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تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
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Cyclophosphamide: Drug information

Cyclophosphamide: Drug information
(For additional information see "Cyclophosphamide: Patient drug information" and see "Cyclophosphamide: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: Canada
  • Procytox
Pharmacologic Category
  • Antineoplastic Agent, Alkylating Agent;
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard);
  • Antirheumatic, Miscellaneous;
  • Immunosuppressant Agent
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 (ASCO [Hesketh 2020]; MASCC [Roila 2016]). Increased hydration and frequent voiding are recommended to help prevent cystitis; some protocols utilize mesna to prevent bladder toxicity/hemorrhagic cystitis (refer to protocol). May require dose reduction or treatment interruption based on clinical response and hematologic toxicity (eg, ANC <1,500 mm3). Antimicrobial prophylaxis may be considered in appropriate patients. Consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia. Patient should be under the care of a clinician experienced with using cyclophosphamide.

Acute lymphoblastic leukemia

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

CALGB 10403 regimen: Patients <40 years of age: IV: Remission consolidation phase (course 2): 1,000 mg/m2 on days 1 and 29; Delayed intensification phase: 1,000 mg/m2 on day 29; phases are part of combination chemotherapy; refer to protocol for details (Stock 2019).

Hyper-CVAD regimen: IV: 300 mg/m2 over 3 hours every 12 hours for 6 doses on days 1, 2, and 3 (in combination with mesna, vincristine, doxorubicin, and dexamethasone) during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase (Kantarjian 2000); plus a BCR-ABL tyrosine kinase inhibitor (for Philadelphia chromosome-positive disease) (Ravandi 2010; Thomas 2004).

CALGB8811 regimen:

Adults <60 years of age: IV: Induction phase: 1,200 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1,000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1,000 mg/m2 on day 29 of an 8-week cycle (Larson 1995).

Adults ≥60 years of age: IV: Induction phase: 800 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1,000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1,000 mg/m2 on day 29 of an 8-week cycle (Larson 1995).

GRAALL 2003 regimen: Patients <60 years of age: IV: Induction phase: 750 mg/m2 on day 1; then 750 mg/m2 on day 15 (in good early responders) or 500 mg/m2 every 12 hours for 4 doses on days 15 and 16 (in poor early responders); Consolidation phase: 500 mg/m2 on days 29 and 30 of consolidation blocks 3, 6, and 9; Late intensification phase: 500 mg/m2 every 12 hours on day 15; phases are part of combination chemotherapy; refer to protocol for further information (Huguet 2009).

GRAALL 2005 regimen: Patients <60 years of age: IV: Induction phase: 750 mg/m2 on day 1; then 750 mg/m2 on day 15 or 300 mg/m2 every 12 hours for 6 doses on days 15 to 17; First, second, and third consolidation phases (block 3, block 6, and block 9, respectively): 500 mg/m2 on days 29 and 30; Late intensification phase (if complete response after first course): 750 mg/m2 on day 1; then 750 mg/m2 on day 15 or 300 mg/m2 every 12 hours for 6 doses on days 15 to 17; phases are part of combination chemotherapy; refer to protocol for further information (Huguet 2018).

MRC UKALL XII/ECOG E2993 regimen: Patients <60 years of age: IV: Induction (phase 2): 650 mg/m2 on days 1, 15, and 29; Consolidation phase (cycle 3): 650 mg/m2 on day 29; phases are part of combination chemotherapy; refer to protocol for further information (Rowe 2005).

Adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (off-label dosing): IV: 350 mg/m2 on day 1 every 28 days (as part of the VCAP-AMP-VECP multiagent chemotherapy regimen) for 6 cycles (Tsukasaki 2007).

Anti-glomerular basement membrane disease

Anti-glomerular basement membrane disease (anti-GBM or Goodpasture disease) (off-label use):

Note: For use in combination with glucocorticoids and plasmapheresis in patients with kidney involvement who do not require immediate dialysis, or in patients with pulmonary hemorrhage regardless of kidney involvement (Kaplan 2021; KDIGO 2012).

Oral: 2 mg/kg once daily; some experts do not exceed 200 mg/day. On plasmapheresis days, administer cyclophosphamide after plasmapheresis. Discontinue therapy after 2 to 3 months; some experts continue therapy for up to 6 months if anti-GBM antibodies are not substantially reduced within 3 months (Huart 2016; Kaplan 2021; KDIGO 2012).

Breast cancer

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).

Castleman disease, idiopathic, multicentric

Castleman disease, idiopathic, multicentric (off-label use; based on limited data): Note: Cyclophosphamide-containing combination chemotherapy regimens (± rituximab) may benefit certain patients with severe idiopathic multicentric Castleman disease (van Rhee 2018).

CHOP regimen: IV: 750 mg/m2 on day 1 every 3 weeks for 4 cycles (in combination with doxorubicin, vincristine, and prednisone ± rituximab) (Seo 2009).

TCP regimen: Oral: 300 mg/m2 once weekly on days 1, 8, 15, and 22 every 4 weeks (in combination with thalidomide and prednisone). TCP was administered for 2 years or until treatment failure; cyclophosphamide and prednisone were administered for 1 year, while thalidomide was administered for 2 years (Zhang 2019).

Chronic lymphocytic leukemia

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).

Dermatomyositis/Polymyositis, severe, life-threatening or refractory

Dermatomyositis/polymyositis, severe, life-threatening or refractory (adjunctive agent) (off-label use):

Note: For use as an adjunct to glucocorticoids and other immunosuppressive agents in patients with severe disease that is refractory to other preferred therapies, or as part of initial combination therapy in patients with impending respiratory failure (Dellaripa 2021; Targoff 2021).

IV: 500 to 750 mg/m2 every 4 weeks; some experts do not exceed 1,200 mg/dose (McCune 2021).

Oral: 1.5 to 2 mg/kg/day; some experts do not exceed 200 mg/day (Marie 2011; McCune 2021).

Duration of therapy: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Dellaripa 2021).

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (off-label use):

Note: For use in combination with glucocorticoids to initiate disease remission in patients with severe, multiorgan disease or severe cardiovascular or CNS involvement (ACR/VF [Chung 2021]; EULAR [Mukhtyar 2009]; King 2021).

IV: 600 mg/m2 once every month (Cohen 2007; Gayraud 1997; Guillevin 1995); some experts do not exceed 1,200 mg/dose (McCune 2021).

Oral: 2 mg/kg once daily (maximum: 200 mg/day) (EULAR [Mukhtyar 2009]; Gayraud 1997; Guillevin 1991).

Duration of therapy: Continue therapy for 6 to 12 months, then transition to an alternative immunosuppressive agent to maintain remission (Cohen 2007; EULAR [Mukhtyar 2009]; Guillevin 1991; King 2021).

Ewing sarcoma

Ewing sarcoma (off-label use): VAC/IE regimen: VAC: IV: 1,200 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 neoplasia, high-risk

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

Graft-vs-host disease, acute and chronic, prophylaxis

Graft-vs-host disease, acute and chronic, prophylaxis (off-label use): IV: 50 mg/kg on days +3 and +4 following allogeneic blood or marrow transplantation (in combination with mesna) (Kanakry 2014a; Kanakry 2014b; Luzkin 2010).

Granulomatosis with polyangiitis and microscopic polyangiitis, organ- or life-threatening

Granulomatosis with polyangiitis and microscopic polyangiitis, organ- or life-threatening (off-label use):

IV: 15 mg/kg (maximum: 1,200 mg) once every 2 weeks for 3 doses, followed by 15 mg/kg (maximum: 1,200 mg) once every 3 weeks for 3 to 6 months. Use in combination with glucocorticoids (de Groot 2009; Harper 2012).

Oral: 1.5 to 2 mg/kg/day (maximum: 200 mg/day) in combination with glucocorticoids until remission is induced (usually within 3 to 6 months) (de Groot 2009; Jayne 2003; Stone 2010).

Duration of therapy: Transition to an alternative immunosuppressive agent to maintain remission; consider alternative induction therapy if remission is not attained after 3 to 6 months of cyclophosphamide therapy (ACR/VF [Chung 2021]; EULAR [Mukhtyar 2009]; Falk 2021a).

Hematopoietic stem cell or marrow transplant

Hematopoietic stem cell or marrow transplant (off-label use):

Conditioning regimens:

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

Myeloablative transplant: IV:

100 mg/kg (based on ideal body weight [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; Cassileth 1998).

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

60 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with busulfan) (Tutschka 1987).

1,800 mg/m2/day for 4 days beginning 7 days prior to transplant (in combination with etoposide and carmustine) (Reece 1991).

Reduced-intensity conditioning regimens: IV:

30 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with thiotepa and fludarabine) (Corradini 2002).

50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with antithymocyte globulin [equine]) (Storb 1997).

Hematopoietic stem cell mobilization: IV: 1,500 mg/m2/day to 2,000 mg/m2/day for 2 days on days 1 and 2 (in combination with mesna and G-CSF [filgrastim]) (Hamadani 2012).

Hodgkin lymphoma

Hodgkin lymphoma (off-label dosing):

BEACOPP regimen: IV: 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: IV: 1,200 mg/m2 on day 1 every 3 weeks (in combination with bleomycin, etoposide, doxorubicin, vincristine, procarbazine, and prednisone) for 8 cycles (Diehl 2003).

