Version July 2025
Dosage guidance:
Safety: Increased hydration and frequent voiding are recommended to help prevent cystitis; some protocols utilize mesna to prevent bladder toxicity/hemorrhagic cystitis. Patient should be under the care of a clinician experienced with using cyclophosphamide.
Clinical considerations: 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 (Ref). 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. Refer to the protocol or institutional guidance for additional details of off-label dosing.
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 (Ref).
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 (Ref); plus a BCR-ABL tyrosine kinase inhibitor (for Philadelphia chromosome-positive disease) (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
Oral: 2 mg/kg once daily (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref). 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 (Ref).
Breast cancer (off-label dosing):
AC regimen: IV: 600 mg/m2 on day 1 every 21 days (in combination with doxorubicin) for 4 cycles (Ref).
CEF regimen: Oral: 75 mg/m2/day days 1 to 14 every 28 days (in combination with epirubicin and fluorouracil) for 6 cycles (Ref).
CMF regimen:
Oral: 100 mg/m2/day days 1 to 14 every 28 days (in combination with methotrexate and fluorouracil) for 6 cycles (Ref).
IV: 600 mg/m2 on day 1 every 21 days (in combination with methotrexate and fluorouracil) (Ref).
Dose dense AC (ddAC) followed by T regimen (adjuvant therapy): IV: 600 mg/m2 on day 1 every 14 days for 4 cycles (in combination with doxorubicin [and filgrastim], then followed by paclitaxel) (Ref).
AC-T regimen (adjuvant therapy): IV: 600 mg/m2 on day 1 every 21 days for 4 cycles (in combination with doxorubicin, then followed by weekly paclitaxel) (Ref).
TAC regimen (adjuvant therapy): IV: 500 mg/m2 on day 1 every 21 days (in combination with doxorubicin and docetaxel) for 6 cycles (Ref).
TC regimen (adjuvant therapy): IV: 600 mg/m2 on day 1 every 21 days (in combination with docetaxel) for 4 cycles (Ref).
EC regimen (adjuvant therapy): IV: 830 mg/m2 on day 1 every 21 days (in combination with epirubicin) for 8 cycles (Ref).
AC-TH (adjuvant/neoadjuvant therapy; HER-2 positive): IV: 600 mg/m2 on day 1 every 21 days (in combination with doxorubicin) for 4 cycles, followed by paclitaxel and trastuzumab (Ref) or 600 mg/m2 on day 1 every 14 days (in combination with doxorubicin) for 4 cycles (with growth factor support; followed by paclitaxel and trastuzumab) (Ref).
AC-THP (neoadjuvant therapy; HER-2 positive): IV: 600 mg/m2 on day 1 every 14 days for 4 cycles (in combination with doxorubicin; followed by paclitaxel, pertuzumab, and trastuzumab (Ref).
Keynote-522 regimen (early triple-negative breast cancer; neoadjuvant therapy): IV: 600 mg/m2 on day 1 every 21 days (in combination with doxorubicin or epirubicin and pembrolizumab) for 4 cycles (second neoadjuvant treatment); first neoadjuvant treatment was 4 cycles of pembrolizumab/paclitaxel/carboplatin, followed by second neoadjuvant treatment of 4 cycles of anthracycline/cyclophosphamide plus pembrolizumab. After definitive surgery, patients received adjuvant therapy with pembrolizumab and radiation for up to 9 cycles (Ref).
EC regimen (initial therapy for metastatic disease): IV: 600 mg/m2 on day 1 every 21 days (in combination with epirubicin) for up to 6 cycles (Ref).
FEC regimen (for metastatic disease): IV: 500 mg/m2 on day 1 every 21 days (in combination with fluorouracil and epirubicin) for up to 6 to 8 cycles (Ref).
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 (Ref).
CHOP regimen: IV: 750 mg/m2 on day 1 every 3 weeks for 4 cycles (in combination with doxorubicin, vincristine, and prednisone ± rituximab) (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
IV: 500 to 750 mg/m2 every 4 weeks; maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref).
Oral: 1.5 to 2 mg/kg/day (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref).
Duration of therapy: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Ref).
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 (Ref).
IV: 600 mg/m2 once every month (Ref); maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref).
Oral: 2 mg/kg once daily (maximum: 200 mg/day) (Ref).
Duration of therapy: Continue therapy for 6 to 12 months, then transition to an alternative immunosuppressive agent to maintain remission (Ref).
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 (Ref).
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 (Ref).
Graft-versus-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) (Ref).
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 (Ref).
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) (Ref).
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 (Ref).
Hematopoietic 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) (Ref).
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) (Ref).
50 mg/kg/day for 4 days beginning 5 days before transplant (with or without antithymocyte globulin [equine]) (Ref).
50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with busulfan) (Ref).
60 mg/kg/day for 2 days (in combination with busulfan and total body irradiation) (Ref).
60 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with busulfan) (Ref).
1,800 mg/m2/day for 4 days beginning 7 days prior to transplant (in combination with etoposide and carmustine) (Ref).
Reduced-intensity conditioning regimens: IV:
30 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with thiotepa and fludarabine) (Ref).
50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with antithymocyte globulin [equine]) (Ref).
Hematopoietic 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]) (Ref).
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 (Ref).
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 (Ref).
Interstitial pneumonia, nonspecific, refractory or rapidly progressive (off-label use):
IV (preferred route): 600 mg/m2 once every month (Ref); maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref). Use in combination with glucocorticoids (Ref).
Oral: 1 to 2 mg/kg once daily (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref). Use in combination with glucocorticoids (Ref).
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 (Ref).
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 (Ref).
IV (longer, high-dose regimen): 500 to 1,000 mg/m2 once every month for 6 doses, then transition to an alternative immunosuppressive agent (Ref). Maximum dose has not been established; some experts do not exceed 1,000 mg/dose (Ref).
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 (Ref). Continue therapy for 2 to 4 months once the dose is stabilized, then transition to an alternative immunosuppressive agent (Ref).
Lymphodepleting therapy prior to autologous T-cell immunotherapy (off-label use):
Prior to afamitresgene autoleucel: IV: 600 mg/m2/day for 3 days (in combination with fludarabine) beginning 7 days (on days -7, -6, and -5) prior to afamitresgene autoleucel infusion on day 0 (Ref).
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 (Ref).
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 (Ref) 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) (Ref).
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 (Ref).
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 (Ref).
Prior to lifileucel : IV: 60 mg/kg once daily for 2 days (with mensa and in combination with fludarabine) beginning 7 days (on days -7 and -6) prior to lifileucel infusion on day 0, followed by in vivo expansion with aldesleukin (Ref).
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 (Ref).
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 (Ref) 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 (Ref).
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 (Ref). Some experts also use cyclophosphamide (in combination with glucocorticoids) as an alternative to other immunosuppressive therapies in patients at moderate risk of disease progression (Ref).
Oral, cyclical (preferred): 2 mg/kg once daily during months 2, 4, and 6 (alternating with glucocorticoid therapy during months 1, 3, and 5) (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref).
Oral, continuous: 1.5 to 2 mg/kg once daily for 12 months (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day, and also limit the total cumulative dose to 25 g to reduce the risk of malignancy (Ref).
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) (Ref).
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 (Ref).
Oral: 2 to 2.5 mg/kg once daily (Ref); some experts continue therapy for 12 weeks, and do not exceed 200 mg/day (Ref). Gradually taper and discontinue glucocorticoids during cyclophosphamide therapy (Ref). Note: Avoid prolonged (>12 weeks) or repeat courses of cyclophosphamide to reduce the risk of adverse effects (Ref).
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 (Ref).
IV: 750 mg/m2 once every month for 3 months (Ref); maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref).
Oral: 2 mg/kg once daily for 2 to 4 months (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref).
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 (Ref) or 500 mg/m2 on days 1, 8, and 15 every 3 weeks (in combination with bortezomib and dexamethasone) for 8 cycles (Ref).
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) (Ref).
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 (Ref).
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 (Ref) or 800 mg/m2/day on days 1 and 2 (Ref), 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) (Ref).
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 (Ref).
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 (Ref). Refer to protocol for dosage adjustments.
Pola-R-CHP regimen (previously untreated diffuse large B-cell lymphoma): IV: 750 mg/m2 on day 1 every 21 days (in combination with polatuzumab vedotin, rituximab, doxorubicin, and prednisone) for 6 cycles; following the completion of 6 cycles of Pola-R-CHP, rituximab monotherapy was continued for 2 cycles (Ref).
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) (Ref).
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 (Ref).
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) (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref). 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) (Ref).
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) (Ref).
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) (Ref) 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 (Ref).
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 (Ref).
Pheochromocytoma, malignant (off-label use): IV: 750 mg/m2 on day 1 every 3 or 4 weeks (in combination with dacarbazine and vincristine) (Ref).
Pneumonitis, immune checkpoint inhibitor induced, grade 3 or 4, steroid refractory (off-label use): IV or Oral: 1 to 2 mg/kg once daily (as an add on to corticosteroids) (Ref).
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 (Ref).
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) (Ref).
IV: 600 mg/m2 once every 2 weeks for 3 doses, then once every 4 weeks thereafter (in combination with glucocorticoids) (Ref). Maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref).
Oral: 2 mg/kg once daily in combination with glucocorticoids (Ref). Maximum dose has not been established; some experts do not exceed 200 mg/day (Ref).
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 (Ref).
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 cell transplant (Ref).
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 (Ref).
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 (Ref).
Duration of therapy:
Acquired PRCA: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Ref).
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 (Ref).
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 (Ref).
Intermediate risk: IV: 2,200 mg/m2 every 21 days (in combination with mesna, vincristine, and dactinomycin) for 14 cycles (Ref).
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 (Ref).
Systemic light chain amyloidosis (off-label use):
CRd regimens:
Oral: 300 mg/m2 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 (Ref).
IV: 300 mg/m2 on days 1 and 8 every 28 days (in combination with lenalidomide and dexamethasone) for 6 cycles, followed by 300 mg/m2 on day 1 only every 28 days (in combination with lenalidomide and dexamethasone) for 6 additional cycles (Ref).
CyBorD regimen: Oral: 300 mg/m2 once weekly (in combination with bortezomib and dexamethasone) (Ref) or 350 mg/m2 on days 1, 8, and 15 (in combination with bortezomib and dexamethasone) for up to 8 cycles (Ref).
