dosage with hepatic impairment: No adjustment required, but caution should be exercised especially with oral
cyclophosphamide

Dosage in the elderly: No dose modification required, but should be used with caution.

Children: Dose adjustment may be required.

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CCO Formulary Revised June 2009

 Cyclophosphamide

F ADMINISTRATION GUIDELINES (see Appendix 3a )

• Oral hydration is strongly encouraged; for PO cyclophosphamide: 8-10 (8oz) glasses of

fluid per day; for IV cyclophosphamide: 2-3 L of fluid/day; poorly hydrated patients may
need more IV hydration. Inadequate total hydration may result in dose-related hemorrhagic
cystitis. Patients should be encouraged to empty their bladder frequently to minimize dwell
times.
Consider usage of mesna with high dose therapy of cyclophosphamide (>1g/m2).
• Smaller doses (<500mg) may be given by direct IV push, followed by a Normal Saline flush,
if no IV line has been set up.
• Larger doses of drug should be given with larger total fluid volumes to the patient; patients
receiving doses >1000mg should receive at least 500-750mL total fluid, either as oral or IV
hydration.
• May mix doses <1000mg in 100mL minibag (Normal Saline); Infuse over 15 minutes.
• Doses >1000mg may be mixed in 250mL minibag Normal Saline; Infuse over 30 minutes.
• Doses >2000mg may be mixed in 250-500mL bag (Normal Saline); Infuse over 30 to 60
minutes.
• High dose (2000 mg/m2 or greater) may be mixed in 1000 mL NS; infuse IV over 1 to 4
hours
Use 0.9% sodium chloride to reconstitute cyclophosphamide.

• Do not reconstitute or dilute with benzyl alcohol-containing solutions (ie. Bacteriostatic

sodium chloride), since it may catalyse the decomposition of cyclophosphamide or cause
toxicity in infants
• Avoid the use of aluminium-containing preparation and administration equipment, since
darkening of aluminium and gas production have been reported
• Oral tablets should be administered as a single dose in the morning, with or without food.

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G SPECIAL PRECAUTIONS

Cyclophosphamide is contraindicated in patients with sensitivity to the drug or to any components

of its dosage forms, or with severe leukopenia, thrombocytopenia, hepatic or renal dysfunction and
patients with pre-existing cystitis or urinary outflow obstruction. Use with caution in patients with
herpes infections or other infections, in combination with neuromuscular blocking agents, and in
patients with adrenal insufficiency. The concomitant use of alcohol and live vaccines should also be
avoided.

Cyclophosphamide is mutagenic, carcinogenic, teratogenic and fetotoxic in humans. Testicular

atrophy and sterility may occur in males. Sperm-banking before treatment should be considered.
Amenorrhea and ovarian failure may occur in females. Gonadal dysfunction may reverse with time,
but future reproductive capacity is uncertain.

Cyclophosphamide is contraindicated during pregnancy due to risk of congenital malformations.

Contraceptives for both sexes are recommended during treatment and for 4 months post-therapy
because of the potential mutagenic effects. Cyclophosphamide is excreted in breast milk; breast
feeding should be terminated prior to use.
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 Cyclophosphamide

H INTERACTIONS

AGENT EFFECT MECHANISM MANAGEMENT

Allopurinol/hydro- enhanced unknown caution; monitor

chlorthiazide myelosuppressive
effects

Prednisone Acute respiratory Unknown Caution, monitor

failure; can be fatal

Sulfonylureas hypoglycemia Unknown caution

Lovastatin and increased Unknown caution, avoid

HMG-CoA pulmonary toxicity, concomitant use
reductase rhabdomyolysis
inhibitors and renal failure

Indomethacin pulmonary edema SIADH caution

Digoxin decreased serum Possibly observe for

digoxin levels decreased decreased
absorption due to pharmacological
alterations in effect of digoxin;
intestinal mucosa increase digoxin
from dose if necessary
cyclophosphamide

Methotrexate Inhibits metabolism clinical

of significance of this
cyclophosphamide interaction is
unknown; observe
for altered effect
of
cyclophosphamide

Drugs which increased activation induction of hepatic clinical

induce hepatic of microsomal enzyme significance of this
microsomal cyclophosphamide oxidation system interaction is
enzymes unknown; observe
(e.g., phenytoin, for altered effect of
phenobarbital, cyclophosphamide
corticosteroids)
Drugs which Decreased inhibition of hepatic Caution,
inhibit hepatic activation of microsomal enzyme
microsomal cyclophosphamide oxidation system Avoid grapefruit
enzymes (e.g. in liver, prolonged juice for 48 hours
chloramphenicol half-life or clearance before and on day
, grapefruit of of dose
juice, cyclophosphamide
itraconazole,
fluconazole)

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 Cyclophosphamide

H INTERACTIONS (continued)

AGENT EFFECT MECHANISM MANAGEMENT

Succinylcholine prolonged post cyclophosphamide Notify

operative apnea inhibits anesthesiologist,
may occur cholinesterase measure
activity (which pseudocholineste-
metabolizes rase levels; if
succinylcholine) decreased,
consider a
decrease in
succinylcholine
dose

Cucurmin may reduce effect inhibits avoid concomitant

(Turmeric) of cyclophosphamide use
Cyclophosphamide induced tumor
regression

exacerbates unknown Caution. Total

Doxorubicin, cardiotoxicity cumulative dose
Pentostatin of doxo-
/daunorubicin
Prior cardiac should not2 exceed
radiation 400mg/m

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I RECOMMENDED CLINICAL MONITORING

Recommended Clinical Monitoring Suggested Clinical Monitoring

• Urinalysis (RBCs)- routine for high • Cystitis assessment, including urinalysis if

intravenous doses (>1000mg/m2); periodic patient complains of symptoms
for low IV dose/and in response to patient
• Baseline and regular hepatic function
complaint / long-term therapy
• Baseline and regular renal function tests
and urinalysis
• Regular CBC’s

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 Cyclophosphamide

J REFERENCES

BC Cancer Agency Chemotherapy Preparation and Stability Chart© version 2.00. Accessed January
21, 2009.

Cyclophosphamide: Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency
(BCCA).

Compendium of Pharmaceuticals and Specialties. Cytoxan®. Canadian Pharmacists Association.

Updated December 6, 2007.

Compendium of Pharmaceuticals and Specialties 2008: .Procytox®. Canadian Pharmacists

Association

Cyclophosphamide drug monograph. Cancer Care Nova Scotia. Accessed June 5, 2009.

De Jonge, ME, Huitema ADR, Rodenhuisz S, et al. Clinical pharmacokinetics of cyclophosphamide.

Clin Pharmacokinet 2005; 44 (11): 1135-64.

Haubitz M, Bohnenstengel F, Brunkhorst R. Cyclophosphamide pharmacokinetics and dose

requirements in patients with renal insufficiency. Kidney International 2002; 61: 1495–501.

Marr KA, Leisenring W, Crippa F, et al. Cyclophosphamide metabolism is affected by azole

antifungals. Blood 2004; 103: 1557-9.

Perry JJ, Fleming RA, Rocco MV. Case report: administration and pharmacokinetics of high-dose
cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation
in acute leukemia and end-stage renal disease. Bone Marrow Transplantation 1999; 23: 839–42.

Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits
chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002
Jul 1; 62(13):3868-75.

Yamamoto R, Kanda Y, Matsuyama T. Case report: myopericarditis caused by cyclophosphamide

used to mobilize peripheral blood stem cells in a myeloma patient with renal failure. Bone Marrow
Transplantation 2000; 26: 685–8.

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CCO Formulary Revised June 2009