Interstitial pneumonia, nonspecific, refractory or rapidly progressive

Interstitial pneumonia, nonspecific, refractory or rapidly progressive (off-label use):

IV (preferred route): 600 mg/m2 once every month (Corte 2009); some experts do not exceed 1,200 mg/dose (McCune 2021). Use in combination with glucocorticoids (Corte 2009; Flaherty 2022; McCune 2021).

Oral: 1 to 2 mg/kg once daily; some experts do not exceed 200 mg/day. Use in combination with glucocorticoids (Kondoh 2005; McCune 2021).

Duration of therapy: Continue therapy for at least 3 to 6 months to determine efficacy; discontinue therapy or transition to an alternative immunosuppressive agent after 6 to 12 months (Corte 2009; Flaherty 2022; Kondoh 2005).

Lupus nephritis, focal or diffuse

Lupus nephritis, focal or diffuse (off-label use):

IV (shorter, low-dose regimen; preferred regimen): 500 mg once every 2 weeks for 6 doses, then transition to an alternative immunosuppressive agent (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]).

IV (longer, high-dose regimen): 500 to 1,000 mg/m2 once every month for 6 doses, then transition to an alternative immunosuppressive agent; some experts do not exceed 1,000 mg/dose (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]; Falk 2021b).

Oral: Initial: 1 to 1.5 mg/kg once daily; some experts increase by 0.5 mg/kg/day every week up to 2 mg/kg once daily if needed based on response, and do not exceed 150 mg/day (Almaani 2017; Falk 2021b). Continue therapy for 2 to 4 months once the dose is stabilized, then transition to an alternative immunosuppressive agent (Almaani 2017).

Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy

Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy (off-label use):

Prior to axicabtagene ciloleucel: IV: 500 mg/m2/day for 3 days (in combination with fludarabine) beginning 5 days (on days −5, −4, and −3) prior to chimeric antigen receptor (CAR) T-cell infusion on day 0 (Locke 2019; Locke 2022; Neelapu 2017).

Prior to brexucabtagene autoleucel: IV: 500 mg/m2/day for 3 days (in combination with fludarabine; for relapsed/refractory mantle cell lymphoma) beginning 5 days (on days −5, −4, and −3) prior to CAR T-cell infusion on day 0 (Wang 2020) or 900 mg/m2 once beginning 2 days (on day −2) prior to CAR T-cell infusion on day 0 (in combination with fludarabine; for relapsed/refractory B-cell precursor acute lymphoblastic leukemia) (Shah 2021).

Prior to ciltacabtagene autoleucel: IV: 300 mg/m2/day for 3 days (in combination with fludarabine) followed 2 to 4 days later by CAR T-cell infusion (Berdeja 2021).

Prior to idecabtagene vicleucel: IV: 300 mg/m2/day for 3 days (in combination with fludarabine) beginning 5 days (on days -5, -4, and -3) prior to CAR T-cell infusion on day 0 (Munshi 2021).

Prior to lisocabtagene maraleucel: IV: 300 mg/m2/day for 3 days (in combination with fludarabine) followed 2 to 7 days later by CAR T-cell infusion (Abramson 2020).

Prior to tisagenlecleucel : IV: 250 mg/m2/day for 3 days (in combination with fludarabine; for relapsed/refractory diffuse large B-cell lymphoma) followed 2 to 11 days later by CAR T-cell infusion (Schuster 2019) or 500 mg/m2/day for 2 days (in combination with fludarabine; for relapsed/refractory B-cell acute lymphoblastic leukemia) followed 2 to 14 days later by CAR T-cell infusion (Maude 2018).

Membranous nephropathy

Membranous nephropathy (off-label use):

Note: For use in combination with glucocorticoids to initiate disease remission in patients at high or very high risk of disease progression, regardless of the presence of lupus (KDIGO [Floege 2019]). Some experts also use cyclophosphamide (in combination with glucocorticoids) as an alternative to other immunosuppressive therapies in patients at moderate risk of disease progression (De Vriese 2021).

Oral, cyclical (preferred): 2 mg/kg once daily during months 2, 4, and 6 (alternating with glucocorticoid therapy during months 1, 3, and 5) (Fernández-Juárez 2021; Jha 2007); some experts do not exceed 200 mg/day (De Vriese 2021).

Oral, continuous: 1.5 to 2 mg/kg once daily for 12 months (du Buf-Vereijken 2004); some experts do not exceed 200 mg/day, and also limit the total cumulative dose to 25 g to reduce the risk of malignancy (De Vriese 2021).

Merkel cell carcinoma, advanced or recurrent

Merkel cell carcinoma, advanced or recurrent (off-label use; based on limited data): IV: CAV regimen: 1,000 mg/m2 on day 1 every 21 days (in combination with doxorubicin and vincristine) (Fenig 1997).

Minimal change disease

Minimal change disease (off-label use):

Note: For use in patients with frequently relapsing or glucocorticoid-dependent disease, regardless of the presence of lupus nephritis. Initiate cyclophosphamide after remission is induced by glucocorticoids (KDIGO [Rovin 2019]).

Oral: 2 to 2.5 mg/kg once daily (Mak 1996; Ponticelli 1993); some experts continue therapy for 12 weeks, and do not exceed 200 mg/day (Meyrier 2022; Waldman 2007). Gradually taper and discontinue glucocorticoids during cyclophosphamide therapy (Mak 1996; Ponticelli 1993). Note: Avoid prolonged (>12 weeks) or repeat courses of cyclophosphamide to reduce the risk of adverse effects (Meyrier 2022).

Mixed cryoglobulinemia syndrome, moderate to severe

Mixed cryoglobulinemia syndrome, moderate to severe (alternative agent) (off-label use):

Note: For use as an alternative to rituximab, in combination with glucocorticoids, to induce disease remission (Fervenza 2021).

IV: 750 mg/m2 once every month for 3 months (Cakir 2005; Fervenza 2021); some experts do not exceed 1,200 mg/dose (McCune 2021).

Oral: 2 mg/kg once daily for 2 to 4 months (Frankel 1992; KDIGO 2012); some experts do not exceed 200 mg/day (McCune 2021).

Multiple myeloma

Multiple myeloma (off-label dosing):

CyBorD regimen: Oral: 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) or 500 mg/m2 on days 1, 8, and 15 every 3 weeks (in combination with bortezomib and dexamethasone) for 8 cycles (Kumar 2012a).

VDT-PACE regimen: IV: 400 mg/m2/day administered as a continuous infusion on days 1 to 4 of each cycle; repeat every 4 to 6 weeks (in combination with bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, and etoposide) (Lee 2003; Pineda-Roman 2008).

Non-Hodgkin lymphomas

Non-Hodgkin lymphomas (off-label dosing):

Burkitt lymphoma:

CALGB 10002 regimen (cycles 1, 3, 5, and 7): IV: 200 mg/m2/day on days 1 to 5 every 3 weeks (in combination with vincristine, prednisone, ifosfamide, dexamethasone, methotrexate, leucovorin, cytarabine, etoposide, rituximab, doxorubicin, intrathecal therapy, and filgrastim); refer to protocol for further information (Rizzieri 2014).

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

R-Hyper-CVAD: IV: 300 mg/m2 every 12 hours on days 1 to 3 (total of 6 doses) of courses 1, 3, 5, and 7 (in combination with rituximab, mesna, vincristine, doxorubicin, and dexamethasone) and alternates with even courses 2, 4, 6, and 8 (rituximab, methotrexate and cytarabine) (Thomas 2006).

Diffuse large B-cell lymphoma:

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

Dose-adjusted EPOCH/EPOCH-R regimen: IV: 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). Refer to protocol for dosage adjustments.

R-CEOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle for 3 to 6 cycles (in combination with rituximab, vincristine, etoposide, and prednisone) (Moccia 2009).

Follicular lymphoma:

CVP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine and prednisone [± rituximab or obinutuzumab]) for 8 cycles (Marcus 2005; Marcus 2017).

R-CHOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle for 6 to 8 cycles (in combination with rituximab, vincristine, doxorubicin, and prednisone) (Hiddemann 2005).

Peripheral T-cell lymphoma:

BV-CHP (or A-CHP) regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with brentuximab vedotin, doxorubicin, and prednisone) for 6 to 8 cycles (Horwitz 2019).

CHOEP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine, doxorubicin, etoposide, and prednisone) for 6 to 8 cycles (Pfreundschuh 2004; Schmitz 2010).

CHOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine, doxorubicin, and prednisone) for 6 to 8 cycles (Schmitz 2010).

Primary mediastinal B-cell lymphoma: DA-EPOCH-R regimen: IV: 750 mg/m2 as a 2-hour infusion on day 5, dose-adjusted for subsequent cycles based on neutrophil and platelet counts during nadir (in combination with etoposide, prednisone, vincristine, doxorubicin, rituximab, and filgrastim); repeat cycle every 3 weeks for a total of 6 to 8 cycles (Dunleavy 2013). Refer to protocol for dosage adjustments.

Other non- Hodgkin lymphoma regimens:

CEPP(B) regimen: IV: Initial: 600 mg/m2 on days 1 and 8; may increase dose with subsequent cycles (refer to protocol for details) every 28 days (in combination with etoposide, procarbazine, prednisone, ± bleomycin) (Chao 1990).

PEP-C regimen: Oral: 50 mg (flat dose) once daily after lunch (length of induction cycle depends on blood counts; frequency may vary based on tolerance in maintenance cycle [refer to protocol for details]; in combination with prednisone, etoposide, and procarbazine) (Coleman 2008).