Daratumumab-CyBorD (or VCD) regimen: IV or Oral: 300 mg/m2 (maximum weekly dose: 500 mg) on days 1, 8, 15, and 22 of a 28-day cycle (in combination with daratumumab/hyaluronidase, bortezomib, and dexamethasone) for 6 cycles, followed by daratumumab/hyaluronidase (as a single agent) until disease progression or unacceptable toxicity or a maximum of 2 years (Ref).
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 (Ref).
IV (preferred route): 600 mg/m2 once every 4 weeks (Ref); maximum dose has not been established; some experts do not exceed 1,200 mg/dose (Ref).
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 (Ref); maximum dose has not been established; some experts do not exceed 200 mg/day (Ref), 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) (Ref).
Duration of therapy: Limit duration of IV therapy to 6 months or oral therapy to 12 months, then transition to an alternative immunosuppressive agent (Ref).
T-cell prolymphocytic leukemia (off-label use): FMC-A regimen: IV: 200 mg/m2 on days 1, 2, and 3 every 28 days (in combination with fludarabine and mitoxantrone [FMC]) for a total of 2 to 4 cycles; if response demonstrated after initial 2 FMC cycles, then an additional 2 cycles of FMC were administered, followed by alemtuzumab consolidation; if stable disease or progression observed after initial 2 FMC cycles, then proceeded directly to alemtuzumab (Ref).
Thymoma or thymic carcinoma, localized, potentially resectable (off-label use):
Neoadjuvant chemotherapy:
Note: The number of primary/induction chemotherapy cycles usually administered prior to reassessment to determine resectability varies (eg, 2 to 4 cycles) (Ref).
CAP (cyclophosphamide, doxorubicin, cisplatin) regimen: IV: 500 mg/m2 on day 1 every 3 weeks (in combination with doxorubicin and cisplatin) (Ref).
CAP with prednisone regimen: Induction: IV: 500 mg/m2 on day 1 every 3 to 4 weeks (in combination with doxorubicin, cisplatin, and prednisone) for 3 cycles, followed by surgical resection, radiation, and consolidation chemotherapy (Ref).
Thymoma or thymic carcinoma, advanced or metastatic (initial therapy) (off-label use):
ADOC regimen: IV: 700 mg/m2 on day 4 every 3 to 4 weeks (in combination with doxorubicin, cisplatin, and vincristine) for up to 6 cycles (Ref).
CAP regimen: IV: 500 mg/m2 on day 1 every 3 weeks for up to 8 cycles (in combination with cisplatin and doxorubicin) (Ref).
Waldenström macroglobulinemia (off-label use):
DRC regimen: Oral: 100 mg/m2 twice daily on days 1 to 5 of a 21-day cycle (in combination with dexamethasone and rituximab) for 6 cycles (Ref).
FCR regimen: IV: 250 mg/m2 once daily on days 2 to 4 of a 28-day cycle (in combination with fludarabine and rituximab) for up to 6 cycles (Ref).
R- CHOP regimen: IV: 750 mg/m2 on day 1 of a 21-day cycle (in combination with rituximab, doxorubicin, vincristine, and prednisone) for 4 to 8 cycles (Ref).
Warm autoimmune hemolytic anemia, relapsed/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 (Ref).
High-dose therapy:
Note: Generally reserved for patients with refractory disease or severe anemia due to greater potential for toxicity (Ref).
IV: 1,000 mg once every 4 weeks for 4 doses (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Ref).
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% (Ref) or 100% (Ref) of normal dose.
CrCl <10 mL/minute: Administer 50% (Ref), 75% (Ref), or 100% (Ref) of normal dose.
Hemodialysis, intermittent (thrice weekly): Moderately dialyzable (20% to 50% removal based on limited data with low-flux dialyzers (Ref)).
Administer 50% (Ref) or 75% (Ref) of the normal dose. On dialysis days, administer after hemodialysis, allowing at least 12 hours before the next hemodialysis session (Ref).
Peritoneal dialysis: Administer 75% of the normal dose (Ref). If possible, allow at least 12 hours before next peritoneal dialysis exchange (Ref).
CRRT: Administer 100% of the normal dose (Ref).
Indication-specific dosage adjustments:
Granulomatosis with polyangiitis or microscopic polyangiitis:
|
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 |
|
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 (Ref). 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 (Ref).
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 (Ref).
Oral regimen: Refer to “General Dosage Adjustment Recommendations” for patients with kidney impairment.
Multiple myeloma: Oral:
Mild to severe impairment: No dosage adjustment necessary (Ref).
Hemodialysis: No dosage adjustment necessary (Ref).
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 (53 to 85.5 micromole/L) or transaminases >3 times ULN: Administer 75% of dose.
Serum bilirubin >5 mg/dL (>85.5 micromole/L): 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.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 (Note: Excludes hematopoietic cell transplantation and CAR T-cell lymphodepletion dosing): Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; 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 (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref).
American Society for Blood and Marrow Transplantation practice guideline committee position statement on conditioning chemotherapy dosing in obesity (Ref):
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)]
Cardiotoxicity: Symptoms may be managed with diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, or inotropics (Ref).
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.
Refer to adult dosing; adjust for renal clearance.
(For additional information see "Cyclophosphamide: Pediatric drug information")
Dosage guidance:
Safety: IV doses ≥1,200 mg/m2 are associated with a high emetic potential and IV doses >500 mg/m2 to <1,200 mg/m2 are associated with a moderate emetic risk; antiemetics are recommended to prevent nausea and vomiting (Ref). To lessen potential toxicity with doses for oncologic uses, hydration, and follow-up mesna therapy are typically administered; refer to specific protocol.
Dosing: For oncology uses, all dosing presented based on clinically recognized trials; consult specific regimens concerning dosing in combination regimens. 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.
Oncologic uses:
Acute lymphoblastic leukemia, B cell (B-ALL):
High risk B-ALL: Limited data available, multiple regimens reported:
AALL0232: Consolidation, delayed intensification I and II: Children and Adolescents: IV: 1,000 mg/m2 on Day 1 (consolidation) and Day 29 (consolidation, intensification phases); use in combination therapy typically with cytarabine, mercaptopurine or thioguanine (dependent on cycle), vincristine, pegaspargase, and intrathecal methotrexate (dependent on cycle); protocols may include other agents (Ref).
NYII Protocol:
Induction: Children and Adolescents: IV: 1,200 mg/m2 on Day 2 in combination with steroid, daunorubicin, vincristine, and asparaginase (Ref).
Maintenance I: Children and Adolescents: IV: 600 mg/m2on Day 4 in combination with steroid, mercaptopurine, vincristine, daunorubicin, methotrexate, cytarabine, and thioguanine (Ref).
Very high-risk B-ALL: Limited data available, multiple regimens reported:
AALL1131, DFCI 05-001: Consolidation, delayed intensification II: Children and Adolescents: IV: 1,000 mg/m2; for consolidation administer on Day 1 and some protocols may repeat on Day 29 depending on consolidation phase; for delayed intensification administer on Day 29; typically in combination with cytarabine, mercaptopurine, some regimens and cycles may include vincristine, asparaginase, thioguanine and/or intrathecal methotrexate, refer to protocols for combinations and days of administration (Ref).
Standard risk B- ALL:
AALL0932: Delayed intensification: Children <10 years: IV: 1,000 mg/m2 once daily on Day 29 in combination with dexamethasone, vincristine, doxorubicin, pegasparaginase, thioguanine, cytarabine, and intrathecal methotrexate (Ref).
Acute lymphoblastic leukemia, relapsed/refractory: Limited data available:
Clofarabine, etoposide combination regimen: 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 (Ref).
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 (Ref).
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 (Ref).
Acute lymphoblastic leukemia (ALL) of infancy: Limited data available:
COG P9407: Infants and Children <1 year of age at diagnosis:
Induction, Re-induction: IV: 250 mg/m2/dose every 12 hours for 4 doses on Days 3 and 4 in combination with prednisone or dexamethasone, vincristine, daunorubicin, L-asparaginase, and triple intrathecal therapy (Ref).
Induction intensification, consolidation, maintenance: IV: 300 mg/m2/dose once daily for 5 days; for induction intensification administer on Days 36 to 40 in combination with methotrexate, etoposide and triple intrathecal therapy; for consolidation administer on Days 15 to 19 in combination with cytarabine, methotrexate, etoposide, L-asparaginase, and triple intrathecal therapy; and in maintenance administer in weeks 25 and 35 in combination with vincristine, dexamethasone or prednisone, etoposide, mercaptopurine and triple intrathecal therapy (Ref).
Interfant 06 Protocol: Infants and Children <1 year of age at diagnosis. Note: Calculate BSA at start of each block and adjust doses accordingly (Ref).
Protocol IB:
Infants <6 months of age: IV: 667 mg/m2/dose over 60 minutes daily on Days 1 and 29 in combination with cytarabine, mercaptopurine and intrathecal methotrexate, cytarabine and prednisolone or hydrocortisone (Ref).
Infants ≥6 months of age: IV: 750 mg/m2/dose over 60 minutes daily on Days 1 and 29 in combination with cytarabine, mercaptopurine and intrathecal methotrexate, cytarabine and prednisolone or hydrocortisone (Ref).
Children diagnosed before 1 year of age: IV: 1,000 mg/m2/dose over 60 minutes daily on Days 1 and 29 in combination with cytarabine, mercaptopurine and intrathecal methotrexate, cytarabine and prednisolone or hydrocortisone (Ref).
OCTADA(D) (second part):
Infants <6 months of age: IV: 333 mg/m2/dose over 60 minutes daily on Days 36 and 49 in combination with cytarabine and thioguanine (Ref).
Infants ≥6 months of age: IV: 375 mg/m2/dose over 60 minutes daily on Days 36 and 49 in combination with cytarabine and thioguanine (Ref).
Children diagnosed before 1 year of age: IV: 500 mg/m2/dose over 60 minutes daily on Days 36 and 49 in combination with cytarabine and thioguanine (Ref).
CNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available: 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) (Ref).
Desmoplastic small round cell tumor (DSRCT): Limited data available:
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 (Ref).
Children ≥10 years and Adolescents: IV: 2,100 mg/m2over 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 (Ref).
Ewing sarcoma: Limited data available; several regimens and protocols reported. Note: A maximum BSA for dose calculation of 2 m2 is used in some protocols (eg, Euro Ewing 2012) (Ref); refer to protocol details for specific information.
VAC regimen (Euro Ewing 2012): Children >2 years and Adolescents: IV: 1,500 mg/m2 with mesna on Day 1 of a 21-day treatment cycle in combination with vincristine and dactinomycin (Ref).
VAC/IE regimen (multiple protocols): Children and Adolescents: IV: 1,200 mg/m2 with mesna on Day 1 of a 14- or 21-day treatment cycle (refer to specific protocol) in combination with vincristine and doxorubicin; alternate with IE (ifosfamide and etoposide); total number of cycles varies with protocol (Ref).
VC/IE regimen (Euro Ewing 2012): Children >2 years and Adolescents: IV: 1,200 mg/m2 with mesna on Day 1 of a 14-day treatment cycle in combination with vincristine; alternate with IE (ifosfamide and etoposide) (Ref).
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 (Ref).
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 (Ref).
Graft-versus-host disease (GVHD), prevention: Very limited data available: Infants, Children, and Adolescents: IV: 50 mg/kg once daily on days +3 and +4 following allogeneic stem cell or marrow transplantation; may be combined with other immunosuppressants; refer to protocol. Dosing based on retrospective reviews; the largest report describes use in 91 patients (age range: 0.03 to 18 years); 28 subjects were matched sibling donor transplants and received only cyclophosphamide; 63 subjects received a matched unrelated donor transplant and received cyclophosphamide in combination with other immunosuppressants (Ref). In a retrospective comparative trial, 11 out of 29 matched related donor patients received single agent posttransplant cyclophosphamide and were compared to traditional GVHD prophylaxis; no patients in cyclophosphamide group developed GVHD and overall and event-free survival rates were similar (Ref).
Hematopoietic stem cell transplant conditioning, myeloablative transplant: Limited data available: Multiple regimens available; refer to specific protocols for specific days and other concomitant therapy.
Infants, Children, and Adolescents: IV: 50 mg/kg/day for 4 days beginning 5 days before transplant (Ref); other regimens have used 60 mg/kg/day for 2 days following busulfan (Ref).
Dosing adjustment in patients who are obese (Ref):
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)].
Hodgkin lymphoma: Limited data available:
High-risk:
BEACOPP: 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 (Ref).
Bv-AVE-PC: Children ≥2 years of age and Adolescents: IV: 600 mg/m2/dose on Days 1 and 2 of a 21-day cycle for 5 cycles in combination with doxorubicin, vincristine, etoposide, prednisone, and brentuximab (Ref).
ABVE-PC: Children ≥2 years of age and Adolescents: IV: 600 mg/m2/dose on Days 1 and 2 of a 21-day cycle for 5 cycles in combination with doxorubicin, bleomycin, vincristine, etoposide, and prednisone (Ref).
Intermediate-risk:
ABVE-PC: 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 (Ref).
L ymphodepleting therapy prior to chimeric antigen receptor T-cell (CAR-T) immunotherapy: Limited data available: Prior to tisagenlecleucel: Children ≥3 years and Adolescents: IV: 500 mg/m2 once daily for 2 doses in combination with fludarabine (Ref).
Lymphoma, primary mediastinal B-cell: Limited data available: DA-EPOCH-R regimen: Children ≥9 years and Adolescents: IV: 750 mg/m2 on day 5 in combination with etoposide, prednisone, vincristine, doxorubicin, and rituximab; adjust dose for subsequent cycles based on neutrophil and platelet counts during nadir (refer to protocol); repeat cycle every 3 weeks for a total of 6 to 8 cycles; pediatric experience with protocol reported in a retrospective review of 156 patients (n=38, age: 9 to 21 years) (Ref).
Neuroblastoma during infancy (unresectable): Limited data available (Ref): INES 99.1 regimen courses 1 and 2:
Infants:
Weight <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.
Weight ≥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: Limited data available:
High-risk, newly diagnosed:
Topotecan-based induction regimen:
Induction cycles 1 and 2:
Infants and Children, weight ≤12 kg: IV: 13.3 mg/kg over 30 minutes on Days 1 to 5 of a 21-day cycle for 2 cycles in combination with topotecan (Ref).
Infants, Children, and Adolescents, weight >12 kg: IV: 400 mg/m2over 30 minutes on Days 1 to 5 of a 21-day cycle for 2 cycles in combination with topotecan (Ref).
Induction cycles 4 and 6:
Infants and Children, weight ≤12 kg: IV: 70 mg/kg over 6 hours with mesna on Days 1 and 2 of a 21-day cycle; in combination with doxorubicin and vincristine (Ref).
Infants, Children, and Adolescents, weight >12 kg: IV: 2,100 mg/m2 over 6 hours with mesna on Days 1 and 2 of a 21-day cycle; in combination with doxorubicin and vincristine (Ref).
Intermediate-risk, newly diagnosed:
ANBL0531 regimen: Used during multiple cycles in differing combination regimens which may include carboplatin, doxorubicin, or etoposide; refer to the protocol for specific details (Ref).
Infants and Children, weight <12 kg: IV: 33 mg/kg on Day 1.
Infants and Children, weight ≥12 kg: IV: 1,000 mg/m2 on Day 1.
Retrieval therapy for progressive, nonmetastatic disease:
Infants and Children, weight <12 kg: IV: 8.33 mg/kg on Days 1 to 5 in combination with topotecan for 6 cycles (Ref).
Infants and Children, weight ≥12 kg: IV: 250 mg/m2on Days 1 to 5 in combination with topotecan for 6 cycles (Ref).
Relapsed or refractory:
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 (Ref).
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 (Ref).
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 (Ref).
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, with or without rituximab (Ref).
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 (Ref).
COPA regimen: Maintenance 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 (Ref).
Non-Hodgkin lymphoma, T-cell or anaplastic large cell lymphoma (ALCL): Limited data available: NHL-BFM90 regimen: 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 (Ref).
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) (Ref).
Posttransplant 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 (Ref).
Retinoblastoma, extraocular: Limited data available: Protocol 94 regimen: Children: IV: 65 mg/kg over 1 hour with mesna on Day 1 of a 21-day treatment cycle in combination with idarubicin and vincristine, alternating cycles with carboplatin and etoposide for a total of 8 cycles (Ref).
Rhabdomyosarcoma:
Low risk: Limited data available: 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 (Ref).
Infants and Children <3 years: IV: 40 mg/kg.
Children ≥3 years and Adolescents: IV: 1,200 mg/m2.
Intermediate risk: Limited data available: VAC regimen: Doses were administered with hydration and mesna every 21 days for 14 cycles in combination with vincristine and dactinomycin (Ref).
Infants: IV: 36 mg/kg.
Children 1 to 3 years: IV: 73 mg/kg.
Children >3 years: IV: 2,200 mg/m2.
Wilms tumor:
Anaplastic (stage II to IV): Limited data available:
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) (Ref).
Relapsed/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) (Ref); 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 continue for 90 weeks (Ref).
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) (Ref).
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 (Ref).
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 not responded 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 (Ref).
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 (Ref); 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 (Ref).
3-month course: 500 mg every 2 weeks for 3 months (Ref).
Oral: 1 to 1.5 mg/kg/day for 2 to 4 months; maximum daily dose: 150 mg/day (Ref); 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) (Ref).
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 (Ref).
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 body weight (Ref). 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) (Ref); 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 (Ref). Note: Some data suggests that pulse IV therapy may be less effective than oral cyclophosphamide (Ref).
Vasculitis, antineutrophilic cytoplasmic antibody 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 (Ref).
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 (Ref).
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.
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.
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 (Ref): 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.
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
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
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)
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; typically, within 2 to 8 weeks of initiation. Onset has also been reported 12 hours up to approximately 10 months after initiation (Ref). In the case of transplantation, onset of SOS has been reported within 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, 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
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)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Postmarketing:
Cardiovascular: Acute myocardial infarction (Ref), atrial fibrillation (Ref), atrial flutter (Ref), bradycardia, cardiac tamponade (Ref), cardiogenic shock, cardiomyopathy, chest pain, edema, flushing, heart failure (Ref), hemorrhagic myocarditis, hypertension, hypotension, myocarditis, palpitations, pericardial effusion (Ref), pericarditis (Ref), peripheral ischemia, prolonged QT interval on ECG, pulmonary embolism, supraventricular cardiac arrhythmia (Ref), tachycardia, vasculitis, venous thrombosis, ventricular arrhythmia (Ref), 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 (Ref), toxic epidermal necrolysis (Ref), urticaria (Ref)
Endocrine & metabolic: Amenorrhea, decreased serum glucose, fluid retention, hot flash, hyponatremia (Ref), 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 (Ref), bladder disease (necrosis, contracture, or atypical epithelial cells), cystitis (ulcerative), defective oogenesis, defective spermatogenesis, hematuria (Ref), hemorrhagic cystitis (Ref), infertility, infrequent uterine bleeding, oligospermia, ovarian failure, ovarian fibrosis, premature labor, pyelitis, testicular atrophy, toxic nephrosis, ureteral disease (ureteritis)
Hematologic & oncologic: Anemia (Ref), bone marrow depression (including bone marrow failure) (Ref), C-reactive protein increased, disseminated intravascular coagulation, febrile neutropenia, hemolytic-uremic syndrome, leukopenia (Ref), myelodysplastic syndrome (Ref), neutropenia (Ref), pulmonary hemorrhage, secondary primary malignant neoplasm (including acute leukemia, malignant lymphoma, malignant neoplasm of urinary tract [pelvic, renal, and ureteric], myelatelia, sarcoma) (Ref), thrombocytopenia (Ref), thrombotic microangiopathy
Hepatic: Ascites (Ref), cholestatic hepatitis, hepatic encephalopathy, hepatic failure (Ref), hepatic sinusoidal obstruction syndrome (Ref), hepatitis (including hepatic cytolysis), hepatomegaly (Ref), increased liver enzymes (Ref), increased serum bilirubin (Ref), jaundice (Ref)
Hypersensitivity: Anaphylactic shock, anaphylaxis (Ref), facial swelling
Immunologic: Immunosuppression (Ref)
Infection: Cytomegalovirus disease (Ref), 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 (Ref), 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]) (Ref), pulmonary edema, pulmonary fibrosis (Ref), pulmonary hypertension, pulmonary veno-occlusive disease, respiratory distress (Ref), respiratory failure (Ref), rhinorrhea
Miscellaneous: Fever, multi-organ failure
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.
Concerns related to adverse effects:
• Hypersensitivity: Possible cross-sensitivity with other alkylating agents may occur.
Disease-related concerns:
• Hepatic impairment: Use with caution in hepatic impairment; see "Dosing: Hepatic Impairment" for additional information.
• Renal impairment: Use with caution in patients with renal impairment; see "Dosing: Altered Kidney Function" for additional information.
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.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 25 mg, 50 mg
Solution, Intravenous:
Frindovyx: 500 mg/mL (1 mL); 1 g/2 mL (2 mL) [contains alcohol, usp]
Generic: 500 mg/5 mL (5 mL); 1000 mg/10 mL (10 mL); 2000 mg/20 mL (20 mL); 500 mg/2.5 mL (2.5 mL); 500 mg/mL (1 mL); 1 g/2 mL (2 mL); 1 g/5 mL (5 mL); 2 g/10 mL (10 mL)
Solution, Intravenous [preservative free]:
Generic: 500 mg/2.5 mL (2.5 mL); 1 g/5 mL (5 mL)
Solution Reconstituted, Injection:
Generic: 500 mg (1 ea); 1 g (1 ea); 2 g (1 ea)
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
Yes
Capsules (cycloPHOSphamide Oral)
25 mg (per each): $3.42 - $9.36
50 mg (per each): $4.80 - $17.75
Solution (cycloPHOSphamide Intravenous)
1 g/5 mL (per mL): $60.00 - $232.39
1GM/2ML (per mL): $1,050.00
2 g/10 mL (per mL): $60.00 - $175.80
500 mg/2.5 mL (per mL): $72.00 - $232.39
500 mg/5 mL (per mL): $105.30
500 mg/mL (per mL): $1,050.00
1000 mg/10 mL (per mL): $105.30
2000 mg/20 mL (per mL): $105.30
Solution (Frindovyx Intravenous)
1GM/2ML (per mL): $1,050.00
500 mg/mL (per mL): $1,050.00
Solution (reconstituted) (cycloPHOSphamide Injection)
1 g (per each): $218.75 - $879.00
2 g (per each): $437.50 - $1,758.00
500 mg (per each): $106.25 - $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.
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)
Generic: 1 g (1 ea); 2 g (1 ea)
Tablet, Oral:
Procytox: 25 mg, 50 mg
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 (Ref).
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 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.
Antiemetics may be recommended to prevent nausea and vomiting; IV doses ≥1,200 mg/m2 are associated with a high emetic potential and IV doses >500 mg/m2 to <1,200 mg/m2 are associated with a moderate emetic risk; antiemetics are recommended to prevent nausea and vomiting (Ref).
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 NS 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 fluid requirements (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 for additional information. Morning administration may be preferred to ensure adequate hydration throughout the day.
Hazardous agent (NIOSH 2024 [table 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 2023; NIOSH 2024; USP-NF 2020).
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 and other malignant lymphomas), 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.
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 cell or marrow transplant; Interstitial pneumonia, nonspecific, refractory or rapidly progressive; Lupus nephritis, focal or diffuse; Lymphodepleting therapy prior to autologous 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); Pneumonitis, immune checkpoint inhibitor-induced, grade 3 or 4, steroid-refractory; 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; T-cell prolymphocytic leukemia; Thymoma or thymic carcinoma; Waldenström macroglobulinemia; Warm autoimmune hemolytic anemia, relapsed or refractory
CycloPHOSphamide may be confused with cycloSERINE, cycloSPORINE, ifosfamide
Cytoxan may be confused with cefOXitin, Ciloxan, cytarabine, CytoGam, Cytosar, Cytosar-U, Cytotec
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral; immunosuppressant agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
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;
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Allopurinol: May increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Amiodarone: CycloPHOSphamide may increase adverse/toxic effects of Amiodarone. Specifically, the risk of pulmonary toxicity may be enhanced. Risk C: Monitor
Anthracyclines: CycloPHOSphamide may increase cardiotoxic effects of Anthracyclines. Risk C: Monitor
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
AzaTHIOprine: May increase hepatotoxic effects of CycloPHOSphamide. AzaTHIOprine may increase adverse/toxic effects of CycloPHOSphamide. Specifically, the risk for malignancy may be increased with azathioprine in patients previously treated with cyclophosphamide. Risk C: Monitor
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Baricitinib. Risk X: Avoid
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of BCG Products. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Brincidofovir. Risk C: Monitor
Brivudine: May increase adverse/toxic effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
BUPivacaine: CycloPHOSphamide may increase adverse/toxic effects of BUPivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor
Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Cladribine. Risk X: Avoid
CloZAPine: Myelosuppressive Agents may increase adverse/toxic effects of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor
Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Cytotoxic Chemotherapy) and Coccidioides immitis Skin Test may alter diagnostic results. 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 decrease therapeutic effects 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 serum concentration of CycloSPORINE (Systemic). Risk C: Monitor
CYP2B6 Inducers (Moderate): May increase active metabolite exposure of CycloPHOSphamide. Risk C: Monitor
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Deferiprone: Myelosuppressive Agents may increase neutropenic effects 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 decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Denosumab: May increase immunosuppressive effects 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
Deucravacitinib: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Etanercept: May increase adverse/toxic effects of CycloPHOSphamide. An increased risk of solid cancer development may be present. Risk X: Avoid
Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid
Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Fluconazole: May increase adverse/toxic effects of CycloPHOSphamide. Specifically, serum bilirubin and serum creatinine may be increased. Fluconazole may increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Fosphenytoin-Phenytoin: May increase active metabolite exposure of CycloPHOSphamide. More specifically, phenytoin may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. Fosphenytoin-Phenytoin may decrease serum concentration of CycloPHOSphamide. Risk C: Monitor
Granulocyte Colony-Stimulating Factors: May increase adverse/toxic effects of CycloPHOSphamide. Specifically, the risk of pulmonary toxicity may be increased. Risk C: Monitor
IDArubicin: CycloPHOSphamide may increase cardiotoxic effects of IDArubicin. Risk X: Avoid
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Inebilizumab. Risk C: Monitor
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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 increase adverse/toxic effects of CycloPHOSphamide. Specifically, serum creatinine and serum bilirubin may be increased. Itraconazole may increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Ketoconazole (Systemic): May increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects 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 increase adverse/toxic effects of CycloPHOSphamide. Specifically, the risk of pulmonary toxicity may be enhanced. CycloPHOSphamide may decrease therapeutic effects 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
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Lipegfilgrastim: May increase adverse/toxic effects of CycloPHOSphamide. Specifically, the risk of pulmonary toxicity may be increased. CycloPHOSphamide may decrease therapeutic effects 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
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Lumacaftor and Ivacaftor: May decrease serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor
MiFEPRIStone: May increase serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor
Mivacurium: CycloPHOSphamide may increase serum concentration of Mivacurium. Risk C: Monitor
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid
Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ocrelizumab. Risk C: Monitor
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ofatumumab. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Palifermin: May increase adverse/toxic effects 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
PHENobarbital: May increase active metabolite exposure of CycloPHOSphamide. More specifically, phenobarbital may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. PHENobarbital may decrease serum concentration of CycloPHOSphamide. Risk C: Monitor
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Pidotimod. Risk C: Monitor
Pimecrolimus: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Piperacillin: May increase hypokalemic effects of Antineoplastic Agents. Risk C: Monitor
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may increase hypersensitivity effects of 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
Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor
Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification
Primidone: May decrease serum concentration of CycloPHOSphamide. Primidone may increase active metabolite exposure of CycloPHOSphamide. More specifically, primidone may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. Risk C: Monitor
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Protease Inhibitors: May increase adverse/toxic effects of CycloPHOSphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Protease Inhibitors may increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider Therapy Modification
Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects 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
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid
Schisandra: May increase serum concentration of CycloPHOSphamide. Risk C: Monitor
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects 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
Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Sphingosine 1-Phosphate (S1P) Receptor Modulators: May increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor
Succinylcholine: CycloPHOSphamide may increase serum concentration of Succinylcholine. Management: Consider alternatives to succinylcholine in patients who have received cyclophosphamide in the past 10 days. If combined, consider reduced succinylcholine doses and close monitoring for increased and prolonged neuromuscular blocking effects. Risk D: Consider Therapy Modification
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects 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
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Tertomotide. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: May increase adverse/toxic effects of CycloPHOSphamide. Specifically, granulocytopenia may be enhanced. Risk C: Monitor
Thiotepa: May decrease active metabolite exposure of CycloPHOSphamide. More specifically, thiotepa may decrease the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. Risk C: Monitor
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Tofacitinib. Risk X: Avoid
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Ublituximab. Risk C: Monitor
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may increase immunosuppressive effects of Upadacitinib. Risk X: Avoid
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may decrease therapeutic effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting chemotherapy when possible. Patients vaccinated less than 14 days before or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider Therapy Modification
Vasopressin: Drugs Suspected of Causing SIADH may increase therapeutic effects of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor
Voclosporin: CycloPHOSphamide may increase adverse/toxic effects of Voclosporin. Risk X: Avoid
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Zoster Vaccine (Live/Attenuated): Immunosuppressants (Cytotoxic Chemotherapy) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid
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]). Patients treated for rheumatic and musculoskeletal diseases should consider discontinuing cyclophosphamide 3 to 6 months prior to conception to allow for disease monitoring and potential change to another immunosuppressant. Cyclophosphamide should also be discontinued 12 weeks prior to attempted conception in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Cyclophosphamide may cause ovarian insufficiency, and infertility and long-term gonadal damage. Dose-related sterility (which may be irreversible) may occur in all patients. Recommendations are available for fertility preservation of adult patients treated with anticancer agents (ASCO [Oktay 2018]). Recommendations for preserving fertility in patients treated with cyclophosphamide for autoimmune and systemic inflammatory diseases are available (ACR [Sammaritano 2020]).
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) approach. 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 long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (877-635-4499).
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).
CBC with differential and platelets, BUN, serum electrolytes, serum creatinine, urinalysis. Evaluate pregnancy status prior to use in patients who can become pregnant. Assess risk for opportunistic infections (eg, Pneumocystis jirovecii pneumonia, herpes virus infection). 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.
Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.
Absorption: Oral: Well absorbed
Distribution: Vd: 30 to 50 L (approximates total body water); crosses into CSF (not in high enough concentrations to treat meningeal leukemia)
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%)
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%.
