cyclophosphamide

Trade Name:

Procytox®

Appearance:

Injection- clear solution mixed into larger bags of fluids; Oral- tablets in various strengths

Monograph Name:

cyclophosphamide

Monograph Body:

Drug Monograph

A - Drug Name

cyclophosphamide

COMMON TRADE NAME(S): Procytox®

B - Mechanism of Action and Pharmacokinetics

Cyclophosphamide is a nitrogen mustard derivative. It is transformed via hepatic and intracellular enzymes to active alkylating metabolites. Cyclophosphamide is an alkylating agent, and prevents cell division primarily by cross-linking DNA and RNA strands. It is considered to be cell cycle phase-nonspecific.

Absorption

Well absorbed from the gastrointestinal tract and parenterally. May also absorbed when applied topically.

Bioavailability

Oral: Yes, bioavailability 75-100%. Oral administration results in increased alkylating activity than IV.

Distribution

Distribution to most tissues, crosses placenta, present in breast milk and ascites

Cross blood brain barrier?

Yes, including metabolites

PPB

12-14%, metabolites 39-67%

Metabolism

Mainly activated by hepatic microsomal enzyme oxidation system (CYP 450). Detoxified by glutathione S transferases and alcohol dehydrogenase.

Active metabolites

Phosphoramide mustard / acrolein / 4-hydroxy cyclophosphamide / aldophosphamide

Inactive metabolites

yes

Elimination

Drug and metabolites excreted by kidney, tubular reabsorption occurs.

Urine

59-82% after 4 days (<20% unchanged)

Half-life

7 hours

C - Indications and Status

Health Canada Approvals:

Pediatric Acute lymphoblastic leukemia
Acute myelogenous leukemia
Breast cancer
Burkitt's Lymphoma
Chronic lymphocytic leukemia
Chronic myelogenous leukemia
Hodgkin lymphoma
Lung cancer (small cell)
Multiple myeloma
Mycosis fungoides
Neuroblastoma (disseminated disease)
Non-Hodgkin lymphomas
Retinoblastoma

Other Uses:

Ewing sarcoma
Endocrine (adrenal, thymoma)
Gynecological cancers (small cell carcinoma, sarcoma)
Small cell carcinomas
Head and Neck cancer
Wilm's Tumour
Soft tissue sarcoma
Prostate cancer

D - Adverse Effects

Emetogenic Potential:

Moderate (IV doses ≤ 1500 mg/ m2)
High (IV doses > 1500 mg/ m2)
Moderate – Consider prophylaxis daily (PO doses ≥ 100 mg/ m2)
Low – No routine prophylaxis; PRN recommended (PO doses < 100 mg/ m2)

Extravasation Potential: None

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (rare)	E
	Arterial thromboembolism (rare)	E
	Cardiotoxicity (rare; including myocarditis)	E
	Flushing (facial, during IV administration)	I
	QT interval prolonged (rare)	E
	Venous thromboembolism (rare)	E
Dermatological	Alopecia (100%) (some degree; severe 5-30%)	E
	Hand-foot syndrome (rare)	E
	Nail disorder / discolouration	E
	Radiation recall reaction (rare)	I E
	Rash (rare, may be severe)	I E
	Skin discolouration (rare)	E
Gastrointestinal	Abdominal pain	E
	Anorexia (rare)	E
	Constipation (rare; sometimes severe)	E
	Diarrhea (rare)	E
	GI hemorrhage (rare)	E
	Mucositis (<1%)	E
	Nausea, vomiting (50%) (moderate to severe)	I
General	Delayed wound healing (rare)	E
	Fatigue (<10%)	E
	Fluid retention (including effusions) (rare)	E
Hematological	Hemolytic uremic syndrome (rare)	E D
	Immunosuppression (≥10%) and opportunistic infection (may be fatal, including reactivation of latent infections)	E D
	Myelosuppression ± infection, bleeding (≥10%) (may be severe)	E
Hepatobiliary	↑ LFTs (<10%) (may be severe)	E D
	Pancreatitis (rare)	E
	Veno-occlusive disease (rare, mostly high dose, especially with busulfan; also reported with long-term low dose)	E
Hypersensitivity	Hypersensitivity (includes anaphylaxis; rare, may be fatal, may be cross-sensitivity with other alkylating agents)	I
Injection site	Injection site reaction	I
Metabolic / Endocrine	SIADH (rare)	E
	Tumor lysis syndrome (rare)	E
Musculoskeletal	Musculoskeletal pain	E
	Rhabdomyolysis (rare)	E
Neoplastic	Secondary malignancy (rare)	L
Nervous System	Dizziness (rare)	I
	Dysgeusia	E D
	Headache (rare)	I
	Neurotoxicity (central and peripheral)	E D
	RPLS / PRES (rare)	E
Ophthalmic	Conjunctivitis (rare)	E D
	Visual disorders (rare)	E
	Watering eyes (rare)	E
Renal	Nephrotoxicity (rare)	E
Reproductive and breast disorders	Estrogen deprivation symptoms and androgen withdrawal symptoms	E D
Respiratory	Pneumonitis /fibrosis (rare)	E D L
Urinary	Bladder fibrosis (rare; and non-hemorrhagic cystitis)	E D
	Hemorrhagic Cystitis (<10%) (BMT >40%)	I E D
Vascular	Vasculitis (rare)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

