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Cyclophosphamide

Pronunciation

Pronunciation

(sye kloe FOS fa mide)

Index Terms

  • CPM
  • CTX
  • CYT
  • Cytoxan
  • Neosar

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 25 mg, 50 mg

Solution Reconstituted, Injection:

Generic: 500 mg (1 ea); 1 g (1 ea); 2 g (1 ea)

Tablet, Oral:

Generic: 25 mg, 50 mg

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
  • Antirheumatic Miscellaneous
  • Immunosuppressant Agent

Pharmacology

Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.

Absorption

Oral: Well absorbed

Distribution

Vd: 30 to 50 L (approximates total body water); crosses into CSF (not in high enough concentrations to treat meningeal leukemia)

Metabolism

Hepatic to active metabolites acrolein, 4-aldophosphamide, 4-hydroperoxycyclophosphamide, and nor-nitrogen mustard

Excretion

Urine (10 to 20% as unchanged drug); feces (4%)

Time to Peak

Oral: ~1 hour; IV: Metabolites: 2 to 3 hours

Half-Life Elimination

IV: 3 to 12 hours; Children: 4 hours; Adults: 6 to 8 hours

Protein Binding

~20%; some metabolites are bound at >60%

Special Populations: Renal Function Impairment

Systemic exposure is increased as renal function declines. The mean (dose-corrected AUC) increased by 38% in patients with moderate renal impairment (CrCl 25 to 50 mL/minute), increased by 64% in patients with severe impairment (CrCl 10 to 24 mL/minute), and by 23% in patients undergoing hemodialysis (CrCl <10 mL/minute), when compared to a control group. Cyclophosphamide and metabolites are dialyzable; differences in amount dialyzed may occur due to dialysis system used.

Special Populations: Hepatic Function Impairment

In patients with severe hepatic impairment, the elimination half-life is prolonged by 64%.

Use: Labeled Indications

Oncology uses: Treatment of acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), breast cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Hodgkin lymphoma, mycosis fungoides, multiple myeloma, neuroblastoma, non-Hodgkin lymphomas (including Burkitt lymphoma), ovarian adenocarcinoma, and retinoblastoma

Limitations of use: Although potentially effective as a single-agent in susceptible malignancies, cyclophosphamide is more frequently used in combination with other chemotherapy drugs

Canadian labeling: Additional use (not in US labeling): Treatment of lung cancer

Nononcology uses: US labeling: Nephrotic syndrome: Treatment of minimal change nephrotic syndrome (biopsy proven) in children who are unresponsive or intolerant to corticosteroid therapy

Limitations of use: The safety and efficacy for the treatment of nephrotic syndrome in adults or in other renal diseases has not been established.

Use: Unlabeled

Oncology-related uses: Ewing sarcoma, gestational trophoblastic tumors (high-risk), ovarian germ cell tumors, pheochromocytoma, rhabdomyosarcoma, small cell lung cancer (refractory), Waldenström macroglobulinemia, Wilms tumor, and hematopoietic stem cell transplant (HSCT) conditioning regimen

Nononcology uses: Severe rheumatoid disorders, granulomatosis with polyangiitis (GPA; Wegener granulomatosis), juvenile idiopathic arthritis, myasthenia gravis, lupus nephritis, autoimmune hemolytic anemia, idiopathic thrombocytic purpura (ITP), antibody-induced pure red cell aplasia

Contraindications

US labeling: Hypersensitivity to cyclophosphamide or any component of the formulation; urinary outflow obstruction

Canadian labeling: Hypersensitivity to cyclophosphamide or its metabolites, urinary outflow obstructions, severe myelosuppression, severe renal or hepatic impairment, active infection (especially varicella zoster), severe immunosuppression

Dosing: Adult

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Roila 2010).

