Note: For oncology uses, details concerning dosing in combination regimens should also be consulted; antiemetics may be recommended (emetogenic potential varies by dose and combination therapy).
Neuroblastoma: Limited data available: INES 99.1 regimen courses 1 and 2: Term neonates: IV: 3.5 mg/kg on Days 1 to 5 administered at 2-week intervals for 2 cycles initially, in combination with vincristine (Rubie 2011)
For oncology uses, all dosing presented based on clinically recognized trials; consult specific regimens concerning dosing in combination regimens. Doses IV ≥1,000 mg/m2 are associated with a high emetic potential and IV doses <1,000 mg/m2 and all oral doses are associated with a moderate emetic risk; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Dupuis 2013; Paw Cho Sing 2019). In pediatric patients, dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations. To lessen potential toxicity with doses for oncologic uses, hydration, and follow-up mesna therapy are typically administered; refer to specific protocol.
Oncologic uses:
Acute lymphoblastic leukemia, high-risk: Limited data available (Steinherz 1993): NYII Protocol:
Induction: Children and Adolescents: IV: 1,200 mg/m2 on Day 2 (in combination with steroid, daunorubicin, vincristine, and asparaginase).
Maintenance I: Children and Adolescents: IV: 600 mg/m2on Day 4 (in combination with steroid, mercaptopurine, vincristine, daunorubicin, methotrexate, cytarabine, and thioguanine).
Acute lymphoblastic leukemia, relapsed or refractory: Limited data available:
Hijiya 2011: Children and Adolescents: IV: 440 mg/m2 over 30 to 60 minutes in combination with clofarabine and etoposide; number of doses dependent on phase of protocol: Induction: Days 1 to 5, and Consolidation: Days 1 to 4.
Parker 2010: UK-ALL R3 protocol: Children and Adolescents:
Phase 2 Consolidation (weeks 5 to 8): IV: 440 mg/m2 on Days 15 to 19 in combination with steroid, vincristine, methotrexate, PEG-asparaginase, and etoposide.
Phase 5, before Continuation (weeks 14 to 29): IV: 300 mg/m2 on Days 42, 49, 99, and 106 in combination with steroid, mercaptopurine, vincristine, methotrexate, etoposide, and cytarabine.
CNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available (Chi 2004; Mason 1998): Head Start II Protocol: Infants and Children <10 years: IV: 65 mg/kg on Days 2 and 3 with mesna every 21 days for 5 cycles (in combination with cisplatin, vincristine, etoposide, and high-dose methotrexate; then followed by an auto-transplantation).
Desmoplastic small round cell tumor (DSRCT): Limited data available (Kushner 1996): High-dose cyclophosphamide: HD-CAV/IE regimen: P6 Protocol:
Children <10 years: IV: 70 mg/kg over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.
Children ≥10 years and Adolescents: IV: 2,100 mg/m2over 6 hours with mesna and hydration on Day 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.
Ewing sarcoma:
VAC/IE regimen: Limited data available (Grier 2003): Children and Adolescents: IV: 1,200 mg/m2 with mesna on Day 1 of a 21-day treatment cycle in combination with vincristine and doxorubicin (then dactinomycin when maximum doxorubicin dose reached), alternate with IE (ifosfamide and etoposide) for a total of 17 cycles.
High-dose cyclophosphamide: HD- CAV/IE regimen: P6 Protocol: Limited data available (Kushner 1996):
Children <10 years: IV: 70 mg/kg over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.
Children ≥10 years and Adolescents: IV: 2,100 mg/m2 over 6 hours with mesna and hydration on Days 1 and 2 of a 21-day treatment cycle in combination with vincristine and doxorubicin for courses 1, 2, 4, and 6, alternate with ifosfamide and etoposide for courses 4, 5, and 7.
Hodgkin lymphoma: Limited data available:
BEACOPP (high-risk): Children and Adolescents: IV: 1,200 mg/m2 on Day 0 of a 21-day treatment cycle for 4 cycles in combination with bleomycin, etoposide, doxorubicin, vincristine, prednisone, and procarbazine (Kelly 2011).
ABVE-PC (intermediate-risk): Children and Adolescents: IV: 800 mg/m2 over 1 hour on the first day of a 21-day cycle for up to 4 cycles (depending upon response) in combination with doxorubicin, vincristine, etoposide, prednisone, and bleomycin (Dharmarajan 2015; Friedman 2014; Schwartz 2009).
HSCT conditioning; myeloablative transplant: Limited data available: Infants, Children, and Adolescents: IV: 50 mg/kg/day for 4 days beginning 5 days before transplant (Champlin 2007); other regimens have used 60 mg/kg/day for 2 days following busulfan (Locatelli 2005; Mårtensson 2013).
Dosing adjustment in obese patients (ASBMT [Bubalo 2014]):
Cy200 (cyclophosphamide total dose of 200 mg/kg): Use the lesser of ideal body weight (IBW) or actual body weight (ABW).
Cy120 (cyclophosphamide total dose of 120 mg/kg): Use IBW or ABW until >120% IBW; then use ABW25 for patients >120% IBW.
ABW25: Adjusted weight (kg) = Ideal body weight (kg) + 0.25 [actual body weight (kg) - ideal body weight (kg)].
Neuroblastoma during infancy (unresectable): Limited data available (Rubie 2011): INES 99.1 regimen courses 1 and 2:
Infants:
<10 kg: IV: 3.5 mg/kg on Days 1 to 5 administered at 2-week intervals for 2 cycles initially, in combination with vincristine.
≥10 kg: IV: 5 mg/kg on Days 1 to 5 administered at 2-week intervals for 2 cycles initially, in combination with vincristine.
Neuroblastoma ; high-risk, newly diagnosed: Limited data available (Park 2011): Infants, Children, and Adolescents:
Induction cycles 1 and 2 (21-day cycles):
Patient weight ≤12 kg: IV: 13.3 mg/kg over 30 minutes on Days 1 to 5 (in combination with topotecan) for 2 cycles.
Patient weight >12 kg: IV: 400 mg/m2over 30 minutes on Days 1 to 5 (in combination with topotecan) for 2 cycles.
Induction cycles 4 and 6 (21-day cycles):
Patient weight ≤12 kg: IV: 70 mg/kg over 6 hours with mesna on Days 1 and 2 (in combination with doxorubicin and vincristine).
Patient weight >12 kg: IV: 2,100 mg/m2 over 6 hours with mesna on Days 1 and 2 (in combination with doxorubicin and vincristine).
Neuroblastoma; relapsed or refractory: Limited data available (Kushner 2010; Kushner 2011): HD-CCV or HD-CTV regimen: Infants and Children ≤10 years: IV: 70 mg/kg on Days 1 and 2 (in combination with irinotecan and vincristine or in combination with topotecan and vincristine).
Non-Hodgkin lymphoma: Limited data available:
COP regimen: Reduction: Infants ≥6 months, Children, and Adolescents: IV: 300 mg/m2over 15 minutes on Day 1 (in combination with vincristine and prednisone) (Cairo 2007; Goldman 2013; Goldman 2014).
COPADM 1 regimen: Induction 1: Infants ≥6 months, Children, and Adolescents: IV: 250 mg/m2/dose over 15 minutes every 12 hours on Days 2 to 4 (6 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate) (Cairo 2007; Goldman 2013; Goldman 2014; Patte 2007).
COPADM 2 regimen: Induction 2: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2/dose over 15 minutes every 12 hours on Days 2 to 4 (6 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate, +/- Rituximab) (Cairo 2007; Goldman 2013; Goldman 2014).
COPADM regimen: Maintenance 1: High-risk patients: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2 over 15 minutes on Days 2 and 3 (2 doses) (in combination with doxorubicin, vincristine, prednisone, methotrexate) (Cairo 2007; Goldman 2013; Goldman 2014).
COPA regimen: Maintenance course 3: High-risk patients: Infants ≥6 months, Children, and Adolescents: IV: 500 mg/m2/dose over 30 minutes on the first 2 days of the cycle (2 doses) (in combination with doxorubicin, vincristine, prednisone) (Cairo 2007; Goldman 2013; Goldman 2014).
Non-Hodgkin lymphoma, T-cell (anaplastic large cell lymphoma [ALCL]): Limited data available (Reiter 1994; Seideman 2001): NHL-BFM90 protocol: Infants, Children, and Adolescents: IV: 200 mg/m2over 1 hour; number of doses, days of administration, and other chemotherapy combinations are dependent on protocol specific phase.
Palliative intent chemotherapy (metronomic therapy): Limited data available: Infants, Children, and Adolescents: Oral: 2.5 mg/kg once daily, maximum dose: 100 mg/dose for 21 days, alternating with a 21-day cycle of etoposide in combination with continuous thalidomide, celecoxib, and fenofibrate therapy; in the trial, the youngest patient reported was 191 days old (around 6 months of age) (Robison 2014).
Post-transplant lymphoproliferative disease (PTLD): Limited data available: Infants, Children, and Adolescents: IV: 600 mg/m2 on Day 1 every 21 days for 6 cycles in combination with prednisone (all 6 cycles) and rituximab (first 2 cycles only); the youngest patient included in the reported experience was 0.8 years of age (Gross 2012).
Retinoblastoma, extraocular: Limited data available (Chantada 2003): Protocol 94 regimen: Children: IV: 65 mg/kg over 1 hour on Day 1 with mesna of a 21-day treatment cycle (in combination with idarubicin and vincristine) alternating cycles with carboplatin and etoposide for a total of 8 cycles.
Rhabdomyosarcoma:
Low risk: Limited data available (Walterhouse 2014): VAC regimen: Doses were administered with hydration and mesna every 21 days for 4 doses of a 22-week cycle in combination with vincristine and dactinomycin.
Infants and Children <3 years: IV: 40 mg/kg.
Children ≥3 years and Adolescents: 1,200 mg/m2.
Intermediate risk: Limited data available (Arndt 2009): VAC regimen: Doses were administered with hydration and mesna every 21 days for 14 cycles in combination with vincristine and dactinomycin.
Infants: IV: 36 mg/kg.
Children 1 to 3 years: IV: 73 mg/kg.
Children >3 years: 2,200 mg/m2.
Wilms tumor; anaplastic (stage II to IV): Limited data available (Green 1994): National Wilms’ Tumor Study (NWTS) protocol 4 regimen J: Children and Adolescents <16 years: IV: 10 mg/kg on Days 1 to 3 (3 doses) every 6 weeks (in combination with vincristine, dactinomycin, and doxorubicin).
Wilms tumor relapsed or refractory: Limited data available: National Wilms’ Tumor Study (NWTS) protocol-5 regimen:
Infants and Children weighing ≤30 kg: IV: 14.7 mg/kg with mesna; reported frequency and combination chemotherapy variable, refer to specific protocols. One regimen alternated the frequency based on week of therapy: Weeks 3, 9, 15, and 21: Doses administered once daily for 5 days (in combination with etoposide); Weeks 6, 12, 18, and 24 administered once daily for 3 days (in combination with doxorubicin and vincristine) (Green 2007); another protocol administered for 5 days, on Weeks 0 and 3 in combination with etoposide; alternate with carboplatin and etoposide on Weeks 6 and 9 and continued for 90 weeks (Malogolowkin 2008).
Children >30 kg and Adolescents <16 years at diagnosis: IV: 440 mg/m2 with mesna; reported frequency and combination chemotherapy variable, refer to specific protocols. One regimen alternated the frequency based on week of therapy: Weeks 3, 9, 15, and 21: Doses administered once daily for 5 days (in combination with etoposide); Weeks 6, 12, 18, and 24 administered once daily for 3 days (in combination with doxorubicin and vincristine) (Green 2007).
Non-Oncologic uses:
Aplastic anemia, severe; refractory: Limited data available: Children and Adolescents ≥2 years: High-dose therapy: IV: 45 to 50 mg/kg/day for 4 days has been used in several small trials; concurrent prophylactic antimicrobial therapy should be considered (Audino 2010; Brodsky 1996; Brodsky 2010; DeZern 2011; Jaime-Perez 2013).
Kawasaki Disease; refractory to multiple therapies: Very limited data available: Infants and Young Children: IV: 2 mg/kg/dose once daily; some have suggested a gradual taper over 1.5 to 7 months; however, details of taper have not been described. Dosing based on a retrospective study of patients with refractory Kawasaki Disease that included two patients (ages 2.7 and 9 years) who had failed to respond to 3 doses of IVIG and required high-dose IV methylprednisolone; after initiation of cyclophosphamide, steroids were able to be successfully tapered and final ECHO showed resolution of aneurysm. While taper schedule was not described, both patients were discharged on a taper over 1.5 to 7 months (AHA [McCrindle 2017]; Wallace 2000).
Lupus nephritis; proliferative: Limited data available: Children and Adolescents:
Initial phase; pulse therapy:
IV:
6-month course: Usual range: 500 to 1,000 mg/m2/dose once monthly (KDIGO 2012); the following regimen has been used for dosage escalation: Initial: 500 mg/m2 then titrate as tolerated every 4 weeks in 250 mg/m2 increments up to 750 or 1,000 mg/m2 every month; maximum monthly dose: 1,500 mg/month (Bertsias 2012; Mina 2012).
3-month course: 500 mg every 2 weeks for 3 months (Bertsias 2012; KDIGO 2012).
Oral: 1 to 1.5 mg/kg/day for 2 to 4 months; maximum daily dose: 150 mg/day (KDIGO 2012); higher doses (2 to 2.5 mg/kg/day for 3 months) may be required in patients with worsening prognostic factors (eg, acute renal function deterioration) (Bertsias 2012).
Maintenance phase: IV: 500 to 1,000 mg/m2 every 3 months for a total of 1.5 to 3 years has been used; however, current guidelines recommend other oral immunosuppressive agents for maintenance therapy (KDIGO 2012; Kliegman 2011; Lehman 2000).
Nephrotic syndrome, minimal change (frequently relapsing): Infants, Children, and Adolescents: Oral: 2 mg/kg/day for 8 to 12 weeks; reported range: 2 to 3 mg/kg/day; maximum cumulative dose: 168 mg/kg; dosing based on ideal bodyweight (Gipson 2009; KDIGO 2012; KDOQI 2013). Treatment beyond 90 days may increase the potential for sterility in males.
Uveitis, severe; recalcitrant, high-risk vision loss: Limited data available: Children and Adolescents: Oral: Initial: 2 mg/kg/day once daily; usual reported range: 1 to 3 mg/kg/day in combination with corticosteroids (which may be decreased while on cyclophosphamide) (Jabs 2000; Pujari 2010; Simonini 2010); dosing based on large, multicenter report of 215 patients with ocular inflammatory disease which included 44 patients with uveitis (age range: 11.5 to 76.4 years); after 12 months of therapy ~89% of patients had no inflammatory disease activity or only slightly active disease (Pujari 2010). Note: Some data suggests that pulse intravenous therapy may be less effective than oral cyclophosphamide (Pujari 2010).
Vasculitis, ANCA-associated (eg, granulomatosis with polyangiitis [GPA], Wegener granulomatosis): Limited data available: Children and Adolescents:
IV: Initial: 15 mg/kg every 2 weeks for 3 doses, then 15 mg/kg every 3 weeks until remission or azathioprine maintenance; dosing based on experience from a pediatric case series (n=5) and a larger adult trial (n=76); in the pediatric case series, the median cumulative dose was 90 mg/kg (range: 63 to 115 mg/kg), most patients received 6 to 7 pulses of therapy; in the adult trial, therapy was continued for 3 months after remission (de Groot 2009; Krmar 2013).
Oral: 2 mg/kg/day in combination with corticosteroids until remission; a subsequent decrease in dose to 1.5 mg/kg/day for another 3 months has been reported (de Groot 2009; Kliegman 2011).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: Infants, Children, and Adolescents:
Hematologic toxicity: May require dose reduction or treatment interruption.
Hemorrhagic cystitis, severe: Discontinue treatment.
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 (Floyd 2006): All patients:
Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.
Serum bilirubin >5 mg/mL: Avoid use.
(For additional information see "Cyclophosphamide: Drug information")
Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; MASCC [Roila 2016]). Increased hydration and frequent voiding are recommended to help prevent cystitis; some protocols utilize mesna to prevent bladder toxicity/hemorrhagic cystitis (refer to protocol). May require dose reduction or treatment interruption based on clinical response and hematologic toxicity (eg, ANC <1,500 mm3). Antimicrobial prophylaxis may be considered in appropriate patients. Consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia. Patient should be under the care of a clinician experienced with using cyclophosphamide.
Acute lymphoblastic leukemia (off-label dosing): Multiple-agent regimens:
CALGB 10403 regimen: Patients <40 years of age: IV: Remission consolidation phase (course 2): 1,000 mg/m2 on days 1 and 29; Delayed intensification phase: 1,000 mg/m2 on day 29; phases are part of combination chemotherapy; refer to protocol for details (Stock 2019).
Hyper-CVAD regimen: IV: 300 mg/m2 over 3 hours every 12 hours for 6 doses on days 1, 2, and 3 (in combination with mesna, vincristine, doxorubicin, and dexamethasone) during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase (Kantarjian 2000); plus a BCR-ABL tyrosine kinase inhibitor (for Philadelphia chromosome-positive disease) (Ravandi 2010; Thomas 2004).
CALGB8811 regimen:
Adults <60 years of age: IV: Induction phase: 1,200 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1,000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1,000 mg/m2 on day 29 of an 8-week cycle (Larson 1995).
Adults ≥60 years of age: IV: Induction phase: 800 mg/m2 on day 1 of a 4-week cycle; Early intensification phase: 1,000 mg/m2 on day 1 of a 4-week cycle (repeat once); Late intensification phase: 1,000 mg/m2 on day 29 of an 8-week cycle (Larson 1995).
GRAALL 2003 regimen: Patients <60 years of age: IV: Induction phase: 750 mg/m2 on day 1; then 750 mg/m2 on day 15 (in good early responders) or 500 mg/m2 every 12 hours for 4 doses on days 15 and 16 (in poor early responders); Consolidation phase: 500 mg/m2 on days 29 and 30 of consolidation blocks 3, 6, and 9; Late intensification phase: 500 mg/m2 every 12 hours on day 15; phases are part of combination chemotherapy; refer to protocol for further information (Huguet 2009).
GRAALL 2005 regimen: Patients <60 years of age: IV: Induction phase: 750 mg/m2 on day 1; then 750 mg/m2 on day 15 or 300 mg/m2 every 12 hours for 6 doses on days 15 to 17; First, second, and third consolidation phases (block 3, block 6, and block 9, respectively): 500 mg/m2 on days 29 and 30; Late intensification phase (if complete response after first course): 750 mg/m2 on day 1; then 750 mg/m2 on day 15 or 300 mg/m2 every 12 hours for 6 doses on days 15 to 17; phases are part of combination chemotherapy; refer to protocol for further information (Huguet 2018).
MRC UKALL XII/ECOG E2993 regimen: Patients <60 years of age: IV: Induction (phase 2): 650 mg/m2 on days 1, 15, and 29; Consolidation phase (cycle 3): 650 mg/m2 on day 29; phases are part of combination chemotherapy; refer to protocol for further information (Rowe 2005).
Adult T-cell leukemia/lymphoma (off-label dosing): IV: 350 mg/m2 on day 1 every 28 days (as part of the VCAP-AMP-VECP multiagent chemotherapy regimen) for 6 cycles (Tsukasaki 2007).
Anti-glomerular basement membrane disease (anti-GBM or Goodpasture disease) (off-label use):
Note: For use in combination with glucocorticoids and plasmapheresis in patients with kidney involvement who do not require immediate dialysis, or in patients with pulmonary hemorrhage regardless of kidney involvement (Kaplan 2021; KDIGO 2012).
Oral: 2 mg/kg once daily; some experts do not exceed 200 mg/day. On plasmapheresis days, administer cyclophosphamide after plasmapheresis. Discontinue therapy after 2 to 3 months; some experts continue therapy for up to 6 months if anti-GBM antibodies are not substantially reduced within 3 months (Huart 2016; Kaplan 2021; KDIGO 2012).
Breast cancer (off-label dosing):
AC regimen: IV: 600 mg/m2 on day 1 every 21 days (in combination with doxorubicin) for 4 cycles (Fisher 1990).
CEF regimen: Oral: 75 mg/m2/day days 1 to 14 every 28 days (in combination with epirubicin and fluorouracil) for 6 cycles (Levine 1998).
CMF regimen: Oral: 100 mg/m2/day days 1 to 14 every 28 days (in combination with methotrexate and fluorouracil) for 6 cycles (Levine 1998) or IV: 600 mg/m2 on day 1 every 21 days (in combination with methotrexate and fluorouracil) (Goldhirsch 1998).
Castleman disease, idiopathic, multicentric (off-label use; based on limited data): Note: Cyclophosphamide-containing combination chemotherapy regimens (± rituximab) may benefit certain patients with severe idiopathic multicentric Castleman disease (van Rhee 2018).
CHOP regimen: IV: 750 mg/m2 on day 1 every 3 weeks for 4 cycles (in combination with doxorubicin, vincristine, and prednisone ± rituximab) (Seo 2009).
TCP regimen: Oral: 300 mg/m2 once weekly on days 1, 8, 15, and 22 every 4 weeks (in combination with thalidomide and prednisone). TCP was administered for 2 years or until treatment failure; cyclophosphamide and prednisone were administered for 1 year, while thalidomide was administered for 2 years (Zhang 2019).
Chronic lymphocytic leukemia (off-label dosing): IV: R-FC regimen: 250 mg/m2/day for 3 days every 28 days (in combination with rituximab and fludarabine) for 6 cycles (Robak 2010).
Dermatomyositis/polymyositis, severe, life-threatening or refractory (adjunctive agent) (off-label use):
Note: For use as an adjunct to glucocorticoids and other immunosuppressive agents in patients with severe disease that is refractory to other preferred therapies, or as part of initial combination therapy in patients with impending respiratory failure (Dellaripa 2021; Targoff 2021).
IV: 500 to 750 mg/m2 every 4 weeks; some experts do not exceed 1,200 mg/dose (McCune 2021).
Oral: 1.5 to 2 mg/kg/day; some experts do not exceed 200 mg/day (Marie 2011; McCune 2021).
Duration of therapy: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Dellaripa 2021).
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (off-label use):
Note: For use in combination with glucocorticoids to initiate disease remission in patients with severe, multiorgan disease or severe cardiovascular or CNS involvement (ACR/VF [Chung 2021]; EULAR [Mukhtyar 2009]; King 2021).
IV: 600 mg/m2 once every month (Cohen 2007; Gayraud 1997; Guillevin 1995); some experts do not exceed 1,200 mg/dose (McCune 2021).
Oral: 2 mg/kg once daily (maximum: 200 mg/day) (EULAR [Mukhtyar 2009]; Gayraud 1997; Guillevin 1991).
Duration of therapy: Continue therapy for 6 to 12 months, then transition to an alternative immunosuppressive agent to maintain remission (Cohen 2007; EULAR [Mukhtyar 2009]; Guillevin 1991; King 2021).
Ewing sarcoma (off-label use): VAC/IE regimen: VAC: IV: 1,200 mg/m2 (plus mesna) on day 1 of a 21-day treatment cycle (in combination with vincristine and doxorubicin [then dactinomycin when maximum doxorubicin dose reached]), alternates with IE (ifosfamide and etoposide) for a total of 17 cycles (Grier 2003).
Gestational trophoblastic tumors, 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, dactinomycin, and vincristine), continue for at least 2 treatment cycles after a normal hCG level (Escobar 2003; Lurain 2006).
Graft-vs-host disease, acute and chronic, prophylaxis (off-label use): IV: 50 mg/kg on days +3 and +4 following allogeneic blood or marrow transplantation (in combination with mesna) (Kanakry 2014a; Kanakry 2014b; Luzkin 2010).
Granulomatosis with polyangiitis and microscopic polyangiitis, organ- or life-threatening (off-label use):
IV: 15 mg/kg (maximum: 1,200 mg) once every 2 weeks for 3 doses, followed by 15 mg/kg (maximum: 1,200 mg) once every 3 weeks for 3 to 6 months. Use in combination with glucocorticoids (de Groot 2009; Harper 2012).
Oral: 1.5 to 2 mg/kg/day (maximum: 200 mg/day) in combination with glucocorticoids until remission is induced (usually within 3 to 6 months) (de Groot 2009; Jayne 2003; Stone 2010).
Duration of therapy: Transition to an alternative immunosuppressive agent to maintain remission; consider alternative induction therapy if remission is not attained after 3 to 6 months of cyclophosphamide therapy (ACR/VF [Chung 2021]; EULAR [Mukhtyar 2009]; Falk 2021a).
Hematopoietic stem cell or marrow transplant (off-label use):
Conditioning regimens:
Nonmyeloablative transplant (allogeneic): IV: 750 mg/m2/day for 3 days beginning 5 days prior to transplant (in combination with fludarabine) (Khouri 2008).
Myeloablative transplant: IV:
100 mg/kg (based on ideal body weight [IBW], unless actual weight <95% of IBW) as a single dose 2 days prior to transplant (in combination with total body irradiation and etoposide) (Thompson 2008).
50 mg/kg/day for 4 days beginning 5 days before transplant (with or without antithymocyte globulin [equine]) (Champlin 2007).
50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with busulfan) (Cassileth 1993; Cassileth 1998).
60 mg/kg/day for 2 days (in combination with busulfan and total body irradiation) (Anderson 1996).
60 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with busulfan) (Tutschka 1987).
1,800 mg/m2/day for 4 days beginning 7 days prior to transplant (in combination with etoposide and carmustine) (Reece 1991).
Reduced-intensity conditioning regimens: IV:
30 mg/kg/day for 2 days beginning 4 days prior to transplant (in combination with thiotepa and fludarabine) (Corradini 2002).
50 mg/kg/day for 4 days beginning 5 days prior to transplant (in combination with antithymocyte globulin [equine]) (Storb 1997).
Hematopoietic stem cell mobilization: IV: 1,500 mg/m2/day to 2,000 mg/m2/day for 2 days on days 1 and 2 (in combination with mesna and G-CSF [filgrastim]) (Hamadani 2012).
Hodgkin lymphoma (off-label dosing):
BEACOPP regimen: IV: 650 mg/m2 on day 1 every 3 weeks (in combination with bleomycin, etoposide, doxorubicin, vincristine, procarbazine, and prednisone) for 8 cycles (Diehl 2003).
BEACOPP escalated regimen: IV: 1,200 mg/m2 on day 1 every 3 weeks (in combination with bleomycin, etoposide, doxorubicin, vincristine, procarbazine, and prednisone) for 8 cycles (Diehl 2003).
Interstitial pneumonia, nonspecific, refractory or rapidly progressive (off-label use):
IV (preferred route): 600 mg/m2 once every month (Corte 2009); some experts do not exceed 1,200 mg/dose (McCune 2021). Use in combination with glucocorticoids (Corte 2009; Flaherty 2022; McCune 2021).
Oral: 1 to 2 mg/kg once daily; some experts do not exceed 200 mg/day. Use in combination with glucocorticoids (Kondoh 2005; McCune 2021).
Duration of therapy: Continue therapy for at least 3 to 6 months to determine efficacy; discontinue therapy or transition to an alternative immunosuppressive agent after 6 to 12 months (Corte 2009; Flaherty 2022; Kondoh 2005).
Lupus nephritis, focal or diffuse (off-label use):
IV (shorter, low-dose regimen; preferred regimen): 500 mg once every 2 weeks for 6 doses, then transition to an alternative immunosuppressive agent (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]).
IV (longer, high-dose regimen): 500 to 1,000 mg/m2 once every month for 6 doses, then transition to an alternative immunosuppressive agent; some experts do not exceed 1,000 mg/dose (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]; Falk 2021b).
Oral: Initial: 1 to 1.5 mg/kg once daily; some experts increase by 0.5 mg/kg/day every week up to 2 mg/kg once daily if needed based on response, and do not exceed 150 mg/day (Almaani 2017; Falk 2021b). Continue therapy for 2 to 4 months once the dose is stabilized, then transition to an alternative immunosuppressive agent (Almaani 2017).
Lymphodepleting therapy prior to chimeric antigen receptor T-cell immunotherapy (off-label use):
Prior to axicabtagene ciloleucel: IV: 500 mg/m2/day for 3 days (in combination with fludarabine) beginning 5 days (on days −5, −4, and −3) prior to chimeric antigen receptor (CAR) T-cell infusion on day 0 (Locke 2019; Neelapu 2017).
Prior to brexucabtagene autoleucel: IV: 500 mg/m2/day for 3 days (in combination with fludarabine; for relapsed/refractory mantle cell lymphoma) beginning 5 days (on days −5, −4, and −3) prior to CAR T-cell infusion on day 0 (Wang 2020) or 900 mg/m2 once beginning 2 days (on day −2) prior to CAR T-cell infusion on day 0 (in combination with fludarabine; for relapsed/refractory B-cell precursor acute lymphoblastic leukemia) (Shah 2021).
Prior to idecabtagene vicleucel: IV: 300 mg/m2/day for 3 days (in combination with fludarabine) beginning 5 days (on days -5, -4, and -3) prior to CAR T-cell infusion on day 0 (Munshi 2021).
Prior to lisocabtagene maraleucel: IV: 300 mg/m2/day for 3 days (in combination with fludarabine) followed 2 to 7 days later by CAR T-cell infusion (Abramson 2020).
Prior to tisagenlecleucel : IV: 250 mg/m2/day for 3 days (in combination with fludarabine; for relapsed/refractory diffuse large B-cell lymphoma) followed 2 to 11 days later by CAR T-cell infusion (Schuster 2019) or 500 mg/m2/day for 2 days (in combination with fludarabine; for relapsed/refractory B-cell acute lymphoblastic leukemia) followed 2 to 14 days later by CAR T-cell infusion (Maude 2018).
Membranous nephropathy (off-label use):
Note: For use in combination with glucocorticoids to initiate disease remission in patients at high or very high risk of disease progression, regardless of the presence of lupus (KDIGO [Floege 2019]). Some experts also use cyclophosphamide (in combination with glucocorticoids) as an alternative to other immunosuppressive therapies in patients at moderate risk of disease progression (De Vriese 2021).
Oral, cyclical (preferred): 2 mg/kg once daily during months 2, 4, and 6 (alternating with glucocorticoid therapy during months 1, 3, and 5) (Fernández-Juárez 2021; Jha 2007); some experts do not exceed 200 mg/day (De Vriese 2021).
Oral, continuous: 1.5 to 2 mg/kg once daily for 12 months (du Buf-Vereijken 2004); some experts do not exceed 200 mg/day, and also limit the total cumulative dose to 25 g to reduce the risk of malignancy (De Vriese 2021).
Merkel cell carcinoma, advanced or recurrent (off-label use; based on limited data): IV: CAV regimen: 1,000 mg/m2 on day 1 every 21 days (in combination with doxorubicin and vincristine) (Fenig 1997).
Minimal change disease (off-label use):
Note: For use in patients with frequently relapsing or glucocorticoid-dependent disease, regardless of the presence of lupus nephritis. Initiate cyclophosphamide after remission is induced by glucocorticoids (KDIGO [Rovin 2019]).
Oral: 2 to 2.5 mg/kg once daily (Mak 1996; Ponticelli 1993); some experts continue therapy for 12 weeks, and do not exceed 200 mg/day (Meyrier 2021; Waldman 2007). Gradually taper and discontinue glucocorticoids during cyclophosphamide therapy (Mak 1996; Ponticelli 1993). Note: Avoid prolonged (>12 weeks) or repeat courses of cyclophosphamide to reduce the risk of adverse effects (Meyrier 2021).
Mixed cryoglobulinemia syndrome, moderate to severe (alternative agent) (off-label use):
Note: For use as an alternative to rituximab, in combination with glucocorticoids, to induce disease remission (Fervenza 2021).
IV: 750 mg/m2 once every month for 3 months (Cakir 2005; Fervenza 2021); some experts do not exceed 1,200 mg/dose (McCune 2021).
Oral: 2 mg/kg once daily for 2 to 4 months (Frankel 1992; KDIGO 2012); some experts do not exceed 200 mg/day (McCune 2021).
Multiple myeloma (off-label dosing):
CyBorD regimen: Oral: 300 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (in combination with bortezomib and dexamethasone) for 4 cycles; may continue beyond 4 cycles (Khan 2012) or 500 mg/m2 on days 1, 8, and 15 every 3 weeks (in combination with bortezomib and dexamethasone) for 8 cycles (Kumar 2012a).
VDT-PACE regimen: IV: 400 mg/m2/day administered as a continuous infusion on days 1 to 4 of each cycle; repeat every 4 to 6 weeks (in combination with bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, and etoposide) (Lee 2003; Pineda-Roman 2008).
Non-Hodgkin lymphomas (off-label dosing):
Burkitt lymphoma:
CALGB 10002 regimen (cycles 1, 3, 5, and 7): IV: 200 mg/m2/day on days 1 to 5 every 3 weeks (in combination with vincristine, prednisone, ifosfamide, dexamethasone, methotrexate, leucovorin, cytarabine, etoposide, rituximab, doxorubicin, intrathecal therapy, and filgrastim); refer to protocol for further information (Rizzieri 2014).
CODOX-M/IVAC: Cycles 1 and 3 (CODOX-M): IV: 800 mg/m2 on day 1, followed by 200 mg/m2/day on days 2 to 5 (Magrath 1996) or 800 mg/m2/day on days 1 and 2 (Lacasce 2004), in combination with vincristine, doxorubicin, and methotrexate; CODOX-M alternates with IVAC (etoposide, ifosfamide, mesna, and cytarabine) for a total of 4 cycles.
R-Hyper-CVAD: IV: 300 mg/m2 every 12 hours on days 1 to 3 (total of 6 doses) of courses 1, 3, 5, and 7 (in combination with rituximab, mesna, vincristine, doxorubicin, and dexamethasone) and alternates with even courses 2, 4, 6, and 8 (rituximab, methotrexate and cytarabine) (Thomas 2006).
Diffuse large B-cell lymphoma:
CHOP/R-CHOP regimen: IV: 750 mg/m2 on day 1 every 3 weeks (in combination with rituximab, doxorubicin, vincristine, and prednisone) for 8 cycles (Coiffier 2002).
Dose-adjusted EPOCH/EPOCH-R regimen: IV: 750 mg/m2 on day 5 every 3 weeks (in combination with rituximab, etoposide, prednisone, vincristine, and doxorubicin) for 6 to 8 cycles (Garcia-Suarez 2007). Refer to protocol for dosage adjustments.
R-CEOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle for 3 to 6 cycles (in combination with rituximab, vincristine, etoposide, and prednisone) (Moccia 2009).
Follicular lymphoma:
CVP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine and prednisone [± rituximab or obinutuzumab]) for 8 cycles (Marcus 2005; Marcus 2017).
R-CHOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle for 6 to 8 cycles (in combination with rituximab, vincristine, doxorubicin, and prednisone) (Hiddemann 2005).
Peripheral T-cell lymphoma:
BV-CHP (or A-CHP) regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with brentuximab vedotin, doxorubicin, and prednisone) for 6 to 8 cycles (Horwitz 2019).
CHOEP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine, doxorubicin, etoposide, and prednisone) for 6 to 8 cycles (Pfreundschuh 2004; Schmitz 2010).
CHOP regimen: IV: 750 mg/m2 on day 1 of a 21-day treatment cycle (in combination with vincristine, doxorubicin, and prednisone) for 6 to 8 cycles (Schmitz 2010).
Primary mediastinal B-cell lymphoma: DA-EPOCH-R regimen: IV: 750 mg/m2 as a 2-hour infusion on day 5, dose-adjusted for subsequent cycles based on neutrophil and platelet counts during nadir (in combination with etoposide, prednisone, vincristine, doxorubicin, rituximab, and filgrastim); repeat cycle every 3 weeks for a total of 6 to 8 cycles (Dunleavy 2013). Refer to protocol for dosage adjustments.
Other non- Hodgkin lymphoma regimens:
CEPP(B) regimen: IV: Initial: 600 mg/m2 on days 1 and 8; may increase dose with subsequent cycles (refer to protocol for details) every 28 days (in combination with etoposide, procarbazine, prednisone, ± bleomycin) (Chao 1990).
PEP-C regimen: Oral: 50 mg (flat dose) once daily after lunch (length of induction cycle depends on blood counts; frequency may vary based on tolerance in maintenance cycle [refer to protocol for details]; in combination with prednisone, etoposide, and procarbazine) (Coleman 2008).
Osteosarcoma, relapsed/refractory (off-label use): IV: 500 mg/m2/day on days 1 to 5 every 21 to 28 days (in combination with mesna, etoposide, and growth factor support) (Rodriguez-Galindo 2002) or 4,000 mg/m2 as a 3-hour infusion on day 1 (in combination with mesna and etoposide) every 21 to 28 days for 2 cycles; refer to protocol for further information (Berger 2009).
Ovarian germ cell tumors, malignant (off-label use): IV: 150 mg/m2 on days 1 to 5 every 28 days (in combination with dactinomycin and vincristine) for at least 10 cycles (Slayton 1985).
Pheochromocytoma, malignant (off-label use): IV: 750 mg/m2 on day 1 every 3 or 4 weeks (in combination with dacarbazine and vincristine) (Huang 2008).
Polyarteritis nodosa, moderate to severe (off-label use):
Note: Some experts prefer the regimen identified as “preferred” below based on clinical experience and data in patients with antineutrophil cytoplasmic antibody-associated vasculitis; this regimen has not been studied in polyarteritis nodosa (Merkel 2021a).
IV (preferred regimen): 15 mg/kg (maximum: 1,200 mg) once every 2 weeks for 3 doses, followed by 15 mg/kg (maximum: 1,200 mg) once every 3 weeks for 3 to 6 months (in combination with glucocorticoids) (de Groot 2009; Harper 2012; Merkel 2021a).
IV: 600 mg/m2 once every 2 weeks for 3 doses, then once every 4 weeks thereafter (in combination with glucocorticoids) (Gayraud 1997; Guillevin 1995); some experts do not exceed 1,200 mg/dose (McCune 2021).
Oral: 2 mg/kg once daily in combination with glucocorticoids (Gayraud 1997; Guillevin 1991); some experts do not exceed 200 mg/day (McCune 2021).
Duration of therapy : Continue therapy for ≥4 months and until disease remission is achieved (maximum duration: 6 months); some experts limit duration to 4 months if remission is achieved by then. Once remission is achieved, transition to an alternative immunosuppressive agent to maintain remission (EULAR [Mukhtyar 2009]; Guillevin 1991; Guillevin 1995; Merkel 2021a).
Primary CNS lymphoma (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 cyclophosphamide), followed by autologous stem cell transplant (DeFilipp 2017; Soussain 2001; Soussain 2008).
Pure red cell aplasia (off-label use):
Note: For use in patients with acquired pure red cell aplasia (PRCA) that is not self-limiting and is refractory to other preferred agents, or as initial therapy in patients with PRCA due to anti-erythropoiesis-stimulating agent antibodies (Berns 2021; Means 2021).
Oral: 50 to 100 mg once daily (in combination with glucocorticoids); initial improvement may be observed after as early as 8 weeks, and complete response after a median of 3 to 6 months (Bennett 2005; Verhelst 2004; Yamada 1997).
Duration of therapy:
Acquired PRCA: Continue therapy for up to 6 months, then transition to an alternative immunosuppressive agent to maintain remission (Sawada 2008).
PRCA due to anti-erythropoiesis-stimulating agent antibodies: Continue treatment until antibody levels become undetectable; switch to alternative therapy if there is no response within 3 to 4 months of treatment initiation (Berns 2021).
Rhabdomyosarcoma (off-label use): Adults <50 years: VAC regimen:
Low risk: IV: 1,200 mg/m2 every 21 days (in combination with mesna, vincristine, and dactinomycin) for 4 cycles (Walterhouse 2014).
Intermediate risk: IV: 2,200 mg/m2 every 21 days (in combination with mesna, vincristine, and dactinomycin) for 14 cycles (Arndt 2009).
Small cell lung cancer, refractory (off-label use): IV: 1,000 mg/m2 (maximum: 2,000 mg) on day 1 every 3 weeks (in combination with doxorubicin and vincristine) until disease progression or unacceptable toxicity (von Pawel 1999).
Systemic light chain amyloidosis (off-label use):
CRd regimens: IV or Oral: 300 mg/m2 orally on days 1, 8, and 15 of a 28-day cycle (in combination with lenalidomide and dexamethasone); cyclophosphamide was administered for a maximum of 12 cycles; refer to protocol for further information (Kumar 2012b) or 300 mg/m2 IV on days 1 and 8 every 28 days (in combination with lenalidomide and dexamethasone) for 6 cycles, followed by 300 mg/m2 IV on day 1 only every 28 days (in combination with lenalidomide and dexamethasone) for 6 additional cycles (Cibeira 2015).
CyBorD regimen: Oral: 300 mg/m2 once weekly (in combination with bortezomib and dexamethasone) (Mikhael 2012; Palladini 2015) or 350 mg/m2 on days 1, 8, and 15 (in combination with bortezomib and dexamethasone) for up to 8 cycles (Venner 2012).
Systemic sclerosis–related interstitial lung disease (alternative agent) (off-label use):
Note: For use in patients with features suggesting high risk for progression (eg, declining pulmonary function) or with symptomatic interstitial lung disease. Generally administered in combination with low-dose glucocorticoids (Varga 2021).
IV (preferred route): 600 mg/m2 once every 4 weeks; some experts do not exceed 1,200 mg/dose (Hoyles 2006; McCune 2021).
Oral: Initial: 1 mg/kg/day (rounded to the nearest 25 mg); may increase daily dose based on response and tolerability by 25 mg once monthly up to 2 mg/kg/day; some experts do not exceed 200 mg/day (Tashkin 2006; McCune 2021), or 50 to 100 mg daily initially (50 mg daily for patients weighing <81 kg and 100 mg daily for patients weighing ≥81 kg), followed by increases in 25 to 50 mg increments each month up to 2 mg/kg/day (maximum: 200 mg/day) (Tashkin 2016).
Duration of therapy: Limit duration of IV therapy to 6 months or oral therapy to 12 months, then transition to an alternative immunosuppressive agent (Tashkin 2006; Tashkin 2016; Varga 2021; Hoyles 2006).
Thymomas, advanced or metastatic (off-label use):
ADOC regimen: IV: 700 mg/m2 on day 4 every 3 weeks (in combination with doxorubicin, cisplatin, and vincristine) (Fornasiero 1991).
CAP regimen: IV: 500 mg/m2 on day 1 every 3 weeks for up to 8 cycles (in combination with cisplatin and doxorubicin) (Loehrer 1994).
Waldenström macroglobulinemia (off-label use):
DRC regimen: Oral: 100 mg/m2 twice daily on days 1 to 5 every 21 days (in combination with dexamethasone and rituximab) for 6 cycles (Dimopoulos 2007).
FCR regimen: IV: 250 mg/m2 once daily on days 2 to 4 every 28 days (in combination with fludarabine and rituximab) for up to 6 cycles (Tedeschi 2012).
Warm autoimmune hemolytic anemia, relapsed or refractory (alternative agent) (off-label use):
Low-dose therapy:
Oral: 1 to 2 mg/kg once daily (maximum dose is not established) or 50 to 150 mg once daily, with or without concomitant glucocorticoids; response typically achieved within 2 to 4 weeks (Go 2017; Salama 2015).
High-dose therapy:
Note: Generally reserved for patients with refractory disease or severe anemia due to greater potential for toxicity (Salama 2015).
IV: 1,000 mg once every 4 weeks for 4 doses (Go 2017; Thabet 2014).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Specific recommendations for kidney dose adjustment have not been established. A dose-effect relationship is difficult to determine due to interpatient variability in pharmacokinetics and pharmacodynamics, and the complex metabolism and precise mechanism of action are not completely understood (Haubitz 2002).
The following general and indication-specific dosage adjustments have been recommended. Use with caution, especially with more severe impairment; consider indication, goals of therapy, and risks versus benefits when selecting a dose, and monitor for signs and symptoms of toxicity; also refer to institution-specific protocols (when available):
General dosage adjustment recommendations: IV, Oral:
Altered kidney function:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 29 mL/minute: Administer 75% (Krens 2019) or 100% (Aronoff 2007; Kintzel 1995) of normal dose.
CrCl <10 mL/minute: Administer 50% (Krens 2019), 75% (Aronoff 2007), or 100% (Kintzel 1995) of normal dose.
Hemodialysis, intermittent (thrice weekly): Moderately dialyzable (20% to 50% removal based on limited data with low-flux dialyzers [Haubitz 2002; Nemecek 2019; Wang 1981]).
Administer 50% (Krens 2019) or 75% (Janus 2010; Pedrazzoli 2017) of the normal dose. On dialysis days, administer after hemodialysis, allowing at least 12 hours before the next hemodialysis session (Haubitz 2002).
Peritoneal dialysis: Administer 75% of the normal dose (Aronoff 2007). If possible, allow at least 12 hours before next peritoneal dialysis exchange (expert opinion).
CRRT: Administer 100% of the normal dose (Aronoff 2007).
Indication-specific dosage adjustments:
Granulomatosis with polyangiitis or microscopic polyangiitis:
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 (Bodge 2014). Refer to "General Dosage Adjustment Recommendations" for patients with kidney impairment.
Lupus nephritis:
IV: Shorter, low-dose regimen (500 mg IV once every 2 weeks for 6 doses): No dosage adjustment necessary (ACCESS Trial 2014; Euro-Lupus Nephritis Trial [Houssiau 2002]).
IV: Longer, high-dose regimen (500 to 1,000 mg/m2 IV pulses):
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Reduce initial dose to 500 mg/m2 (Austin 1986; Gourley 1996).
Oral regimen: Refer to “General Dosage Adjustment Recommendations” for patients with kidney impairment.
Multiple myeloma: Oral:
Mild to severe impairment: No dosage adjustment necessary (IMWG [Dimopoulos 2016]).
Hemodialysis: No dosage adjustment necessary (IMWG [Dimopoulos 2016]).
The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy. Some dosage forms may contain ethanol; consider alcohol content of the product when administering to patients with hepatic impairment.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adjustments have been recommended:
Floyd 2006:
Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.
Serum bilirubin >5 mg/dL: Avoid use.
Krens 2019:
Mild or moderate impairment: Dosage adjustment is not likely needed.
Severe impairment: Use is not recommended due to risk of reduced efficacy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Generic: 25 mg, 50 mg
Solution, Intravenous:
Generic: 500 mg/2.5 mL (2.5 mL); 1 g/5 mL (5 mL); 2 g/10 mL (10 mL)
Solution Reconstituted, Injection:
Generic: 500 mg (1 ea [DSC]); 1 g (1 ea [DSC]); 2 g (1 ea [DSC])
Solution Reconstituted, Injection [preservative free]:
Generic: 500 mg (1 ea); 1 g (1 ea); 2 g (1 ea)
Tablet, Oral:
Generic: 25 mg, 50 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Procytox: 200 mg (1 ea); 500 mg (1 ea); 1 g (50 mL); 2 g (100 mL)
Tablet, Oral:
Procytox: 25 mg, 50 mg
Antiemetics may be recommended to prevent nausea and vomiting; doses ≥1,200 mg/m2 IV are associated with a high emetic potential and doses of 1,000 mg/m2 IV are associated with a moderate emetic risk (POGO [Dupuis 2011]; POGO [Paw Cho Sing 2019]).
Oral: Capsules and tablets should be swallowed whole. Tablets are not scored and should not be cut, crushed, or chewed. Capsules should not be opened, crushed, or chewed. Wear gloves when handling capsules/tablets and container; avoid exposure to broken capsules. If exposure to capsule contents or crushed/cut tablets, wash hands immediately and thoroughly. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer tablets/capsules at bedtime.
Parenteral:
IV push: May administer reconstituted solution without further dilution (20 mg/mL); rate may vary based on protocols (refer to specific protocols)
IV infusion (intermittent or continuous): Infusion rate may vary based on protocol (refer to specific protocol for infusion rate); usually over 15 to 60 minutes; larger doses (>1,800 mg/m2) have been infused over 1 to 6 hours by some centers and protocols
Bladder toxicity: To minimize bladder toxicity, increase normal fluid intake during and for 1 to 2 days after cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day and in pediatric patients twice maintenance (3 L/m2/day). High-dose regimens and depending upon the protocol some standard (low) cyclophosphamide doses should be accompanied by vigorous hydration with mesna therapy (refer to specific protocols and Mesna monograph for additional information). Morning administration may be preferred to ensure adequate hydration throughout the day.
Cyclophosphamide is associated with a moderate or high emetic potential (depending on dose, regimen, or administration route); antiemetics may be recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; MASCC [Roila 2016]).
IV: Infusion rate may vary based on protocol (refer to specific protocol for infusion rate). Administer by direct IV injection, IVPB, or continuous IV infusion. Refer to product labeling for specific information regarding reconstitution and dilution.
Bladder toxicity: To minimize bladder toxicity, increase normal fluid intake during and for 1 to 2 days after cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day. High-dose regimens should be accompanied by vigorous hydration with or without mesna therapy. Morning administration may be preferred to ensure adequate hydration throughout the day.
Hematopoietic stem cell transplant (off-label use): Approaches to reduction of hemorrhagic cystitis include infusion of 0.9% NaCl 3 L/m2/24 hours, infusion of 0.9% NaCl 3 L/m2/24 hours with continuous 0.9% NaCl bladder irrigation 300 to 1000 mL/hour, and infusion of 0.9% NaCl 1.5 to 3 L/m2/24 hours with intravenous mesna. Hydration should begin at least 4 hours before cyclophosphamide and continue at least 24 hours after completion of cyclophosphamide. The daily mesna dose (as a percentage of cyclophosphamide dose) may vary; refer to protocol and/or primary literature for mesna dose. Mesna can be administered as a continuous 24-hour intravenous infusion or be given in divided doses every 4 hours. Mesna should begin at the start of treatment, and continue at least 24 hours following the last dose of cyclophosphamide.
Oral: Swallow whole; do not crush or chew; do not open capsules. To minimize bladder toxicity, increase normal fluid intake. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer at bedtime. Avoid exposure to broken capsules and tablets; if contact occurs, wash hands immediately and thoroughly.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Injection: Storage time may vary by product; refer to individual product labeling for details. Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.
Powder for reconstitution: Store intact vials of powder at ≤25°C (77°F). Exposure to excessive temperatures during transport or storage may cause active ingredient to melt (vials with melting may have a clear to yellow viscous liquid which may appear as droplets); do not use vials with signs of melting. Solutions reconstituted in sterile water for injection should be further diluted immediately. According to the manufacturer, reconstituted solutions in NS are stable for 24 hours at room temperature and for 6 days refrigerated at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion in 1/2NS are stable for 24 hours at room temperature and for 6 days refrigerated and solutions diluted in D5W or D5NS are stable for 24 hours at room temperature and for 36 hours refrigerated (according to product labeling).
Multi-dose solution: Store intact vials at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion (20 mg/mL or 2 mg/mL concentration) may be stored for up to 24 hours at room temperature or for up to 6 days at 2°C to 8°C (36°F to 46°F). After first use, partially used vials should be stored at 2°C to 8°C (36°F to 46°F) in the original carton and used within 28 days.
Single-dose solution: Store intact vials at 2°C to 8°C (36°F to 46°F). Vials diluted with SWFI may be stored at room temperature or in the refrigerator for up to 24 hours. Infusion solutions diluted in ½NS are stable for up to 24 hours at room temperature or for up to 6 days refrigerated. Infusion solutions diluted in D5W or D5NS are stable for up to 24 hours at room temperature or for up to 36 hours refrigerated.
Oral:
Capsules, tablets: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Oncologic uses: Treatment of Hodgkin lymphoma, non-Hodgkin lymphomas (including Burkitt lymphoma), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphocytic leukemia (ALL), mycosis fungoides, multiple myeloma, neuroblastoma, retinoblastoma, breast cancer, ovarian adenocarcinoma [Oral, parenteral: All indications: FDA approved in pediatric patients (age not specified) and adults]; has also been used for Ewing sarcoma, rhabdomyosarcoma, Wilms tumor, ovarian germ cell tumors, small cell lung cancer, testicular cancer, pheochromocytoma, CNS tumors, and in hematopoietic stem cell transplant (HSCT) conditioning regimens
Nononcologic uses: Treatment of minimal change nephrotic syndrome [Oral: FDA approved in pediatric patients (age not specified)]; has also been used for treatment of aplastic anemia, lupus nephritis, uveitis, vasculitis (ANCA positive, eg, granulomatosis with polyangiitis [GPA]; Wegener granulomatosis) and Kawasaki Disease refractory to IVIG
Cyclophosphamide may be confused with cycloSPORINE, ifosfamide
Cytoxan may be confused with cefOXitin, Ciloxan, cytarabine, CytoGam, Cytosar, Cytosar-U, Cytotec
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined.
Cardiovascular: Acute myocardial infarction, atrial fibrillation, atrial flutter, bradycardia, cardiac failure, cardiac tamponade, cardiogenic shock, cardiomyopathy, chest pain, edema, flushing, hemorrhagic myocarditis, hypertension, hypotension, myocarditis, palpitations, pericardial effusion, pericarditis, peripheral ischemia, prolonged QT interval on ECG, pulmonary embolism, supraventricular cardiac arrhythmia, tachycardia, vasculitis, venous thrombosis, ventricular arrhythmia, ventricular fibrillation, ventricular tachyarrhythmia
Dermatologic: Alopecia, changes in nails, dermatitis, erythema multiforme, erythema of skin, facial swelling, hyperhidrosis, palmar-plantar erythrodysesthesia, pruritus, skin abnormalities related to radiation recall, skin blister, skin rash, skin toxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Amenorrhea, decreased serum glucose, fluid retention, hot flash, hyponatremia,, increased lactate dehydrogenase, increased serum glucose, infrequent uterine bleeding, nephrogenic diabetes insipidus, ovarian failure, 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 disease (necrosis, contracture, or atypical epithelial cells), cystitis (ulcerative), defective oogenesis, defective spermatogenesis, hematuria, hemorrhagic cystitis, infertility, oligospermia, ovarian fibrosis, premature labor, pyelitis, testicular atrophy, toxic nephrosis, ureteral disease (ureteritis)
Hematologic & oncologic: Anemia, bladder carcinoma, bone marrow depression (including bone marrow failure), C-reactive protein increased, disseminated intravascular coagulation, febrile neutropenia, hemolytic-uremic syndrome, hemorrhagic ureteritis, leukopenia, myelodysplastic syndrome, neutropenia, pulmonary hemorrhage, renal cell carcinoma, secondary primary malignant neoplasm (including acute leukemia, malignant lymphoma, malignant neoplasm of thyroid, malignant neoplasm of urinary tract [pelvic, renal, and ureteric], myelatelia, sarcoma), thrombocytopenia, thrombotic microangiopathy
Hepatic: Abnormal liver function, ascites, cholestatic hepatitis, hepatic encephalopathy, hepatic failure, hepatic sinusoidal obstruction syndrome, hepatitis (including cytolytic hepatitis), hepatomegaly, hepatotoxicity, increased liver enzymes, increased serum bilirubin, jaundice
Hypersensitivity: Anaphylactic shock, anaphylaxis, hypersensitivity reaction
Immunologic: Immunosuppression
Infection: Cytomegalovirus disease (Goldsmith 2021), infection (including reactivation of latent infection)
Local: Infusion site reaction (including erythema, inflammation, necrosis, pain, phlebitis, swelling, and thrombosis), injection site reaction (including erythema at injection site, inflammation at injection site, injection site phlebitis, pain at injection site, swelling at injection site, tissue necrosis at injection site, venous thrombosis at injection site)
Nervous system: Altered sense of smell, chills, confusion, dizziness, dysesthesia, encephalopathy, fatigue, headache, hypoesthesia, malaise, neuralgia, neurotoxicity, pain, paresthesia, peripheral neuropathy, polyneuropathy, reversible posterior leukoencephalopathy syndrome, seizure
Neuromuscular & skeletal: Arthralgia, asthenia, muscle spasm, myalgia, myelopathy, rhabdomyolysis, systemic sclerosis, tremor
Ophthalmic: Conjunctivitis, lacrimation, visual impairment
Otic: Auditory impairment, deafness, tinnitus
Renal: Renal failure syndrome, renal insufficiency, renal tubular disease
Respiratory: Acute respiratory distress syndrome, 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]), pulmonary edema, pulmonary fibrosis, pulmonary hypertension, pulmonary veno-occlusive disease, respiratory distress, respiratory failure, 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:
• Bone marrow suppression: Leukopenia, neutropenia, thrombocytopenia, and anemia may commonly occur; may be dose related. Bone marrow failure has been reported. Bone marrow failure and severe immunosuppression may lead to serious (and fatal) infections, including sepsis and septic shock, or may reactive latent infections. Antimicrobial prophylaxis may be considered in appropriate patients. Platelet and neutrophil nadirs are usually at weeks 1 and 2 of treatment and recovery is expected after ~20 days. Severe myelosuppression may be more prevalent in heavily pretreated patients or in patients receiving concomitant chemotherapy and/or radiation therapy.
• Cardiotoxicity: Cardiotoxicity has been reported (some fatal), usually with high doses associated with transplant conditioning regimens, although may rarely occur with lower doses. Cardiac abnormalities do not appear to persist. Cardiotoxicities reported have included arrhythmias (supraventricular and ventricular [some with QT prolongation]), congestive heart failure, heart block, hemopericardium (secondary to hemorrhagic myocarditis and myocardial necrosis), myocarditis (including hemorrhagic), pericarditis, pericardial effusion including cardiac tamponade, and tachyarrhythmias. Cardiotoxicity may be related to endothelial capillary damage (Floyd 2005). The risk for cardiotoxicity may be increased with higher doses, advanced age, prior radiation to the cardiac region, and in patients who have received prior or concurrent cardiotoxic medication. Use with caution in patients with preexisting cardiovascular disease or those at risk for cardiotoxicity. In a scientific statement from the American Heart Association, cyclophosphamide has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).
• Hepatotoxicity: Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease, has been reported in patients receiving chemotherapy regimens containing cyclophosphamide. A major risk factor for SOS is cytoreductive conditioning transplantation regimens with cyclophosphamide used in combination with total body irradiation or busulfan (or other agents). Other risk factors include preexisting hepatic dysfunction, prior radiation to the abdominal area, and low performance status. Children <3 years of age are reported to be at increased risk for hepatic SOS; signs or symptoms of hepatic SOS include bilirubin >1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, or unexplained right upper quadrant pain (Arndt 2004). SOS has also been reported in patients receiving long-term lower doses for immunosuppressive indications.
• Hypersensitivity: Anaphylactic reactions have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents may occur.
• Hyponatremia: Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) has been reported; some have been fatal.
• Immunosuppression: Immunosuppression and serious infections may occur.
• Pulmonary toxicities: Pulmonary toxicities, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. Cyclophosphamide-induced pneumonitis is rare and may present as early (within 1 to 6 months) or late onset (several months to years). Early onset may be reversible with discontinuation; late onset is associated with pleural thickening and may persist chronically (Malik 1996). In addition, late onset pneumonitis (>6 months after therapy initiation) may be associated with increased mortality.
• Secondary malignancies: Secondary malignancies (bladder cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported with both single-agent cyclophosphamide and with combination chemotherapy regimens; onset may be delayed (up to several years after treatment). Bladder cancer usually occurs in patients previously experiencing hemorrhagic cystitis; risk may be reduced by preventing hemorrhagic cystitis.
• Urinary/renal toxicity: Cyclophosphamide is associated with the development of hemorrhagic cystitis, pyelitis, ureteritis, and hematuria. Hemorrhagic cystitis may rarely be severe or fatal. Bladder fibrosis may also occur, either with or without cystitis. Urotoxicity is due to excretion of cyclophosphamide metabolites in the urine and appears to be dose- and treatment duration-dependent, although may occur with short-term use. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases. Exclude or correct any urinary tract obstructions prior to treatment initiation. Use with caution (if at all) in patients with active urinary tract infection.
• Wound healing impairment: Cyclophosphamide may interfere with wound healing.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment. The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy.
• Renal impairment: Use with caution in patients with renal impairment. Decreased renal excretion and increased serum levels (cyclophosphamide and metabolites) may occur in patients with severe renal impairment (CrCl 10 to 24 mL/minute); monitor for signs/symptoms of toxicity. Cyclophosphamide and metabolites are dialyzable; differences in amount dialyzed may occur due to dialysis system used. If dialysis is required, maintain a consistent interval between administration and dialysis.
Dosage form specific issues:
• Cyclophosphamide injection: Some cyclophosphamide injection dosage forms may contain alcohol. The alcohol content (in some dosage forms) may affect the CNS and impair the ability to drive or operate machinery; review available dosage forms for ethanol content in order to select the appropriate product, particularly for patients who should avoid or minimize alcohol intake, including patients with hepatic impairment.
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
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Allopurinol: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, bone marrow suppression. Risk C: Monitor therapy
Amiodarone: Cyclophosphamide may enhance the adverse/toxic effect of Amiodarone. Specifically, the risk of pulmonary toxicity may be enhanced. Risk C: Monitor therapy
Anthracyclines: Cyclophosphamide may enhance the cardiotoxic effect of Anthracyclines. Risk C: Monitor therapy
AzaTHIOprine: May enhance the hepatotoxic effect of Cyclophosphamide. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Bupivacaine: Cyclophosphamide may enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Cyclophosphamide may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: When using IV cyclophosphamide for rheumatic or musculoskeletal disease, administer cyclophosphamide 1 week after each vaccine dose, if possible. Consider a 3rd dose of COVID-19 vaccine in patients 5 years of age and older taking cyclophosphamide. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
CycloSPORINE (Systemic): Cyclophosphamide may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP2B6 Inducers (Moderate): May increase serum concentrations of the active metabolite(s) of Cyclophosphamide. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants, such cytotoxic chemotherapy. If combined, monitor for reduced efficacy of cytotoxic chemotherapy. Risk D: Consider therapy modification
Etanercept: May enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgrastim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Risk C: Monitor therapy
Fluconazole: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, serum bilirubin and serum creatinine may be increased. Fluconazole may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Itraconazole: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, serum creatinine and serum bilirubin may be increased. Itraconazole may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy
Ketoconazole (Systemic): May increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be enhanced. Cyclophosphamide may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of bleomycin infusion. Monitor for enhanced pulmonary toxicity when cyclophosphamide and lenograstim are given in combination. Risk D: Consider therapy modification
Lipegfilgrastim: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the risk of pulmonary toxicity may be increased. Cyclophosphamide may diminish the therapeutic effect of Lipegfilgrastim. Management: Lipegfilgrastim should be administered at least 24 hours after the completion of cyclophosphamide. Consider monitoring for enhanced pulmonary toxicity when cyclophosphamide and lipegfilgrastim are given in combination. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy
MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Mivacurium: Cyclophosphamide may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Pentostatin: May enhance the cardiotoxic effect of Cyclophosphamide. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Protease Inhibitors: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Protease Inhibitors may increase the serum concentration of Cyclophosphamide. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sargramostim: Cyclophosphamide may enhance the adverse/toxic effect of Sargramostim. Specifically, the risk of pulmonary toxicity may be enhanced. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Succinylcholine: Cyclophosphamide may increase the serum concentration of Succinylcholine. Management: Consider alternatives to succinylcholine in patients who have received cyclophosphamide in the past 10 days, or reduced succinylcholine doses (a serum pseudocholinesterase assay may help inform this reduction) with close monitoring. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: May enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Risk C: Monitor therapy
Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Voclosporin: Cyclophosphamide may enhance the adverse/toxic effect of Voclosporin. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Evaluate pregnancy status prior to use in females of reproductive potential.
Females of reproductive potential should use effective contraception while receiving cyclophosphamide and for up to 1 year after completion of cyclophosphamide treatment. Males with female partners who are or may become pregnant should use a condom during and for at least 4 months after cyclophosphamide treatment.
Cyclophosphamide is used off label in the management of lupus nephritis in nonpregnant adults (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020]). Females treated for rheumatic and musculoskeletal diseases should consider discontinuing cyclophosphamide 3 to 6 months prior to attempted pregnancy to allow for disease monitoring and potential change to another immunosuppressant. Cyclophosphamide should also be discontinued 12 weeks prior to attempted conception in males with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Cyclophosphamide may cause ovarian insufficiency in females, and infertility and long-term gonadal damage in males. Dose-related sterility (which may be irreversible) may occur in both males and females. Recommendations are available for fertility preservation of male and female adult patients treated with anticancer agents (ASCO [Oktay 2018]). Recommendations for preserving fertility in females and males treated with cyclophosphamide for autoimmune and systemic inflammatory diseases are available (ACR [Sammaritano 2020]).
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 women with breast cancer as part of some combination chemotherapy regimens; chemotherapy should not be administered during the first trimester, after 35 weeks' gestation, or within 3 weeks of planned delivery (Amant 2010; Loibl 2015; Shachar 2017). Use of regimens containing cyclophosphamide are generally avoided for the treatment of Hodgkin or non-Hodgkin lymphoma in pregnancy. However, use of cyclophosphamide may be considered as part of some regimens to treat patients diagnosed with aggressive non-Hodgkin lymphomas during the second or third trimester (Lishner 2016; Moshe 2017). The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (ESMO [Peccatori 2013]).
Cyclophosphamide is used off label in the management of lupus nephritis in nonpregnant adults (ACR [Hahn 2012]; EULAR/ERA-EDTA [Fanouriakis 2020). In patients with life- or organ-threatening maternal disease, cyclophosphamide may be used in the second or third trimesters only when an alternative therapy is not available (ACR [Sammaritano 2020]).
A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (1-877-635-4499).
CBC with differential and platelet count, BUN, urinalysis, urine specific gravity, urine output, serum electrolytes, serum creatinine, monitor for signs/symptoms of hemorrhagic cystitis or other urinary/renal toxicity, pulmonary, cardiac, and/or hepatic toxicity.
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%)
Renal function impairment: Systemic exposure is increased as renal function declines. The mean (dose-corrected AUC) increased by 38% in patients with moderate renal impairment (CrCl 25 to 50 mL/minute), increased by 64% in patients with severe impairment (CrCl 10 to 24 mL/minute), and by 23% in patients undergoing hemodialysis (CrCl <10 mL/minute), when compared to a control group.
Hepatic function impairment: In patients with severe hepatic impairment, the elimination half-life is prolonged by 64%.
Liquid solutions for oral administration may be prepared by dissolving cyclophosphamide injection in Aromatic Elixir, N.F. Store refrigerated (in glass container) for up to 14 days.
A 10 mg/mL oral suspension may be prepared by reconstituting one 2 g vial for injection with 100 mL of NaCl 0.9%, providing an initial concentration of 20 mg/mL. Mix this solution in a 1:1 ratio with either Simple Syrup, NF or Ora-Plus to obtain a final concentration of 10 mg/mL. Label “shake well” and “refrigerate”. Stable for 56 days refrigerated.
Capsules (Cyclophosphamide Oral)
25 mg (per each): $6.00 - $9.36
50 mg (per each): $8.40 - $17.75
Solution (Cyclophosphamide Intravenous)
1 g/5 mL (per mL): $175.20 - $175.80
2 g/10 mL (per mL): $175.80
500 mg/2.5 mL (per mL): $175.20 - $175.80
Solution (reconstituted) (Cyclophosphamide Injection)
1 g (per each): $444.00 - $879.00
2 g (per each): $888.00 - $1,758.00
500 mg (per each): $222.00 - $439.50
Tablets (Cyclophosphamide Oral)
25 mg (per each): $3.54
50 mg (per each): $5.05
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