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

The most common side effects for cyclophosphamide include alopecia, nausea, vomiting, immunosuppression, myelosuppression ± infection, bleeding.

Myelosuppression is the major dose limiting toxicity. Immunosuppression, opportunistic infections and reactivation of latent infections may occur, including progressive multifocal leucoencephalopathy.

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 or busulfan treatment may increase the risk. 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 diuresis and the administration of mesna, and should be implemented for patients at high risk (e.g. high dose for stem cell transplant).

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 have been reported and may be acute or chronic. 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 and non-Hodgkin lymphomas. There does not appear to be a duration, route, dose, or schedule relationship.

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 myocarditis 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 older patients and those 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 lymphoma. Patients who develop bladder cancer usually have a history of hemorrhagic cystitis.

Veno-occlusive liver disease (VOD) may develop in patients who have received high doses (preparation for bone marrow transplantation) in combination with whole-body radiation and other cytotoxic agents. Patients with pre-existing liver dysfunction, radiation to the abdomen and low performance status may be at increased risk following high-dose cytoreductive therapy. VOD may also develop gradually with the use of long-term low-dose treatment with cyclophosphamide

E - Dosing

Refer to protocol by which patient is being treated.

Dosage may be reduced and/or delayed in:

patients with bone marrow depression due to cytotoxic/radiation therapy, or
adrenalectomized patients

Recommendations for hydration should be followed, with ample fluids and frequent voiding.

Before starting treatment:

Exclude or correct any electrolyte imbalances
Exclude or correct any obstructions of the urinary tract, cystitis and infections

Adults:

Intravenous:

Q3W: Example - 500 mg/m² (ie. FEC regimen) to 1200mg/m² (ie. VAC regimen)

Oral:

Q28D: Example - 100mg/m² daily for 14 days (ie. CMF PO)

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

Dosage with Toxicity:

Toxicity	*Action (% of previous dose)**
ANC < 1.5 x 10⁹/L or platelets < 100 x 10⁹/L	Hold or manage as per protocol
Grade 4 ANC or platelets, febrile neutropenia or thrombocytopenic bleeding	75%
Grade 3 non hematologic / organ	75%
Grade 4 non hematologic /organ	Discontinue
Pneumonitis	Hold, investigate and if confirmed, discontinue
Hematuria	Hold until resolution; discontinue if severe hemorrhagic cystitis
* do not retreat until ANC ≥ 1.5 x 10⁹/L, platelets ≥ 100 x 10⁹/L and other toxicity recovered to ≤ grade 2

Dosage with Hepatic Impairment:

No adjustment required, but caution should be exercised especially with oral cyclophosphamide.

Bilirubin	Cyclophosphamide (% previous dose)
1-2 x ULN	100%
>2 x ULN	Caution

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. Cyclophosphamide is hemodialysable and should be administered after hemodialysis.