US labeling: Malignancy:

IV: 40 to 50 mg/kg in divided doses over 2 to 5 days or 10 to 15 mg/kg every 7 to 10 days or 3 to 5 mg/kg twice weekly

Oral: 1 to 5 mg/kg/day (initial and maintenance dosing)

Canadian labeling: Malignancy:

IV: Initial: 40 to 50 mg/kg (1500 to 1800 mg/m2) administered as 10 to 20 mg/kg/day over 2 to 5 days; Maintenance: 10 to 15 mg/kg (350 to 550 mg/m2) every 7 to 10 days or 3 to 5 mg/kg (110 to 185 mg/m2) twice weekly

Oral: Initial 1 to 5 mg/kg/day (depending on tolerance); Maintenance: 1 to 5 mg/kg/day

Indication specific and/or off-label uses/dosing:

Acute lymphoblastic leukemia (off-label dosing): Multiple-agent regimens:

Hyper-CVAD regimen: IV: 300 mg/m2 over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase (Kantarjian 2004)

CALGB8811 regimen: IV:

Adults <60 years: Induction phase: 1200 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1000 mg/m2 on day 29 of an 8-week cycle (Larson 1995)

Adults ≥60 years: Induction phase: 800 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1000 mg/m2 on day 29 of an 8-week cycle (Larson 1995)

Breast cancer (off-label dosing):

AC regimen: IV: 600 mg/m2 on day 1 every 21 days (in combination with doxorubicin) for 4 cycles (Fisher 1990)

CEF regimen: Oral: 75 mg/m2/day days 1 to 14 every 28 days (in combination with epirubicin and fluorouracil) for 6 cycles (Levine 1998)

CMF regimen: Oral: 100 mg/m2/day days 1 to 14 every 28 days (in combination with methotrexate and fluorouracil) for 6 cycles (Levine 1998) or IV: 600 mg/m2 on day 1 every 21 days (in combination with methotrexate and fluorouracil); Goldhirsch 1998)

Chronic lymphocytic leukemia (off-label dosing): IV: R-FC regimen: 250 mg/m2/day for 3 days every 28 days (in combination with rituximab and fludarabine) for 6 cycles (Robak 2010)

Ewing sarcoma (off-label use): IV: VAC/IE regimen: VAC: 1200 mg/m2 (plus mesna) on day 1 of a 21-day treatment cycle (in combination with vincristine and doxorubicin [then dactinomycin when maximum doxorubicin dose reached]), alternates with IE (ifosfamide and etoposide) for a total of 17 cycles (Grier 2003)

Gestational trophoblastic tumors, high-risk (off-label use): IV: EMA/CO regimen: 600 mg/m2 on day 8 of 2-week treatment cycle (in combination with etoposide, methotrexate, dactinomycin, and vincristine), continue for at least 2 treatment cycles after a normal hCG level (Escobar 2003; Lurain 2006)

Granulomatosis with polyangiitis (GPA; Wegener granulomatosis) (off-label use; in combination with glucocorticoids):

Low-dose: Oral: 1.5 to 2 mg/kg/day (Jayne 2003; Stone 2010) or 2 mg/kg/day until remission, followed by 1.5 mg/kg/day for 3 additional months (de Groot 2009; Harper 2012)

Pulse: IV: 15 mg/kg (maximum dose: 1200 mg) every 2 weeks for 3 doses, followed by maintenance pulses of either 15 mg/kg IV (maximum dose: 1200 mg) every 3 weeks or 2.5 to 5 mg/kg/day orally on days 1, 2, and 3 every 3 weeks for 3 months after remission achieved (de Groot 2009; Harper 2012)

Hodgkin lymphoma (off-label dosing): IV:

BEACOPP regimen: 650 mg/m2 on day 1 every 3 weeks (in combination with bleomycin, etoposide, doxorubicin, vincristine, procarbazine, and prednisone) for 8 cycles (Diehl 2003)

BEACOPP escalated regimen: 1200 mg/m2 on day 1 every 3 weeks (in combination with bleomycin, etoposide, doxorubicin, vincristine, procarbazine, and prednisone) for 8 cycles (Diehl 2003)

Multiple myeloma (off-label dosing): Oral: CyBorD regimen: 300 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (in combination with bortezomib and dexamethasone) for 4 cycles; may continue beyond 4 cycles (Khan 2012)