Osteosarcoma, relapsed/refractory

Osteosarcoma, relapsed/refractory (off-label use): IV: 500 mg/m2/day on days 1 to 5 every 21 to 28 days (in combination with mesna, etoposide, and growth factor support) (Rodriguez-Galindo 2002) or 4,000 mg/m2 as a 3-hour infusion on day 1 (in combination with mesna and etoposide) every 21 to 28 days for 2 cycles; refer to protocol for further information (Berger 2009).

Ovarian germ cell tumors, malignant

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

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).

Polyarteritis nodosa, moderate to severe

Polyarteritis nodosa, moderate to severe (off-label use):

Note: Some experts prefer the regimen identified as “preferred” below based on clinical experience and data in patients with antineutrophil cytoplasmic antibody-associated vasculitis; this regimen has not been studied in polyarteritis nodosa (Merkel 2021a).

IV (preferred regimen): 15 mg/kg (maximum: 1,200 mg) once every 2 weeks for 3 doses, followed by 15 mg/kg (maximum: 1,200 mg) once every 3 weeks for 3 to 6 months (in combination with glucocorticoids) (de Groot 2009; Harper 2012; Merkel 2021a).

IV: 600 mg/m2 once every 2 weeks for 3 doses, then once every 4 weeks thereafter (in combination with glucocorticoids) (Gayraud 1997; Guillevin 1995); some experts do not exceed 1,200 mg/dose (McCune 2021).

Oral: 2 mg/kg once daily in combination with glucocorticoids (Gayraud 1997; Guillevin 1991); some experts do not exceed 200 mg/day (McCune 2021).

Duration of therapy : Continue therapy for ≥4 months and until disease remission is achieved (maximum duration: 6 months); some experts limit duration to 4 months if remission is achieved by then. Once remission is achieved, transition to an alternative immunosuppressive agent to maintain remission (EULAR [Mukhtyar 2009]; Guillevin 1991; Guillevin 1995; Merkel 2021a).

Primary CNS lymphoma

Primary CNS lymphoma (off-label use): TBC conditioning regimen: IV: 60 mg/kg/day for 2 days beginning 3 days prior to transplant (in combination with thiotepa and busulfan), followed by autologous stem cell transplant (DeFilipp 2017; Soussain 2001; Soussain 2008).

Pure red cell aplasia

Pure red cell aplasia (off-label use):

Note: For use in patients with acquired pure red cell aplasia (PRCA) that is not self-limiting and is refractory to other preferred agents, or as initial therapy in patients with PRCA due to anti-erythropoiesis-stimulating agent antibodies (Berns 2021; Means 2022).

Oral: 50 to 100 mg once daily (in combination with glucocorticoids); initial improvement may be observed after as early as 8 weeks, and complete response after a median of 3 to 6 months (Bennett 2005; Verhelst 2004; Yamada 1997).

Duration of therapy:

Acquired PRCA: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Sawada 2008).

PRCA due to anti-erythropoiesis-stimulating agent antibodies: Continue treatment until antibody levels become undetectable; switch to alternative therapy if there is no response within 3 to 4 months of treatment initiation (Berns 2021).

Rhabdomyosarcoma

Rhabdomyosarcoma (off-label use): Adults <50 years: VAC regimen:

Low risk: IV: 1,200 mg/m2 every 21 days (in combination with mesna, vincristine, and dactinomycin) for 4 cycles (Walterhouse 2014).

Intermediate risk: IV: 2,200 mg/m2 every 21 days (in combination with mesna, vincristine, and dactinomycin) for 14 cycles (Arndt 2009).

Small cell lung cancer, refractory

Small cell lung cancer, refractory (off-label use): IV: 1,000 mg/m2 (maximum: 2,000 mg) on day 1 every 3 weeks (in combination with doxorubicin and vincristine) until disease progression or unacceptable toxicity (von Pawel 1999).

Systemic light chain amyloidosis

Systemic light chain amyloidosis (off-label use):

CRd regimens: IV or Oral: 300 mg/m2 orally on days 1, 8, and 15 of a 28-day cycle (in combination with lenalidomide and dexamethasone); cyclophosphamide was administered for a maximum of 12 cycles; refer to protocol for further information (Kumar 2012b) or 300 mg/m2 IV on days 1 and 8 every 28 days (in combination with lenalidomide and dexamethasone) for 6 cycles, followed by 300 mg/m2 IV on day 1 only every 28 days (in combination with lenalidomide and dexamethasone) for 6 additional cycles (Cibeira 2015).

CyBorD regimen: Oral: 300 mg/m2 once weekly (in combination with bortezomib and dexamethasone) (Mikhael 2012; Palladini 2015) or 350 mg/m2 on days 1, 8, and 15 (in combination with bortezomib and dexamethasone) for up to 8 cycles (Venner 2012).

Systemic sclerosis–related interstitial lung disease

Systemic sclerosis–related interstitial lung disease (alternative agent) (off-label use):

Note: For use in patients with features suggesting high risk for progression (eg, declining pulmonary function) or with symptomatic interstitial lung disease. Generally administered in combination with low-dose glucocorticoids (Varga 2021).

IV (preferred route): 600 mg/m2 once every 4 weeks; some experts do not exceed 1,200 mg/dose (Hoyles 2006; McCune 2021).

Oral: Initial: 1 mg/kg/day (rounded to the nearest 25 mg); may increase daily dose based on response and tolerability by 25 mg once monthly up to 2 mg/kg/day; some experts do not exceed 200 mg/day (Tashkin 2006; McCune 2021), or 50 to 100 mg daily initially (50 mg daily for patients weighing <81 kg and 100 mg daily for patients weighing ≥81 kg), followed by increases in 25 to 50 mg increments each month up to 2 mg/kg/day (maximum: 200 mg/day) (Tashkin 2016).

Duration of therapy: Limit duration of IV therapy to 6 months or oral therapy to 12 months, then transition to an alternative immunosuppressive agent (Tashkin 2006; Tashkin 2016; Varga 2021; Hoyles 2006).

Thymomas, advanced or metastatic

Thymomas, advanced or metastatic (off-label use):

ADOC regimen: IV: 700 mg/m2 on day 4 every 3 weeks (in combination with doxorubicin, cisplatin, and vincristine) (Fornasiero 1991).

CAP regimen: IV: 500 mg/m2 on day 1 every 3 weeks for up to 8 cycles (in combination with cisplatin and doxorubicin) (Loehrer 1994).

Waldenström macroglobulinemia

Waldenström macroglobulinemia (off-label use):

DRC regimen: Oral: 100 mg/m2 twice daily on days 1 to 5 every 21 days (in combination with dexamethasone and rituximab) for 6 cycles (Dimopoulos 2007).

FCR regimen: IV: 250 mg/m2 once daily on days 2 to 4 every 28 days (in combination with fludarabine and rituximab) for up to 6 cycles (Tedeschi 2012).

Warm autoimmune hemolytic anemia, relapsed or refractory

Warm autoimmune hemolytic anemia, relapsed or refractory (alternative agent) (off-label use):

Low-dose therapy:

Oral: 1 to 2 mg/kg once daily (maximum dose is not established) or 50 to 150 mg once daily, with or without concomitant glucocorticoids; response typically achieved within 2 to 4 weeks (Go 2017; Salama 2015).

High-dose therapy:

Note: Generally reserved for patients with refractory disease or severe anemia due to greater potential for toxicity (Salama 2015).

IV: 1,000 mg once every 4 weeks for 4 doses (Go 2017; Thabet 2014).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Specific recommendations for kidney dose adjustment have not been established. A dose-effect relationship is difficult to determine due to interpatient variability in pharmacokinetics and pharmacodynamics, and the complex metabolism and precise mechanism of action are not completely understood (Haubitz 2002).

The following general and indication-specific dosage adjustments have been recommended. Use with caution, especially with more severe impairment; consider indication, goals of therapy, and risks versus benefits when selecting a dose, and monitor for signs and symptoms of toxicity; also refer to institution-specific protocols (when available):

General dosage adjustment recommendations: IV, Oral:

Altered kidney function:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 29 mL/minute: Administer 75% (Krens 2019) or 100% (Aronoff 2007; Kintzel 1995) of normal dose.

CrCl <10 mL/minute: Administer 50% (Krens 2019), 75% (Aronoff 2007), or 100% (Kintzel 1995) of normal dose.

Hemodialysis, intermittent (thrice weekly): Moderately dialyzable (20% to 50% removal based on limited data with low-flux dialyzers [Haubitz 2002; Nemecek 2019; Wang 1981]).

Administer 50% (Krens 2019) or 75% (Janus 2010; Pedrazzoli 2017) of the normal dose. On dialysis days, administer after hemodialysis, allowing at least 12 hours before the next hemodialysis session (Haubitz 2002).

Peritoneal dialysis: Administer 75% of the normal dose (Aronoff 2007). If possible, allow at least 12 hours before next peritoneal dialysis exchange (expert opinion).

CRRT: Administer 100% of the normal dose (Aronoff 2007).

Indication-specific dosage adjustments:

Granulomatosis with polyangiitis or microscopic polyangiitis:

Cyclophosphamide Oral Initial Dosage Adjustment for Granulomatosis With Polyangiitis or Microscopic Polyangiitisa

CrCl

Cyclophosphamide oral dose (mg/kg/day)b

a Regan 2001; Merkel 2021b.

b Maximum dose: 200 mg/dose (de Groot 2009).

≥100 mL/minute

2 mg/kg/day

50 to <100 mL/minute

1.5 mg/kg/day

25 to <50 mL/minute

1.2 mg/kg/day

15 to <25 mL/minute

1 mg/kg/day

<15 mL/minute or on dialysis

0.8 mg/kg/day

Cyclophosphamide IV Dosage Adjustment for Granulomatosis With Polyangiitis or Microscopic Polyangiitisa

Age

CrCl >30 mL/minuteb,d,e

CrCl <30 mL/minuteb,c,d,e

a de Groot 2009.

b The original protocol reduced doses when SCr was above 3.4 mg/dL (300 mcmol/L), but in clinical practice this has often been translated as a CrCl <30 mL/minute (expert opinion).

c Some experts use a reduced dose of 7.5 mg/kg in all patients with CrCl <30 mL/minute regardless of age (Merkel 2021b).

d Maximum dose: 1,200 mg/dose (de Groot 2009).

e Doses are administered every 2 weeks for 3 doses, followed by maintenance pulses every 3 weeks for 3 months after remission achieved.

<60 years

15 mg/kg

12.5 mg/kg

60 to 70 years

12.5 mg/kg

10 mg/kg

>70 years

10 mg/kg

7.5 mg/kg

Hematopoietic stem cell transplantation: There are no specific dosage adjustments recommended; a reduced dose may be considered in moderate to severe impairment (Bodge 2014). Refer to "General Dosage Adjustment Recommendations" for patients with kidney impairment.

Lupus nephritis:

IV: Shorter, low-dose regimen (500 mg IV once every 2 weeks for 6 doses): No dosage adjustment necessary (ACCESS Trial 2014; Euro-Lupus Nephritis Trial [Houssiau 2002]).

IV: Longer, high-dose regimen (500 to 1,000 mg/m2 IV pulses):

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Reduce initial dose to 500 mg/m2 (Austin 1986; Gourley 1996).

Oral regimen: Refer to “General Dosage Adjustment Recommendations” for patients with kidney impairment.

Multiple myeloma: Oral:

Mild to severe impairment: No dosage adjustment necessary (IMWG [Dimopoulos 2016]).

Hemodialysis: No dosage adjustment necessary (IMWG [Dimopoulos 2016]).

Dosing: Hepatic Impairment: Adult

The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy. Some dosage forms may contain ethanol; consider alcohol content of the product when administering to patients with hepatic impairment.

There are no dosage adjustments provided in the manufacturer's labeling.

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.

Krens 2019:

Mild or moderate impairment: Dosage adjustment is not likely needed.

Severe impairment: Use is not recommended due to risk of reduced efficacy.

Dosing: Pediatric

(For additional information see "Cyclophosphamide: Pediatric drug information")

For oncology uses, all dosing presented based on clinically recognized trials; consult specific regimens concerning dosing in combination regimens. Doses IV ≥1,000 mg/m2 are associated with a high emetic potential and IV doses <1,000 mg/m2 and all oral doses are associated with a moderate emetic risk; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Dupuis 2013; Paw Cho Sing 2019). In pediatric patients, dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations. To lessen potential toxicity with doses for oncologic uses, hydration, and follow-up mesna therapy are typically administered; refer to specific protocol.

Oncologic uses:

Acute lymphoblastic leukemia, high-risk: Limited data available (Steinherz 1993): NYII Protocol:

Induction: Children and Adolescents: IV: 1,200 mg/m2 on Day 2 (in combination with steroid, daunorubicin, vincristine, and asparaginase).

Maintenance I: Children and Adolescents: IV: 600 mg/m2on Day 4 (in combination with steroid, mercaptopurine, vincristine, daunorubicin, methotrexate, cytarabine, and thioguanine).

Acute lymphoblastic leukemia, relapsed or refractory: Limited data available:

Hijiya 2011: Children and Adolescents: IV: 440 mg/m2 over 30 to 60 minutes in combination with clofarabine and etoposide; number of doses dependent on phase of protocol: Induction: Days 1 to 5, and Consolidation: Days 1 to 4.

Parker 2010: UK-ALL R3 protocol: Children and Adolescents:

Phase 2 Consolidation (weeks 5 to 8): IV: 440 mg/m2 on Days 15 to 19 in combination with steroid, vincristine, methotrexate, PEG-asparaginase, and etoposide.

Phase 5, before Continuation (weeks 14 to 29): IV: 300 mg/m2 on Days 42, 49, 99, and 106 in combination with steroid, mercaptopurine, vincristine, methotrexate, etoposide, and cytarabine.

CNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available (Chi 2004; Mason 1998): Head Start II Protocol: Infants and Children <10 years: IV: 65 mg/kg on Days 2 and 3 with mesna every 21 days for 5 cycles (in combination with cisplatin, vincristine, etoposide, and high-dose methotrexate; then followed by an auto-transplantation).

Desmoplastic small round cell tumor (DSRCT): Limited data available (Kushner 1996): High-dose cyclophosphamide: HD-CAV/IE regimen: P6 Protocol:

Children <10 years: IV: 70 mg/kg over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.

Children 10 years and Adolescents: IV: 2,100 mg/m2over 6 hours with mesna and hydration on Day 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.

Ewing sarcoma:

VAC/IE regimen: Limited data available (Grier 2003): Children and Adolescents: IV: 1,200 mg/m2 with mesna on Day 1 of a 21-day treatment cycle in combination with vincristine and doxorubicin (then dactinomycin when maximum doxorubicin dose reached), alternate with IE (ifosfamide and etoposide) for a total of 17 cycles.

High-dose cyclophosphamide: HD- CAV/IE regimen: P6 Protocol: Limited data available (Kushner 1996):

Children <10 years: IV: 70 mg/kg over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.

Children ≥10 years and Adolescents: IV: 2,100 mg/m2 over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.

Hodgkin lymphoma: Limited data available:

BEACOPP (high-risk): Children and Adolescents: IV: 1,200 mg/m2 on Day 0 of a 21-day treatment cycle for 4 cycles in combination with bleomycin, etoposide, doxorubicin, vincristine, prednisone, and procarbazine (Kelly 2011).

ABVE-PC (intermediate-risk): Children and Adolescents: IV: 800 mg/m2 over 1 hour on the first day of a 21-day cycle for up to 4 cycles (depending upon response) in combination with doxorubicin, vincristine, etoposide, prednisone, and bleomycin (Dharmarajan 2015; Friedman 2014; Schwartz 2009).

HSCT conditioning; myeloablative transplant: Limited data available: Infants, Children, and Adolescents: IV: 50 mg/kg/day for 4 days beginning 5 days before transplant (Champlin 2007); other regimens have used 60 mg/kg/day for 2 days following busulfan (Locatelli 2005; Mårtensson 2013).

Dosing adjustment in obese patients (ASBMT [Bubalo 2014]):

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

Cy120 (cyclophosphamide total dose of 120 mg/kg): Use IBW or ABW until >120% IBW; then use ABW25 for patients >120% IBW.

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

Neuroblastoma during infancy (unresectable): Limited data available (Rubie 2011): INES 99.1 regimen courses 1 and 2:

Infants:

<10 kg: IV: 3.5 mg/kg on Days 1 to 5 administered at 2-week intervals for 2 cycles initially, in combination with vincristine.

≥10 kg: IV: 5 mg/kg on Days 1 to 5 administered at 2-week intervals for 2 cycles initially, in combination with vincristine.

Neuroblastoma ; high-risk, newly diagnosed: Limited data available (Park 2011): Infants, Children, and Adolescents:

Induction cycles 1 and 2 (21-day cycles):

Patient weight ≤12 kg: IV: 13.3 mg/kg over 30 minutes on Days 1 to 5 (in combination with topotecan) for 2 cycles.

Patient weight >12 kg: IV: 400 mg/m2over 30 minutes on Days 1 to 5 (in combination with topotecan) for 2 cycles.

Induction cycles 4 and 6 (21-day cycles):

Patient weight ≤12 kg: IV: 70 mg/kg over 6 hours with mesna on Days 1 and 2 (in combination with doxorubicin and vincristine).

Patient weight >12 kg: IV: 2,100 mg/m2 over 6 hours with mesna on Days 1 and 2 (in combination with doxorubicin and vincristine).

Neuroblastoma; relapsed or refractory: Limited data available (Kushner 2010; Kushner 2011): HD-CCV or HD-CTV regimen: Infants and Children ≤10 years: IV: 70 mg/kg on Days 1 and 2 (in combination with irinotecan and vincristine or in combination with topotecan and vincristine).

Non-Hodgkin lymphoma: Limited data available:

COP regimen: Reduction: Infants ≥6 months, Children, and Adolescents: IV: 300 mg/m2over 15 minutes on Day 1 (in combination with vincristine and prednisone) (Cairo 2007; Goldman 2013; Goldman 2014).

COPADM 1 regimen: Induction 1: Infants ≥6 months, Children, and Adolescents: IV: 250 mg/m2/dose over 15 minutes every 12 hours on Days 2 to 4 (6 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate) (Cairo 2007; Goldman 2013; Goldman 2014; Patte 2007).

COPADM 2 regimen: Induction 2: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2/dose over 15 minutes every 12 hours on Days 2 to 4 (6 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate, +/- Rituximab) (Cairo 2007; Goldman 2013; Goldman 2014).

COPADM regimen: Maintenance 1: High-risk patients: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2 over 15 minutes on Days 2 and 3 (2 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate) (Cairo 2007; Goldman 2013; Goldman 2014).

COPA regimen: Maintenance course 3: High-risk patients: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2/dose over 30 minutes on the first 2 days of the cycle (2 doses) (in combination with doxorubicin, vincristine, prednisone) (Cairo 2007; Goldman 2013; Goldman 2014).

Non-Hodgkin lymphoma, T-cell (anaplastic large cell lymphoma [ALCL]): Limited data available (Reiter 1994; Seideman 2001): NHL-BFM90 protocol: Infants, Children, and Adolescents: IV: 200 mg/m2over 1 hour; number of doses, days of administration, and other chemotherapy combinations are dependent on protocol specific phase.

Palliative intent chemotherapy (metronomic therapy): Limited data available: Infants, Children, and Adolescents: Oral: 2.5 mg/kg once daily, maximum dose: 100 mg/dose for 21 days, alternating with a 21-day cycle of etoposide in combination with continuous thalidomide, celecoxib, and fenofibrate therapy; in the trial, the youngest patient reported was 191 days old (around 6 months of age) (Robison 2014).

Post-transplant lymphoproliferative disease (PTLD): Limited data available: Infants, Children, and Adolescents: IV: 600 mg/m2 on Day 1 every 21 days for 6 cycles in combination with prednisone (all 6 cycles) and rituximab (first 2 cycles only); the youngest patient included in the reported experience was 0.8 years of age (Gross 2012).

Retinoblastoma, extraocular: Limited data available (Chantada 2003): Protocol 94 regimen: Children: IV: 65 mg/kg over 1 hour on Day 1 with mesna of a 21-day treatment cycle (in combination with idarubicin and vincristine) alternating cycles with carboplatin and etoposide for a total of 8 cycles.

Rhabdomyosarcoma:

Low risk: Limited data available (Walterhouse 2014): VAC regimen: Doses were administered with hydration and mesna every 21 days for 4 doses of a 22-week cycle in combination with vincristine and dactinomycin.

Infants and Children <3 years: IV: 40 mg/kg.

Children ≥3 years and Adolescents: 1,200 mg/m2.

Intermediate risk: Limited data available (Arndt 2009): VAC regimen: Doses were administered with hydration and mesna every 21 days for 14 cycles in combination with vincristine and dactinomycin.

Infants: IV: 36 mg/kg.

Children 1 to 3 years: IV: 73 mg/kg.

Children >3 years: 2,200 mg/m2.

Wilms tumor; anaplastic (stage II to IV): Limited data available (Green 1994): National Wilms’ Tumor Study (NWTS) protocol 4 regimen J: Children and Adolescents <16 years: IV: 10 mg/kg on Days 1 to 3 (3 doses) every 6 weeks (in combination with vincristine, dactinomycin, and doxorubicin).

Wilms tumor relapsed or refractory: Limited data available: National Wilms’ Tumor Study (NWTS) protocol-5 regimen:

Infants and Children weighing ≤30 kg: IV: 14.7 mg/kg with mesna; reported frequency and combination chemotherapy variable, refer to specific protocols. One regimen alternated the frequency based on week of therapy: Weeks 3, 9, 15, and 21: Doses administered once daily for 5 days (in combination with etoposide); Weeks 6, 12, 18, and 24 administered once daily for 3 days (in combination with doxorubicin and vincristine) (Green 2007); another protocol administered for 5 days, on Weeks 0 and 3 in combination with etoposide; alternate with carboplatin and etoposide on Weeks 6 and 9 and continued for 90 weeks (Malogolowkin 2008).

Children >30 kg and Adolescents <16 years at diagnosis: IV: 440 mg/m2 with mesna; reported frequency and combination chemotherapy variable, refer to specific protocols. One regimen alternated the frequency based on week of therapy: Weeks 3, 9, 15, and 21: Doses administered once daily for 5 days (in combination with etoposide); Weeks 6, 12, 18, and 24 administered once daily for 3 days (in combination with doxorubicin and vincristine) (Green 2007).

Non-Oncologic uses:

Aplastic anemia, severe; refractory: Limited data available: Children and Adolescents ≥2 years: High-dose therapy: IV: 45 to 50 mg/kg/day for 4 days has been used in several small trials; concurrent prophylactic antimicrobial therapy should be considered (Audino 2010; Brodsky 1996; Brodsky 2010; DeZern 2011; Jaime-Perez 2013).

Kawasaki Disease; refractory to multiple therapies: Very limited data available: Infants and Young Children: IV: 2 mg/kg/dose once daily; some have suggested a gradual taper over 1.5 to 7 months; however, details of taper have not been described. Dosing based on a retrospective study of patients with refractory Kawasaki Disease that included two patients (ages 2.7 and 9 years) who had failed to respond to 3 doses of IVIG and required high-dose IV methylprednisolone; after initiation of cyclophosphamide, steroids were able to be successfully tapered and final ECHO showed resolution of aneurysm. While taper schedule was not described, both patients were discharged on a taper over 1.5 to 7 months (AHA [McCrindle 2017]; Wallace 2000).

Lupus nephritis; proliferative: Limited data available: Children and Adolescents:

Initial phase; pulse therapy:

IV:

6-month course: Usual range: 500 to 1,000 mg/m2/dose once monthly (KDIGO 2012); the following regimen has been used for dosage escalation: Initial: 500 mg/m2 then titrate as tolerated every 4 weeks in 250 mg/m2 increments up to 750 or 1,000 mg/m2 every month; maximum monthly dose: 1,500 mg/month (Bertsias 2012; Mina 2012).

3-month course: 500 mg every 2 weeks for 3 months (Bertsias 2012; KDIGO 2012).

Oral: 1 to 1.5 mg/kg/day for 2 to 4 months; maximum daily dose: 150 mg/day (KDIGO 2012); higher doses (2 to 2.5 mg/kg/day for 3 months) may be required in patients with worsening prognostic factors (eg, acute renal function deterioration) (Bertsias 2012).

Maintenance phase: IV: 500 to 1,000 mg/m2 every 3 months for a total of 1.5 to 3 years has been used; however, current guidelines recommend other oral immunosuppressive agents for maintenance therapy (KDIGO 2012; Kliegman 2011; Lehman 2000).

Nephrotic syndrome, minimal change (frequently relapsing): Infants, Children, and Adolescents: Oral: 2 mg/kg/day for 8 to 12 weeks; reported range: 2 to 3 mg/kg/day; maximum cumulative dose: 168 mg/kg; dosing based on ideal bodyweight (Gipson 2009; KDIGO 2012; KDOQI 2013). Treatment beyond 90 days may increase the potential for sterility in males.

Uveitis, severe; recalcitrant, high-risk vision loss: Limited data available: Children and Adolescents: Oral: Initial: 2 mg/kg/day once daily; usual reported range: 1 to 3 mg/kg/day in combination with corticosteroids (which may be decreased while on cyclophosphamide) (Jabs 2000; Pujari 2010; Simonini 2010); dosing based on large, multicenter report of 215 patients with ocular inflammatory disease which included 44 patients with uveitis (age range: 11.5 to 76.4 years); after 12 months of therapy ~89% of patients had no inflammatory disease activity or only slightly active disease (Pujari 2010). Note: Some data suggests that pulse intravenous therapy may be less effective than oral cyclophosphamide (Pujari 2010).

Vasculitis, ANCA-associated (eg, granulomatosis with polyangiitis [GPA], Wegener granulomatosis): Limited data available: Children and Adolescents:

IV: Initial: 15 mg/kg every 2 weeks for 3 doses, then 15 mg/kg every 3 weeks until remission or azathioprine maintenance; dosing based on experience from a pediatric case series (n=5) and a larger adult trial (n=76); in the pediatric case series, the median cumulative dose was 90 mg/kg (range: 63 to 115 mg/kg), most patients received 6 to 7 pulses of therapy; in the adult trial, therapy was continued for 3 months after remission (de Groot 2009; Krmar 2013).

Oral: 2 mg/kg/day in combination with corticosteroids until remission; a subsequent decrease in dose to 1.5 mg/kg/day for another 3 months has been reported (de Groot 2009; Kliegman 2011).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Infants, Children, and Adolescents:

Hematologic toxicity: May require dose reduction or treatment interruption.

Hemorrhagic cystitis, severe: Discontinue treatment.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; decreased renal excretion of cyclophosphamide and its metabolites may occur; monitor patients with severe impairment (CrCl 10 to 24 mL/minute) for signs and symptoms of toxicity. The following guidelines have been used by some clinicians:

Aronoff 2007: Infants, Children, and Adolescents:

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

CrCl <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.

KDIGO 2012: Lupus nephritis: Children and Adolescents:

CrCl 25 to 50 mL/minute: Administer 80% of normal dose.

CrCl 10 to <25 mL/minute: Administer 70% of normal dose.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; in severe hepatic impairment, conversion to an active metabolite may be reduced potentially affecting efficacy. The half-life and clearance of cyclophosphamide metabolites may be increased/decreased respectively.

The following adjustments have been recommended with oncologic uses (Floyd 2006): All patients:

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

Serum bilirubin >5 mg/mL: Avoid use.

Dosing: Older Adult

Refer to adult dosing; adjust for renal clearance.

Dosing: Obesity: Adult

American Society of Clinical Oncology (ASCO) guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2 (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 patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved and performance status has markedly improved (ASCO [Griggs 2021]).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity (ASBMT [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 (preferred) or ABW for patients ≤120% IBW. Use ABW25 for patients >120% IBW.

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

Dosing: Adjustment for Toxicity: Adult

Cardiotoxicity: Symptoms may be managed with diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, or inotropics (Floyd 2005).

Hematologic toxicity: May require dose reduction or treatment interruption. Initiate antibiotics for neutropenic fever; antifungal and antiviral medications may also be necessary. For oncology uses, consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia.

Hemorrhagic cystitis, severe: Discontinue cyclophosphamide treatment. Severe or prolonged hemorrhagic cystitis may require medical or surgical treatment.

Infection (serious): May require dose reduction, or interruption or discontinuation of treatment.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Generic: 25 mg, 50 mg

Solution, Intravenous:

Generic: 500 mg/2.5 mL (2.5 mL); 1 g/5 mL (5 mL); 2 g/10 mL (10 mL)

Solution Reconstituted, Injection:

Generic: 500 mg (1 ea [DSC]); 1 g (1 ea [DSC]); 2 g (1 ea [DSC])

Solution Reconstituted, Injection [preservative free]:

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

Tablet, Oral:

Generic: 25 mg, 50 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Solution Reconstituted, Injection:

Procytox: 200 mg (1 ea); 500 mg (1 ea); 1 g (50 mL); 2 g (100 mL)

Tablet, Oral:

Procytox: 25 mg, 50 mg

Administration: Adult

Cyclophosphamide is associated with a moderate or high emetic potential (depending on dose, regimen, or administration route); antiemetics may be recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; MASCC [Roila 2016]).

IV: Infusion rate may vary based on protocol (refer to specific protocol for infusion rate). Administer by direct IV injection, IVPB, or continuous IV infusion. Refer to product labeling for specific information regarding reconstitution and dilution.

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 (off-label use): 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 daily mesna dose (as a percentage of cyclophosphamide dose) may vary; refer to protocol and/or primary literature for mesna dose. 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: Swallow whole; do not crush or chew; do not open capsules. To minimize bladder toxicity, increase normal fluid intake. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer at bedtime. Avoid exposure to broken capsules and tablets; if contact occurs, wash hands immediately and thoroughly.

Administration: Pediatric

Antiemetics may be recommended to prevent nausea and vomiting; doses ≥1,200 mg/m2 IV are associated with a high emetic potential and doses of 1,000 mg/m2 IV are associated with a moderate emetic risk (POGO [Dupuis 2011]; POGO [Paw Cho Sing 2019]).

Oral: Capsules and tablets should be swallowed whole. Tablets are not scored and should not be cut, crushed, or chewed. Capsules should not be opened, crushed, or chewed. Wear gloves when handling capsules/tablets and container; avoid exposure to broken capsules. If exposure to capsule contents or crushed/cut tablets, wash hands immediately and thoroughly. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer tablets/capsules at bedtime.

Parenteral:

IV push: May administer reconstituted solution without further dilution (20 mg/mL); rate may vary based on protocols (refer to specific protocols)

IV infusion (intermittent or continuous): Infusion rate may vary based on protocol (refer to specific protocol for infusion rate); usually over 15 to 60 minutes; larger doses (>1,800 mg/m2) have been infused over 1 to 6 hours by some centers and protocols

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 and in pediatric patients twice maintenance (3 L/m2/day). High-dose regimens and depending upon the protocol some standard (low) cyclophosphamide doses should be accompanied by vigorous hydration with mesna therapy (refer to specific protocols and Mesna monograph for additional information). Morning administration may be preferred to ensure adequate hydration throughout the day.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Oncology uses: Treatment of acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, 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.

Nononcology uses: 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: Off-Label: Adult

Anti-glomerular basement membrane disease (anti-GBM or Goodpasture disease); Castleman disease (idiopathic, multicentric); Dermatomyositis/polymyositis, severe, life-threatening or refractory; Eosinophilic granulomatosis with polyangiitis (Churg-Strauss); Ewing sarcoma; Gestational trophoblastic neoplasia, high-risk; Graft-vs-host disease (acute and chronic), prophylaxis; Granulomatosis with polyangiitis and microscopic polyangiitis, organ- or life-threatening; Hematopoietic stem cell or marrow transplant; Interstitial pneumonia, nonspecific, refractory or rapidly progressive; Lupus nephritis, focal or diffuse; Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy; Membranous nephropathy; Merkel cell carcinoma (advanced or recurrent); Minimal change disease; Mixed cryoglobulinemia syndrome, moderate to severe; Osteosarcoma (relapsed/refractory); Ovarian germ cell tumors (malignant); Pheochromocytoma (malignant); Polyarteritis nodosa, moderate to severe; Primary CNS lymphoma; Pure red cell aplasia; Rhabdomyosarcoma; Small cell lung cancer (refractory); Systemic light chain amyloidosis; Systemic sclerosis–related interstitial lung disease; Thymomas (advanced or metastatic); Waldenström macroglobulinemia; Warm autoimmune hemolytic anemia, relapsed or refractory

Medication Safety Issues
Sound-alike/look-alike issues:

Cyclophosphamide may be confused with cycloSPORINE, ifosfamide

Cytoxan may be confused with cefOXitin, Ciloxan, cytarabine, CytoGam, Cytosar, Cytosar-U, Cytotec

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions (Significant): Considerations
Bone marrow suppression and infection

Leukopenia, neutropenia, thrombocytopenia, and anemia commonly occur. 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 reactive latent infections. Serious infections have been reported in patients receiving high-dose concurrent corticosteroids (Ref). No difference has been found between oral and intravenous cyclophosphamide (Ref). Recovery of platelet and neutrophil nadirs is expected after ~20 days.

Mechanism: Dose-related (Ref); related to pharmacologic action. Alkylating agent that induces DNA damage in all rapidly dividing cells, including those of the bone marrow (Ref).

Onset: Intermediate; platelet and neutrophil nadirs are usually at weeks 1 and 2 of treatment.

Risk factors:

• Concurrent corticosteroid use (≥20 mg/day of prednisone equivalent) (Ref)

• Concurrent/multidrug chemotherapy and/or radiation therapy

• Heavy pretreatment

Cardiotoxicity

Cardiotoxicities reported include arrhythmias (supraventricular cardiac arrhythmia and ventricular arrhythmia [some with prolonged QT interval on ECG]), heart failure, heart block, hemopericardium (secondary to hemorrhagic myocarditis and myocardial necrosis), myocarditis (including fatal hemorrhagic), pericarditis, pericardial effusion including cardiac tamponade, and tachyarrhythmias.

Mechanism: Dose-related; not clearly established. Metabolites, specifically acrolein and/or phosphoramide mustard, are believed to cause oxidative stress to the myocardium and direct endothelial capillary damage. This leads to extravasation of erythrocytes, proteins, and toxic metabolites that cause direct damage to the myocardium, manifesting as arrhythmias and/or heart failure (Ref). Capillary microthrombosis and fibrin deposition occur with cyclophosphamide-induced cardiac injury (Ref).

Onset: Varied; usually within the first 48 hours but may occur up to 10 days after initiation (Ref).

Risk factors:

• Higher doses commonly used in hematopoietic stem cell transplantation. Acute heart failure is reported in 7% to 33% of patients receiving a total dose >150 mg/kg (Ref)

• Preexisting arrhythmias, cardiac disease, diabetes, hypertension (Ref)

• Older age (>55 years) (Ref)

• Prior radiation therapy to the chest

• Prior or concurrent cardiotoxic medications

• Heavy pretreatment

Hemorrhagic cystitis

Cyclophosphamide is associated with the development of hemorrhagic cystitis, which may lead to pyelitis, ureteral disease (ureteritis), and hematuria. Hemorrhagic cystitis may rarely be severe or fatal. Bladder fibrosis, necrosis or contracture may also occur, either with or without cystitis. Occurrence of hemorrhagic cystitis increases risk of bladder cancer. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases.

Mechanism: Dose- and duration-related; hemorrhagic cystitis is due to excretion of cyclophosphamide metabolite, acrolein, in the urine. Acrolein irritates the lining of the bladder, specifically the transitional cells, causing damage and sloughing of those cells leading to hemorrhagic cystitis (Ref). Chloroacetaldehyde may also be implicated in bladder and kidney toxicity through oxidative effects (Ref).

Onset: Varied; within hours or days of treatment with intravenous cyclophosphamide (Ref), but may occur up to a median of 2 weeks later (Ref). With oral therapy for Wegener granulomatosis, median time to development was 37 months (Ref).

Risk factors:

• Higher doses associated such as with bone marrow transplantation (Ref)

• Cumulative dose when used in rheumatic diseases (Ref)

• In bone marrow transplant, male patients (Ref)

• Active urinary tract infections, especially BK viruria, or obstructions (Ref)

• Dehydration (due to lower frequency of voiding) (Ref)

• Older patients (Ref)

Hepatotoxicity

Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease, has been reported in patients receiving chemotherapy regimens containing cyclophosphamide. Signs and symptoms of hepatic SOS include bilirubin >1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, and unexplained right upper quadrant pain (Ref). Patients may also experience cholestatic hepatitis or cytolytic hepatitis, including hepatic failure with associated liver function test abnormalities and sequelae.

Mechanism: Direct toxicity of cyclophosphamide and its metabolites (phosphoramide mustard and acrolein) to hepatic sinusoids (Ref). These metabolites induce oxidative stress by producing free radicals that inhibit the activity of antioxidant enzymes such as superoxide dismutase, glutathione, and catalase (Ref).

Onset: Varied; within 2 to 8 weeks of initiation. In the case of transplantation, onset of SOS is usually within 10 to 20 days of myeloablation (Ref).

Risk factors:

• Cytoreductive conditional transplantation regimens in combination with total body irradiation, busulfan or other hepatotoxic agents (Ref)

• Concurrent azathioprine (Ref)

• Concurrent dactinomycin (Ref)

• Long-term lower doses for immunosuppressive indications (Ref)

• Preexisting hepatic dysfunction (Ref)

• Prior radiation to the abdominal area (Ref)

• Children <3 years of age (Ref)

• Patients with CYP2B6*7 variant (Ref)

Pulmonary toxicity

Pulmonary toxicity, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. Pulmonary toxicity may be difficult to identify due to confounding pulmonary conditions occurring in the same population, including infections and pulmonary malignancies. This toxicity often presents as dyspnea, fever, cough, parenchymal infiltrates, abnormal pulmonary function tests and pleural thickening. Early onset pulmonary toxicity may be reversible, but late onset is associated with pleural thickening and may persist (Ref). Late onset pneumonitis develops rarely in patients receiving prolonged treatment over several months to years with lower doses of cyclophosphamide and may be associated with increased mortality (Ref).

Mechanism: Exact mechanism unknown; metabolism of cyclophosphamide in lung to alkylating metabolites and acrolein, a reactive aldehyde, is in part responsible for pulmonary toxicity. Acrolein may cause direct injury to the pulmonary epithelium, leading to alveolitis and fibrosis (Ref). Alterations in pulmonary mixed-function oxidase activity, glutathione content, along with cyclophosphamide- and acrolein-induced alterations in the physical state of membrane lipid bilayer may be the major cause of inactivation of membrane-bound enzymes (Ref).

Onset: Varied; onset can be early (within 1 to 6 months of initiation) or late (several months to years after initiation) (Ref).

Risk factors:

• Oxygen therapy (hyperoxic conditions) may potentiate the effects (Ref)

• Concurrent use of pulmonary toxic medications, including bleomycin, busulfan, and carmustine (Ref)

• Prior or concurrent thoracic radiation (Ref)

• Concurrent therapies such as amiodarone and G-CSF or GM-CSF

• Preexisting lung disease

Second primary malignancy

Secondary primary malignant neoplasm (acute leukemia, bladder carcinoma, malignant lymphoma, malignant neoplasm of thyroid, myelodysplastic syndrome, sarcoma, and other solid tumors) have been reported with both single-agent cyclophosphamide and with combination chemotherapy regimens.

Mechanism: Dose-related; as an alkylating agent, cyclophosphamide is directly genotoxic. DNA-induced damage causes double-strand breaks, leading to genomic instability due to loss of DNA repair (Ref). Inherited genetic polymorphisms may affect the risk post-alkylator exposure (Ref). Bladder inflammation, secondary to acrolein exposure, is also associated with increased risk of bladder cancer after therapy (Ref).

Onset: Delayed; several years to decades after treatment (Ref).

Risk factors:

• Higher cumulative doses (Ref)

• Higher doses associated with stem cell transplantation (Ref)

• Concurrent use of other carcinogenic chemotherapy agents (Ref)

• Patients previously experiencing hemorrhagic cystitis (bladder cancer)

• Tobacco smoking (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Postmarketing:

Cardiovascular: Acute myocardial infarction (Yeh 2021), atrial fibrillation (Yeh 2021), atrial flutter (Yeh 2021), bradycardia, cardiac tamponade (Yeh 2021), cardiogenic shock, cardiomyopathy, chest pain, edema, flushing, heart failure (Yeh 2021), hemorrhagic myocarditis, hypertension, hypotension, myocarditis, palpitations, pericardial effusion (Yeh 2021), pericarditis (Yeh 2021), peripheral ischemia, prolonged QT interval on ECG, pulmonary embolism, supraventricular cardiac arrhythmia (Yeh 2021), tachycardia, vasculitis, venous thrombosis, ventricular arrhythmia (Yeh 2021), ventricular fibrillation, ventricular tachyarrhythmia

Dermatologic: Alopecia, changes in nails, dermatitis, erythema multiforme, erythema of skin, hyperhidrosis, palmar-plantar erythrodysesthesia, pruritus, skin abnormalities related to radiation recall, skin blister, skin rash, skin toxicity, Stevens-Johnson syndrome (Assier-Bonnet 1996), toxic epidermal necrolysis (Sasak 2016), urticaria (Thong 2002)

Endocrine & metabolic: Amenorrhea, decreased serum glucose, fluid retention, hot flash, hyponatremia, increased lactate dehydrogenase, increased serum glucose, malignant neoplasm of thyroid, nephrogenic diabetes insipidus, water intoxication

Gastrointestinal: Acute pancreatitis, ageusia, cholestasis, colitis, constipation, dysgeusia, enteritis, gastrointestinal hemorrhage, hemorrhagic colitis, nausea, neutropenic typhlitis, oral mucosa ulcer, parotitis, stomatitis, vomiting

Genitourinary: Azoospermia, bladder carcinoma (Brown 2005), bladder disease (necrosis, contracture, or atypical epithelial cells), cystitis (ulcerative), defective oogenesis, defective spermatogenesis, hematuria (Wang 2015), hemorrhagic cystitis (Wang 2015), infertility, infrequent uterine bleeding, oligospermia, ovarian failure, ovarian fibrosis, premature labor, pyelitis, testicular atrophy, toxic nephrosis, ureteral disease (ureteritis)

Hematologic & oncologic: Anemia (Malpica 2020), bone marrow depression (including bone marrow failure) (Malpica 2020), C-reactive protein increased, disseminated intravascular coagulation, febrile neutropenia, hemolytic-uremic syndrome, leukopenia (Malpica 2020), myelodysplastic syndrome (Brown 2005), neutropenia (Malpica 2020), pulmonary hemorrhage, secondary primary malignant neoplasm (including acute leukemia, malignant lymphoma, malignant neoplasm of urinary tract [pelvic, renal, and ureteric], myelatelia, sarcoma) (Brown 2005), thrombocytopenia (Malpica 2020), thrombotic microangiopathy

Hepatic: Ascites (Arndt 2004), cholestatic hepatitis, hepatic encephalopathy, hepatic failure (Arndt 2004), hepatic sinusoidal obstruction syndrome (Arndt 2004), hepatitis (including hepatic cytolysis), hepatomegaly (Arndt 2004), increased liver enzymes (Arndt 2004), increased serum bilirubin (Arndt 2004), jaundice (Arndt 2004)

Hypersensitivity: Anaphylactic shock, anaphylaxis (Garas 1995; Jones 1989), facial swelling

Immunologic: Immunosuppression (Malpica 2020)

Infection: Cytomegalovirus disease (Goldsmith 2021), infection (including reactivation of latent infection)

Local: Infusion-site reaction (including erythema, inflammation, necrosis, pain, phlebitis, swelling, and thrombosis), injection-site reaction (including erythema at injection site, inflammation at injection site, injection-site phlebitis, pain at injection site, swelling at injection site, tissue necrosis at injection site, venous thrombosis at injection site)

Nervous system: Altered sense of smell, asthenia, chills, confusion, dizziness, dysesthesia, encephalopathy, fatigue, headache, hypoesthesia, malaise, neuralgia, neurotoxicity, pain, paresthesia, peripheral neuropathy, polyneuropathy, reversible posterior leukoencephalopathy syndrome, seizure, tremor

Neuromuscular & skeletal: Arthralgia, muscle spasm, myalgia, myelopathy, rhabdomyolysis, systemic sclerosis

Ophthalmic: Conjunctivitis, lacrimation, visual impairment

Otic: Auditory impairment, deafness, tinnitus

Renal: Hemorrhagic ureteritis, renal cell carcinoma, renal failure syndrome, renal insufficiency, renal tubular disease

Respiratory: Acute respiratory distress syndrome (Malik 1996), bronchiolitis obliterans, bronchospasm, cough, dyspnea, flu-like symptoms, hypersensitivity pneumonitis, hypoxia, interstitial pulmonary disease, nasal congestion, nasal discomfort, oropharyngeal pain, pleural effusion, pneumonia, pneumonitis (can be late onset [>6 months]) (Malik 1996), pulmonary edema, pulmonary fibrosis (Malik 1996), pulmonary hypertension, pulmonary veno-occlusive disease, respiratory distress (Malik 1996), respiratory failure (Malik 1996), rhinorrhea

Miscellaneous: Fever, multi-organ failure

Contraindications

History of severe hypersensitivity to cyclophosphamide, its metabolites, or any component of the formulation; urinary outflow obstruction.

Canadian labeling: Additional contraindications (not in the US labeling): Severe myelosuppression, severe renal or hepatic impairment, active infection (especially varicella zoster), severe immunosuppression.

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. 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 may be related to endothelial capillary damage (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. In a scientific statement from the American Heart Association, cyclophosphamide has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

• Hepatotoxicity: Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease, 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; signs or symptoms of hepatic SOS include 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 with cyclophosphamide. Possible 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: Immunosuppression and serious infections may occur.

• Pulmonary toxicities: Pulmonary toxicities, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. 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 cyclophosphamide 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. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases. Exclude or correct any urinary tract obstructions prior to treatment initiation. Use with caution (if at all) in patients with active urinary tract infection.

• Wound healing impairment: Cyclophosphamide may interfere with wound healing.

Disease-related concerns:

• Hepatic impairment: 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. 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. 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.

Dosage form specific issues:

• Cyclophosphamide injection: Some cyclophosphamide injection dosage forms may contain alcohol. The alcohol content (in some dosage forms) may affect the CNS and impair the ability to drive or operate machinery; review available dosage forms for ethanol content in order to select the appropriate product, particularly for patients who should avoid or minimize alcohol intake, including patients with hepatic impairment.

Metabolism/Transport Effects

Substrate of CYP2A6 (minor), CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Allopurinol: May increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy

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

Anthracyclines: Cyclophosphamide may enhance the cardiotoxic effect of Anthracyclines. Risk C: Monitor therapy

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

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

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

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Bupivacaine: Cyclophosphamide may enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

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

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccines: Cyclophosphamide may diminish the therapeutic effect of COVID-19 Vaccines. Management: Adjust timing of intravenous cyclophosphamide so that administration occurs 1 week after each vaccine dose, if feasible; hold oral cyclophosphamide for 1 to 2 weeks after vaccine administration as permitted by the underlying disease. Risk D: Consider therapy modification

CycloSPORINE (Systemic): Cyclophosphamide may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

CYP2B6 Inducers (Moderate): May increase serum concentrations of the active metabolite(s) of Cyclophosphamide. Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

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

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

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

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

Fluconazole: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, serum bilirubin and serum creatinine may be increased. Fluconazole may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Itraconazole: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, serum creatinine and serum bilirubin may be increased. Itraconazole may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: 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. Risk D: Consider therapy modification

Lipegfilgrastim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be increased. Cyclophosphamide may diminish the therapeutic effect of Lipegfilgrastim. Management: Lipegfilgrastim should be administered at least 24 hours after the completion of cyclophosphamide. Consider monitoring for enhanced pulmonary toxicity when cyclophosphamide and lipegfilgrastim are given in combination. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Mivacurium: Cyclophosphamide may increase the serum concentration of Mivacurium. Risk C: Monitor therapy

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

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

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

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

Schisandra: May increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: 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. Risk D: Consider therapy modification

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

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

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy

Voclosporin: Cyclophosphamide may enhance the adverse/toxic effect of Voclosporin. Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who could become pregnant.

Patients who could become pregnant should use effective contraception while receiving cyclophosphamide and for up to 1 year after completion of cyclophosphamide treatment. Patients with partners who are or could become pregnant should use a condom during and for at least 4 months after cyclophosphamide treatment.

Cyclophosphamide is used off label in the management of lupus nephritis in nonpregnant adults (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]). Females treated for rheumatic and musculoskeletal diseases should consider discontinuing cyclophosphamide 3 to 6 months prior to attempted pregnancy to allow for disease monitoring and potential change to another immunosuppressant. Cyclophosphamide should also be discontinued 12 weeks prior to attempted conception in males with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).

Cyclophosphamide may cause ovarian insufficiency in females, and infertility and long-term gonadal damage in males. Dose-related sterility (which may be irreversible) may occur in both males and females. Recommendations are available for fertility preservation of male and female adult patients treated with anticancer agents (ASCO [Oktay 2018]). Recommendations for preserving fertility in females and males treated with cyclophosphamide for autoimmune and systemic inflammatory diseases are available (ACR [Sammaritano 2020]).

Pregnancy Considerations

Cyclophosphamide crosses the placenta and can be detected in amniotic fluid (D'Incalci 1982).

Birth defects (including malformations of the skeleton, palate, limbs, and eyes), miscarriage, fetal growth retardation, and fetotoxic effects in the newborn (including anemia, gastroenteritis leukopenia, pancytopenia, and severe bone marrow hypoplasia) have been reported.

Cyclophosphamide, if indicated, may be administered to pregnant patients with breast cancer as part of some combination chemotherapy regimens; chemotherapy should not be administered during the first trimester, after 35 weeks' gestation, or within 3 weeks of planned delivery (Amant 2010; Loibl 2015; Shachar 2017). Use of regimens containing cyclophosphamide are generally avoided for the treatment of Hodgkin or non-Hodgkin lymphoma in pregnancy. However, use of cyclophosphamide may be considered as part of some regimens to treat patients diagnosed with aggressive non-Hodgkin lymphomas during the second or third trimester (Lishner 2016; Moshe 2017). 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 (ESMO [Peccatori 2013]).

Cyclophosphamide is used off label in the management of lupus nephritis in nonpregnant adults (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020). In patients with life- or organ-threatening maternal disease, cyclophosphamide may be used in the second or third trimesters only when an alternative therapy is not available (ACR [Sammaritano 2020]).

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (1-877-635-4499).

Breastfeeding Considerations

Cyclophosphamide and its metabolites are present in breast milk (Codacci-Pisanelli 2019).

Cyclophosphamide breast milk concentrations were evaluated following maternal treatment for stage IV diffuse large B-cell lymphoma at 4 months postpartum. Peak breast milk concentrations occurred within 7 days; however, cyclophosphamide was detectable in breast milk for 21 days after the first dose (Codacci-Pisanelli 2019). Leukopenia and thrombocytopenia were noted in an infant exposed to cyclophosphamide while breastfeeding. The mother was treated with one course of cyclophosphamide 6 weeks prior to delivery then cyclophosphamide IV 6 mg/kg (300 mg) once daily for 3 days beginning 20 days postpartum. CBCs were obtained in the breastfed infant on each day of therapy; WBC and platelets decreased by day 3 (Durodola 1979).

Cyclophosphamide is not recommended for use in breastfeeding mothers with autoimmune and systemic inflammatory diseases (ACR [Sammaritano 2020]). Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last cyclophosphamide dose. Others recommend breastfeeding be avoided for at least 6 weeks after the last dose of cyclophosphamide (Codacci-Pisanelli 2019).

Monitoring Parameters

CBC with differential and platelets, BUN, serum electrolytes, serum creatinine, urinalysis. Evaluate pregnancy status prior to use in patients who can become pregnant. Monitor for signs/symptoms of hemorrhagic cystitis or other urinary/renal toxicity, pulmonary toxicity (if suspect pneumonitis, consider pulmonary function testing to assess the severity of pneumonitis [Morgan 2011]), cardiac toxicity (particularly in patients with cardiac risk factors or preexisting cardiac disease), hepatic toxicity (including hepatic sinusoidal obstruction syndrome), secondary malignancies, and/or wound healing impairment. Monitor adherence (for oral dosing).

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

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.

Pharmacokinetics

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)

Protein binding: ~20%; some metabolites are bound at >60%

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

Bioavailability: >75%

Half-life elimination: IV: 3 to 12 hours; Children: 4 hours; Adults: 6 to 8 hours

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

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

Pharmacokinetics: Additional Considerations

Altered kidney function: 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.

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

Pricing: US

Capsules (Cyclophosphamide Oral)

25 mg (per each): $6.00 - $9.36

50 mg (per each): $8.40 - $17.75

Solution (Cyclophosphamide Intravenous)

1 g/5 mL (per mL): $175.20 - $175.80

2 g/10 mL (per mL): $175.80

500 mg/2.5 mL (per mL): $175.20 - $175.80

Solution (reconstituted) (Cyclophosphamide Injection)

1 g (per each): $444.00 - $879.00

2 g (per each): $888.00 - $1,758.00

500 mg (per each): $222.00 - $439.50

Tablets (Cyclophosphamide Oral)

25 mg (per each): $3.54

50 mg (per each): $5.05

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Alkyloxan (EG, KR, SG);
  • Alkyroxan (KR);
  • Cryofaxol (CR, DO, GT, HN, MX, NI, PA, SV);
  • Cycloblastin (AU, NZ);
  • Cycloblastine (LU);
  • Cyclonex (AU);
  • Cyclostin (DE);
  • Cyclostin N (DE);
  • Cycram (EG, VN);
  • Cyphos (LK);
  • Cytoxan (CO, HU, ID);
  • Endoksan (UA);
  • Endoxan (AT, AU, BE, BG, CL, CZ, DE, EE, EG, GR, HN, HR, HU, ID, IL, IT, JP, KR, LT, LU, LV, NL, NZ, PK, PL, PT, RO, RU, SG, SI, SK, TR, UY, VN, ZA);
  • Endoxan-Asta (AE, BH, CH, CY, FR, HK, IN, IQ, IR, JO, KW, LB, LY, MY, OM, PH, QA, SA, SY, TH, TW, YE);
  • Endoxana (GB, IE);
  • Endoxon-Asta (AU);
  • Enduxan (BR);
  • Formitex (CR, DO, GT, HN, NI, PA, SV);
  • Genoxal (BR, ES);
  • Hidrofosmin (CR, DO, GT, HN, NI, PA, SV);
  • Ledoxan (PH);
  • Ledoxina (MX);
  • Neophamid (KR);
  • Neophos (EG, LB);
  • Oncomide (LK);
  • Sendoxan (DK, FI, NO, SE);
  • Syklofosfamid (TR);
  • Uniphos (LK);
  • Xyclomed (PH)


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