Suggested:

Creatinine Clearance (mL/min)	Cyclophosphamide (% previous dose)
> 50	100%
10 - 50	May consider 75%
< 10	50%; use with caution and monitor closely

Dosage in the elderly:

No dose modification routinely required, but should be used with caution.

Children:

Dose adjustment may be required.

F - Administration Guidelines

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.
Morning administration of cyclophosphamide is recommended, to decrease the amount of drug dwelling in the bladder overnight.
Consider usage of mesna with high dose therapy of cyclophosphamide (>1 g/m²).

Oral tablets should be administered as a single dose in the morning, with or without food.
Patients should avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
An oral preparation may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir USP (refer to product monograph).
For direct IV injection, reconstitute with sodium chloride 0.9% injection only. Do not reconstitute with sterile water for injection, as this will result in a hypotonic solution.
For IV infusion (recommended), may reconstitute cyclophosphamide with sodium chloride 0.9% or sterile water for injection and further dilute as follows:

Dose Dilution volume

≤ 1000 mg 100 mL sodium chloride 0.9% or dextrose 5%

> 1000 mg 250 mL sodium chloride 0.9% or dextrose 5%

Higher doses (e.g. bone marrow transplant) may need higher dilution volume (500-1000mL)

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 aluminum-containing preparation and administration equipment, since darkening of aluminum and gas production have been reported

Store unopened vial in the original packaging at room temperature, away from heat, light or moisture

G - Special Precautions

Contraindications:

patients with severe hepatic or renal impairment
patients with severe myelosuppression (leukocytes < 2.5 x 10⁹/L and/or platelets < 50 x 10⁹/L) and/or immunosuppression
patients who have a hypersensitivity to this drug or any of its components
patients with active infection, particularly varicella zoster infection
patients with urinary outflow obstruction

Other Warnings/Precautions:

Exercise caution in patients:
- with adrenal insufficiency
- with risk factors for cardiotoxicity or pre-existing cardiac disease
- using cyclophosphamide in combination with neuromuscular blockers
- with tumour infiltration in the bone marrow
Avoid live or live-attenuated vaccines as use may result in serious or fatal infections in immunocompromised patients. Reduced immunogenicity may occur with use of inactivated vaccines.
Use caution when driving or operating machinery since cyclophosphamide may produce symptoms of vasomotor ataxia (e.g. dizziness, blurred vision, etc.).

Other Drug Properties:

Carcinogenicity: Yes

Pregnancy and Lactation:

Teratogenicity: Yes
Mutagenicity: Yes
Genotoxicity: Yes
Fetotoxicity: Yes

Cyclophosphamide is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months (for males) and at least 12 months (for females) after the last dose.
Excretion into breast milk: Yes
Breastfeeding is not recommended.
Fertility effects: Yes

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.

H - Interactions

Metabolized by CYP2B6, 2C8, 2C9, 2C19, 3A4 and 3A5.