Non-Hodgkin lymphoma (off-label dosing): IV:

R-CHOP regimen: 750 mg/m2 on day 1 every 3 weeks (in combination with rituximab, doxorubicin, vincristine, and prednisone) for 8 cycles (Coiffier 2002)

R-EPOCH (dose adjusted) regimen: 750 mg/m2 on day 5 every 3 weeks (in combination with rituximab, etoposide, prednisone, vincristine, and doxorubicin) for 6 to 8 cycles (Garcia-Suarez 2007)

CODOX-M/IVAC (Burkitt lymphoma): Cycles 1 and 3 (CODOX-M): 800 mg/m2 on day 1, followed by 200 mg/m2 on days 2 to 5 (Magrath 1996) or 800 mg/m2 on days 1 and 2 (Lacasce 2004), in combination with vincristine, doxorubicin, and methotrexate; CODOX-M alternates with IVAC (etoposide, ifosfamide, and cytarabine) for a total of 4 cycles

Immune thrombocytopenia, refractory (off-label use; Provan 2010):

Oral: 1 to 2 mg/kg/day for at least 16 weeks

IV: 300 to 1,000 mg/m2 for 1 to 3 doses every 2 to 4 weeks

Lupus nephritis (off-label use): IV: 500 mg once every 2 weeks for 6 doses or 500 to 1000 mg/m2 once every month for 6 doses (Hahn 2012) or 500 to 1000 mg/m2 every month for 6 months, then every 3 months for a total of at least 2.5 years (Austin 1986; Gourley 1996)

Ovarian germ cell tumors (malignant; off-label use): IV: 150 mg/m2 on days 1 to 5 every 28 days (in combination with dactinomycin and vincristine) for at least 10 cycles (Slayton 1985)

Pheochromocytoma, malignant (off-label use): IV: 750 mg/m2 on day 1 every 3 or 4 weeks (in combination with dacarbazine and vincristine) (Huang 2008). Additional data may be necessary to further define the role of dacarbazine in this condition.

Small cell lung cancer (SCLC), refractory (off-label use): IV: 1000 mg/m2 (maximum: 2000 mg) on day 1 every 3 weeks (in combination with doxorubicin and vincristine) until disease progression or unacceptable toxicity (von Pawel 1999)

Stem cell transplant conditioning (off-label use): IV:

Nonmyeloablative transplant (allogeneic): 750 mg/m2/day for 3 days beginning 5 days prior to transplant (in combination with fludarabine) (Khouri 2008)

Myeloablative transplant:

100 mg/kg (based on IBW, unless actual weight <95% of IBW) as a single dose 2 days prior to transplant (in combination with total body irradiation and etoposide) (Thompson 2008)

50 mg/kg/day for 4 days beginning 5 days before transplant (with or without antithymocyte globulin [equine]) (Champlin 2007)

50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with busulfan) (Cassileth 1993)

60 mg/kg/day for 2 days (in combination with busulfan and total body irradiation) (Anderson 1996)

1800 mg/m2/day for 4 days beginning 7 days prior to transplant (in combination with etoposide and carmustine) (Reece 1991)

Dosing: Geriatric

Refer to adult dosing; adjust for renal clearance.

Dosing: Pediatric

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

US labeling:

Malignancy:

IV: 40 to 50 mg/kg in divided doses over 2 to 5 days or 10 to 15 mg/kg every 7 to 10 days or 3 to 5 mg/kg twice weekly

Oral: 1 to 5 mg/kg/day (initial and maintenance dosing)

Nephrotic syndrome, corticosteroid refractory or intolerant, or corticosteroid sparing: Oral: Initial: 2 mg/kg once daily for 8 to 12 weeks (maximum cumulative dose: 168 mg/kg); treatment beyond 90 days may increase the potential for sterility in males; treatment beyond 1 course is not recommended (Lombel 2013)

Canadian labeling: Malignancy:

IV: Initial: 2 to 8 mg/kg (60 to 250 mg/m2) in divided doses for 6 or more days; Maintenance: 10 to 15 mg/kg every 7 to 10 days or 30 mg/kg every 3 to 4 weeks or when bone marrow function recovers

Oral: Initial: 2 to 8 mg/kg (60 to 250 mg/m2) in divided doses for 6 or more days; Maintenance: 2 to 5 mg/kg (50 to 150 mg/m2) twice weekly

Indication specific and/or off-label uses/dosing:

Ewing sarcoma (off-label use): IV: VAC/IE regimen: VAC: 1200 mg/m2 (plus mesna) on day 1 of a 21-day treatment cycle (in combination with vincristine and doxorubicin [then dactinomycin when maximum doxorubicin dose reached]), alternates with IE (ifosfamide and etoposide) for a total of 17 cycles (Grier 2003)

Hodgkin lymphoma (off-label dosing): IV: BEACOPP escalated regimen: 1200 mg/m2 on day 0 of a 21-day treatment cycle (in combination with bleomycin, etoposide, doxorubicin, vincristine, prednisone, and procarbazine) for 4 cycles (Kelly 2011)

Lupus nephritis (off-label use): IV: 500 to 1000 mg/m2 every month for 6 months, then every 3 months for a total of 2.5 to 3 years (Austin 1986; Gourley 1996; Lehman 2000)

Ovarian germ cell tumors (malignant; off-label use): IV: 150 mg/m2 on days 1 to 5 every 28 days (in combination with dactinomycin and vincristine) for at least 10 cycles (Slayton 1985)

Neuroblastoma (off-label dosing): IV: CE-CAdO regimen, courses 3 and 4: 300 mg/m2 days 1 to 5 every 21 days for 2 cycles (Rubie 1998) or 10 mg/kg days 1 to 5 every 21 days for 2 cycles (Rubie 2001). Note: Decreased doses may be recommended for newborns or children <10 kg.

Stem cell transplant conditioning (off-label use): Myeloablative transplant: IV: 50 mg/kg/day for 4 days beginning 5 days before transplant (with or without antithymocyte globulin [equine]) (Champlin 2007)

Wilms tumor, relapsed (off-label use): Infants, Children, and Adolescents: IV (in combination with vincristine, doxorubicin, mesna, etoposide, filgrastim, and radiation therapy) (Green 2007):

Pediatrics ≤30 kg: 14.7 mg/kg days 1 to 5 of weeks 3, 9, 15, and 21 and 14.7 mg/kg days 1 to 3 of weeks 6, 12, 18, and 24

Pediatrics >30 kg: 440 mg/m2 days 1 to 5 of weeks 3, 9, 15, and 21 and 440 mg/m2 days 1 to 3 of weeks 6, 12, 18, and 24

Dosing: Renal Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (use with caution; elevated levels of metabolites may occur).

Canadian labeling:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling

Moderate impairment: Dose reduction may be necessary; manufacturer’s labeling does not provide specific dosing recommendations

Severe impairment: Use is contraindicated.

The following adjustments have also been recommended:

Aronoff 2007: Children and Adults:

Clcr ≥10 mL/minute: No dosage adjustment required.

Clcr <10 mL/minute: Administer 75% of normal dose.

Hemodialysis: Moderately dialyzable (20% to 50%); administer 50% of normal dose; administer after hemodialysis

Continuous ambulatory peritoneal dialysis (CAPD): Administer 75% of normal dose.

Continuous renal replacement therapy (CRRT): Administer 100% of normal dose.

Janus 2010: Hemodialysis: Administer 75% of normal dose; administer after hemodialysis

Dosing: Hepatic Impairment

The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy.

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling.

Canadian labeling:

Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

The following adjustments have been recommended (Floyd 2006):

Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.

Serum bilirubin >5 mg/dL: Avoid use.

Dosing: Adjustment for Toxicity

Hematologic toxicity: May require dose reduction or treatment interruption; Canadian labeling recommends reducing initial dose by 30% to 50% if bone marrow function compromised (due to prior radiation therapy, prior chemotherapy, or tumor infiltration)

Hemorrhagic cystitis, severe: Discontinue treatment.

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity (Bubalo 2014):

Cy200 (cyclophosphamide total dose of 200 mg/kg): Use the lesser of IBW or actual body weight (ABW).

Cy120 (cyclophosphamide total dose of 120 mg/kg): Use either IBW or ABW for patients ≤120% IBW (preferred method for adults of all body sizes); use ABW25 for patients >120% IBW (preferred for pediatric patients).

ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Injection powder for reconstitution: Reconstitute with 25 mL for a 500 mg vial, 50 mL for a 1,000 mg vial, or 100 mL for a 2,000 mg vial to a concentration of 20 mg/mL using NS or SWFI. Solutions reconstituted in SWFI are hypotonic and should not be used for direct IV push administration. May reconstitute with NS or SWFI for solutions that will be further diluted for IV infusion. Swirl gently to mix. For IV infusion, further dilute for infusion in D5W, 1/2NS, or D5NS, to a minimum concentration of 2 mg/mL.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When compounding an oral solution or suspension, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

Liquid solutions for oral administration may be prepared by dissolving cyclophosphamide injection in Aromatic Elixir, N.F. Store refrigerated (in glass container) for up to 14 days.

Cyclophosphamide Prescribing Information, Baxter Healthcare Corporation, Deerfield, Il, May, 2013.20103616

A 10 mg/mL oral suspension may be prepared by reconstituting one 2 g vial for injection with 100 mL of NaCl 0.9%, providing an initial concentration of 20 mg/mL. Mix this solution in a 1:1 ratio with either Simple Syrup, NF or Ora-Plus® to obtain a final concentration of 10 mg/mL. Label “shake well” and “refrigerate”. Stable for 56 days refrigerated.

Kennedy R, Groepper D, Tagen M, et al, "Stability of Cyclophosphamide in Extemporaneous Oral Suspensions," Ann Pharmacother, 2010, 44(2):295-301.20103616

Administration

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

IV: Infusion rate may vary based on protocol (refer to specific protocol for infusion rate). Administer by direct IV injection (if reconstituted in NS), IVPB, or continuous IV infusion

Bladder toxicity: To minimize bladder toxicity, increase normal fluid intake during and for 1 to 2 days after cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day. High-dose regimens should be accompanied by vigorous hydration with or without mesna therapy. Morning administration may be preferred to ensure adequate hydration throughout the day.

Hematopoietic stem cell transplant: Approaches to reduction of hemorrhagic cystitis include infusion of 0.9% NaCl 3 L/m2/24 hours, infusion of 0.9% NaCl 3 L/m2/24 hours with continuous 0.9% NaCl bladder irrigation 300 to 1000 mL/hour, and infusion of 0.9% NaCl 1.5 to 3 L/m2/24 hours with intravenous mesna. Hydration should begin at least 4 hours before cyclophosphamide and continue at least 24 hours after completion of cyclophosphamide. The dose of daily mesna used may be 67% to 100% of the daily dose of cyclophosphamide. Mesna can be administered as a continuous 24-hour intravenous infusion or be given in divided doses every 4 hours. Mesna should begin at the start of treatment, and continue at least 24 hours following the last dose of cyclophosphamide.

Oral: Tablets are not scored and should not be cut, chewed, or crushed. Swallow capsules whole; do not open, crush, or chew. To minimize bladder toxicity, increase normal fluid intake. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer tablets/capsules at bedtime.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Wear gloves when handling capsules/tablets and container. NIOSH recommends single gloving for administration of intact capsules or tablets (NIOSH 2014). Avoid exposure to broken capsules; if contact occurs, wash hands immediately and thoroughly.

Compatibility

Stable in D5LR, D5NS, D5W, LR, 1/2NS, NS.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex.

Storage

Injection powder for reconstitution: Store intact vials of powder at ≤25°C (77°F). Exposure to excessive temperatures during transport or storage may cause active ingredient to melt (vials with melting may have a clear to yellow viscous liquid which may appear as droplets); do not use vials with signs of melting. Solutions reconstituted in sterile water for injection should be further diluted immediately. According to the manufacturer, reconstituted solutions in normal saline (NS) are stable for 24 hours at room temperature and for 6 days refrigerated at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion in 1/2NS are stable for 24 hours at room temperature and for 6 days refrigerated and solutions diluted in D5W or D5NS are stable for 24 hours at room temperature and for 36 hours refrigerated (according to product labeling).

Capsules: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Tablets: Store tablets at ≤25°C (77°F); brief excursions are permitted up to 30°C (86°F); protect from temperatures >30°C (86°F).

Drug Interactions

Allopurinol: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, bone marrow suppression. Monitor therapy

Amiodarone: Cyclophosphamide may enhance the adverse/toxic effect of Amiodarone. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

Antineoplastic Agents (Anthracycline, Systemic): Cyclophosphamide may enhance the cardiotoxic effect of Antineoplastic Agents (Anthracycline, Systemic). Monitor therapy

AzaTHIOprine: May enhance the hepatotoxic effect of Cyclophosphamide. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the adverse/toxic effect of Cyclophosphamide. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CycloSPORINE (Systemic): Cyclophosphamide may enhance the immunosuppressive effect of CycloSPORINE (Systemic). Cyclophosphamide may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Etanercept: May enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Avoid combination

Filgrastim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Cyclophosphamide may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of bleomycin infusion. Monitor for enhanced pulmonary toxicity when cyclophosphamide and lenograstim are given in combination. Consider therapy modification

Lumacaftor: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pentostatin: May enhance the cardiotoxic effect of Cyclophosphamide. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Protease Inhibitors: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sargramostim: Cyclophosphamide may enhance the adverse/toxic effect of Sargramostim. Specifically, the risk of pulmonary toxicity may be enhanced. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Succinylcholine: Cyclophosphamide may increase the serum concentration of Succinylcholine. Management: Consider alternatives to succinylcholine in patients who have received cyclophosphamide in the past 10 days, or reduced succinylcholine doses (a serum pseudocholinesterase assay may help inform this reduction) with close monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Monitor therapy

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Frequency not defined.

Dermatologic: Alopecia (reversible; onset: 3 to 6 weeks after start of treatment)

Endocrine & metabolic: Amenorrhea, increased gonadotropin secretion

Gastrointestinal: Abdominal pain, anorexia, diarrhea, mucositis, nausea and vomiting (dose-related), stomatitis

Genitourinary: Azoospermia, defective oogenesis, hemorrhagic cystitis, oligospermia, sterility

Hematologic & oncologic: Anemia, bone marrow depression, febrile neutropenia, leukopenia (dose-related; recovery: 7 to 10 days after cessation), neutropenia, thrombocytopenia

Infection: Infection

<1% (Limited to important or life-threatening): Acute respiratory distress, anaphylaxis, auditory disturbance, blurred vision, cardiac arrhythmia (with high-dose [HSCT] therapy), cardiac failure (with high-dose [HSCT] therapy), cardiac tamponade (with high-dose [HSCT] therapy), cardiotoxicity, confusion, C-reactive protein increased, dizziness, dyschromia (skin/fingernails), dyspnea, erythema multiforme, gastrointestinal hemorrhage, heart block, hematuria, hemopericardium, hemorrhagic colitis, hemorrhagic myocarditis (with high-dose [HSCT] therapy), hemorrhagic ureteritis, hepatic veno-occlusive disease (also called hepatic sinusoidal obstruction syndrome), hepatitis, hepatotoxicity, hypersensitivity reaction, hyperuricemia, hypokalemia, hyponatremia, increased lactate dehydrogenase, interstitial pneumonitis, ischemia (acute; mesenteric), jaundice, malaise, metastases, methemoglobinemia (with high-dose [HSCT] therapy), multi-organ failure, myocardial necrosis (with high-dose [HSCT] therapy), neurotoxicity, neutrophilic eccrine hidradenitis, ovarian fibrosis, pancreatitis, pericarditis, pneumonia, pulmonary hypertension, pulmonary infiltrates, pulmonary interstitial fibrosis (with high doses), pulmonary veno-occlusive disease, pyelonephritis, radiation recall phenomenon, reactivation of disease, reduced ejection fraction, renal tubular necrosis, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, sepsis, septic shock, SIADH, skin rash, Stevens-Johnson syndrome, testicular atrophy, thrombocytopenia (immune mediated), thrombosis (arterial and venous), toxic epidermal necrolysis, toxic megacolon, tumor lysis syndrome, urinary fibrosis, weakness, wound healing impairment

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Leukopenia, neutropenia, thrombocytopenia, and anemia may commonly occur; may be dose related. Bone marrow failure has been reported. Bone marrow failure and severe immunosuppression may lead to serious (and fatal) infections, including sepsis and septic shock, or may reactive latent infections. Antimicrobial prophylaxis may be considered in appropriate patients. Initiate antibiotics for neutropenic fever; antifungal and antiviral medications may also be necessary. Monitor blood counts during treatment. Avoid use if neutrophils are ≤1,500/mm3 and platelets are <50,000/mm3. Consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia. Platelet and neutrophil nadirs are usually at weeks 1 and 2 of treatment and recovery is expected after ~20 days. Severe myelosuppression may be more prevalent in heavily pretreated patients or in patients receiving concomitant chemotherapy and/or radiation therapy.

• Cardiotoxicity: Cardiotoxicity has been reported (some fatal), usually with high doses associated with transplant conditioning regimens, although may rarely occur with lower doses. Cardiac abnormalities do not appear to persist. Cardiotoxicities reported have included arrhythmias (supraventricular and ventricular [some with QT prolongation]), congestive heart failure, heart block, hemopericardium (secondary to hemorrhagic myocarditis and myocardial necrosis), myocarditis (including hemorrhagic), pericarditis, pericardial effusion including cardiac tamponade, and tachyarrhythmias. Cardiotoxicity is related to endothelial capillary damage; symptoms may be managed with diuretics, ACE inhibitors, beta-blockers, or inotropics (Floyd 2005). The risk for cardiotoxicity may be increased with higher doses, advanced age, prior radiation to the cardiac region, and in patients who have received prior or concurrent cardiotoxic medication. Use with caution in patients with preexisting cardiovascular disease or those at risk for cardiotoxicity. For patients with cardiac risk factors or preexisting cardiac disease, monitor during treatment.

• Fertility effects: May impair fertility; interferes with oogenesis and spermatogenesis. Effect on fertility is generally dependent on dose and duration of treatment and may be irreversible. The age at treatment initiation and cumulative dose were determined to be risk factors for ovarian failure in cyclophosphamide use for the treatment of systemic lupus erythematosus (SLE) (Mok 1998).

• Gastrointestinal adverse effects: Nausea and vomiting commonly occur. Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010). Stomatitis/mucositis may also occur.

• Hepatotoxicity: Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease (VOD), has been reported in patients receiving chemotherapy regimens containing cyclophosphamide. A major risk factor for SOS is cytoreductive conditioning transplantation regimens with cyclophosphamide used in combination with total body irradiation or busulfan (or other agents). Other risk factors include preexisting hepatic dysfunction, prior radiation to the abdominal area, and low performance status. Children <3 years of age are reported to be at increased risk for hepatic SOS; monitor for signs or symptoms of hepatic SOS, including bilirubin >1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, or unexplained right upper quadrant pain (Arndt 2004). SOS has also been reported in patients receiving long-term lower doses for immunosuppressive indications.

• Hypersensitivity: Anaphylactic reactions have been reported. Cross-sensitivity with other alkylating agents may occur.

• Hyponatremia: Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) has been reported; some have been fatal.

• Immunosuppression: Monitor for infections; immunosuppression and serious infections may occur. Serious infections may require dose reduction, or interruption or discontinuation of treatment.

• Pulmonary toxicities: Pulmonary toxicities, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. Monitor for signs/symptoms of pulmonary toxicity. Consider pulmonary function testing to assess the severity of pneumonitis (Morgan 2011). Cyclophosphamide-induced pneumonitis is rare and may present as early (within 1 to 6 months) or late onset (several months to years). Early onset may be reversible with discontinuation; late onset is associated with pleural thickening and may persist chronically (Malik 1996). In addition, late onset pneumonitis (>6 months after therapy initiation) may be associated with increased mortality.

• Secondary malignancies: Secondary malignancies (bladder cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported with both single-agent and with combination chemotherapy regimens; onset may be delayed (up to several years after treatment). Bladder cancer usually occurs in patients previously experiencing hemorrhagic cystitis; risk may be reduced by preventing hemorrhagic cystitis.

• Urinary/renal toxicity: Cyclophosphamide is associated with the development of hemorrhagic cystitis, pyelitis, ureteritis, and hematuria. Hemorrhagic cystitis may rarely be severe or fatal. Bladder fibrosis may also occur, either with or without cystitis. Urotoxicity is due to excretion of cyclophosphamide metabolites in the urine and appears to be dose- and treatment duration-dependent, although may occur with short-term use. Increased hydration and frequent voiding is recommended to help prevent cystitis; some protocols utilize mesna to protect against hemorrhagic cystitis. Monitor urinalysis for hematuria or other signs of urotoxicity. Severe or prolonged hemorrhagic cystitis may require medical or surgical treatment. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases. Discontinue cyclophosphamide with severe hemorrhagic cystitis. Exclude or correct any urinary tract obstructions prior to treatment initiation (use is contraindicated with bladder outlet obstruction). Use with caution (if at all) in patients with active urinary tract infection.

• Wound healing impairment: May interfere with wound healing.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be needed. Use is contraindicated in severe impairment in the Canadian labeling. The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed. Decreased renal excretion and increased serum levels (cyclophosphamide and metabolites) may occur in patients with severe renal impairment (CrCl 10 to 24 mL/minute); monitor for signs/symptoms of toxicity. Use is contraindicated in severe impairment in the Canadian labeling. Cyclophosphamide and metabolites are dialyzable; differences in amount dialyzed may occur due to dialysis system used. If dialysis is required, maintain a consistent interval between administration and dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Cyclophosphamide may potentiate the cardiotoxicity of anthracyclines.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

CBC with differential and platelets, BUN, UA, serum electrolytes, serum creatinine; monitor for signs/symptoms of hemorrhagic cystitis or other urinary/renal toxicity, pulmonary, cardiac, and/or hepatic toxicity

Pregnancy Risk Factor

D

Pregnancy Considerations

Cyclophosphamide crosses the placenta and can be detected in amniotic fluid (D'Incalci 1982). Based on the mechanism of action, cyclophosphamide may cause fetal harm if administered during pregnancy. Adverse events (including ectrodactylia) were observed in human studies following exposure to cyclophosphamide. Women of childbearing potential should avoid pregnancy while receiving cyclophosphamide and for up to 1 year after completion of treatment. Males with female partners who are or may become pregnant should use a condom during and for at least 4 months after cyclophosphamide treatment. Cyclophosphamide may cause sterility in males and females (may be irreversible) and amenorrhea in females. When treatment is needed for lupus nephritis, cyclophosphamide should be avoided in women who are pregnant or those who wish to preserve their fertility (Hahn 2012).

Chemotherapy, if indicated, may be administered to pregnant women with breast cancer as part of a combination chemotherapy regimen (common regimens administered during pregnancy include doxorubicin (or epirubicin), cyclophosphamide, and fluorouracil); chemotherapy should not be administered during the first trimester, after 35 weeks gestation, or within 3 weeks of planned delivery (Amant 2010; Loibl 2006). The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, diarrhea, hair loss, skin discoloration, nail changes, nausea, vomiting, or abdominal pain. Have patient report immediately to prescriber signs of infection; signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe loss of strength and energy, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, arrhythmia, wound healing impairment, blood in urine, painful urination, urinary retention, or change in amount of urine passed (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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