AGENT	EFFECT	MECHANISM	MANAGEMENT
alcohol	May ↑ cyclophosphamide-induced nausea and vomiting; reduced anti-tumour activity observed in animal studies	Unknown	Avoid
allopurinol, thiazide diuretics, ACE inhibitors	↑ myelosuppressive effect	Unknown; additive leukopenia with ACE inhibitors	Caution; monitor
amiodarone	↑ pulmonary toxicity	Additive	Caution; monitor
azathioprine	↑ hepatotoxicity	Additive	Caution; monitor
bupropion	↑ bupropion concentration and/or toxicity	both are CYP2D6 substrates	Caution; monitor
busulfan	↑ risk of hepatic veno-occlusive disease and mucositis	Additive; may reduce cyclophosphamide clearance	Caution; monitor
cardiotoxic drugs (i.e. anthracyclines, cytarabine, pentostatin, trastuzumab, prior cardiac radiation)	↑ cardiotoxicity	Additive	Caution; monitor
ciprofloxacin	↓ cyclophosphamide concentration and/or efficacy	Unknown	Caution; monitor
cyclosporine	↑ risk of graft vs host disease	↓ serum concentrations of cyclosporine	Caution; monitor
depolarizing muscle relaxants (i.e. succinylcholine)	prolonged post-operative apnea may occur	cyclophosphamide inhibits cholinesterase activity	Notify anesthesiologist, measure pseudo-cholinesterase levels; if decreased, consider a decrease in succinylcholine dose.
digoxin, verapamil	↓ serum drug levels	↓ intestinal absorption of digoxin, verapamil	Caution; monitor for reduced drug effect
drugs which induce hepatic microsomal enzymes (especially 2B6, 2C9 and 3A4) e.g. phenytoin, phenobarbital, corticosteroids, St. John's Wort, protease inhibitors	↑ activation of cyclophosphamide, ↑ cytotoxic metabolites	induction of hepatic microsomal enzyme oxidation system	Caution; monitor
drugs which inhibit hepatic microsomal enzymes (e.g. chloramphenicol, grapefruit juice, itraconazole, fluconazole)	↓ activation of cyclophosphamide	inhibition of hepatic microsomal enzyme oxidation system	Caution, monitor. Avoid grapefruit juice for 48 hours before and on day of dose.
etanercept	Higher incidence of non-cutaneous solid malignancies	Unknown	Avoid if possible; monitor closely if concomitant use
G-CSF, GM-CSF	↑ pulmonary toxicity	Unknown	Monitor closely
indomethacin	pulmonary edema	SIADH	Caution; monitor
lovastatin	↑ rhabdomyolysis and renal failure	Unknown	Caution; avoid concomitant use where possible
methotrexate	↑ cyclophosphamide toxicity	↓ metabolism of cyclophosphamide	Caution; monitor
Nephrotoxic drugs (i.e. aminoglycosides, amphotericin B, methotrexate)	↑ risk of nephrotoxicity	Additive	Caution; monitor renal function closely
paclitaxel	↑ hematotoxicity reported when cyclophosphamide given after paclitaxel	Additive	Caution; monitor
prednisone	Acute respiratory failure (may be fatal)	Unknown	Monitor closely
metronidazole	acute encephalopathy reported	Unknown	Caution; monitor
ondansetron	↓ cyclophosphamide effect (high dose)	Unknown	Caution; monitor
sulfonylureas	↑ hypoglycemia	Unknown	Caution
tamoxifen	↑ risk of thromboembolism	Additive	Caution; monitor
warfarin	increased and decreased warfarin effect reported	Unknown	Caution; monitor INR closely

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
CBC	Baseline and before each cycle
Renal function tests	Baseline and before each cycle
Liver function tests	Baseline and as clinically indicated
Electrolytes	Baseline and as clinically indicated
Urinalysis	Baseline and as clinically indicated
Urinalysis (RBCs)	Routine for high intravenous doses (>1000mg/m2)
Clinical toxicity assessment for gastrointestinal, cystitis, infection, bleeding, thromboembolism, cardiac or pulmonary adverse effects	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Monitor Type	Monitor Frequency
INR; for patients on warfarin	Baseline and as clinically indicated
ECGs	As clinically indicated
Pulmonary function tests	As clinically indicated

J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

cyclophosphamide - oral tablets ()

K - References

Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 97, 170.

BC Cancer Agency Chemotherapy Preparation and Stability Chart. British Columbia Cancer Agency (BCCA). Accessed Nov 28, 2018.

BCCA drug monograph: Cyclophosphamide. Accessed November 28, 2018.

Compendium of Pharmaceuticals and Specialties: Cytoxan®. Canadian Pharmacists Association. Updated December 6, 2007.

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

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.

Lexi-comp drug monograph: Cyclophosphamide. Accessed November 28, 2018.

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.

Procytox (cyclophosphamide) Product Monograph. Baxter Corporation, September 2012.

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.

Summary of Product Characteristics: Cyclophosphamide Injection 1g. Baxter Healthcare Ltd. (UK), June 2016.

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.

June 2019 Updated emetic risk category

L - Disclaimer

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References: