Cyclophosphamide

Dosage Forms

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

Capsule, Oral:

Generic: 25 mg, 50 mg

Solution Reconstituted, Injection:

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

Solution Reconstituted, Injection [preservative free]:

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

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Well absorbed

Distribution

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

Metabolism

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

Excretion

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

Time to Peak

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

Half-Life Elimination

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

Protein Binding

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

Use in Specific Populations

Special Populations: Renal Function Impairment

Systemic exposure is increased as renal function declines. The mean (dose-corrected AUC) increased by 38% in patients with moderate renal impairment (CrCl 25 to 50 mL/minute), increased by 64% in patients with severe impairment (CrCl 10 to 24 mL/minute), and by 23% in patients undergoing hemodialysis (CrCl <10 mL/minute), when compared to a control group.

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

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

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

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

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

Use: Off Label

Autoimmune hemolytic anemia (relapsed or refractory)c

Data from a small study suggests cyclophosphamide may be of benefit in the management of severe, refractory autoimmune hemolytic anemia (AIHA) Moyo 2002. Data from another study in which some patients received cyclophosphamide as second-line therapy also suggests it may be of benefit in the management of refractory AIHA Roumier 2015. Clinical experience also suggests the utility of cyclophosphamide for management of relapsed or refractory AIHA Go 2017, Salama 2015.

Ewing sarcomaa

Data from a large randomized trial support the use of cyclophosphamide (as a part of the VAC/IE regimen; vincristine doxorubicin/dactinomycin, and mesna alternating with ifosfamide and etoposide) in the treatment of Ewing sarcoma Grier 2003.

Gestational trophoblastic tumors, high-riskb

Data from a small study (including updated results) support the use of cyclophosphamide (in combination with etoposide, methotrexate, dactinomycin, and vincristine) in the management of high-risk and metastatic gestational trophoblastic tumors Escobar 2003, Lurain 2006.

Granulomatosis with polyangiitis (Wegener granulomatosis)a

Data from four studies support the use of cyclophosphamide (in combination with a corticosteroid) in the treatment of granulomatosis with polyangiitis (GPA) de Groot 2009, Harper 2012, Jayne 2003, Stone 2010.

Hematopoietic stem cell transplant conditioninga

Data from multiple studies support the use of cyclophosphamide as part of a conditioning regimen in myeloablative hematopoietic stem cell transplant Khouri 2008 and in nonmyeloablative hematopoietic stem cell transplant Thompson 2008, Champlin 2007, Cassileth 1993, Anderson 1996, Reece 1991.

Immune thrombocytopenia, refractorycyes

Cyclophosphamide in the management of refractory immune thrombocytopenia (ITP) has been primarily evaluated in noncontrolled settings enrolling a limited number of patients, demonstrating benefit. In some consensus guidelines, cyclophosphamide is recommended as second-line therapy for the management of refractory ITP in adults. Mild to moderate toxicities were reported in ITP patients; however, cases of neoplasms have been associated with cyclophosphamide treatment and sterility after treatment is a safety concern Pamuk 2002, Provan 2010, Reiner 1995.

Lupus nephritisayes

Data from two studies support the use of cyclophosphamide in the management of lupus nephritis Austin 1986, Gourley 1996.

Based on the American College of Rheumatology guidelines for screening, treatment and management of lupus nephritis, cyclophosphamide (in combination with a corticosteroid) is effective and recommended in the management of lupus nephritis in adults Hahn 2012.

Microscopic polyangiitisa

Data from several studies support the use of cyclophosphamide (in combination with a corticosteroid) in the treatment of microscopic polyangiitis de Groot 2009, Harper 2012, Stone 2010.

Ovarian germ cell tumors (malignant)b

Data from a small study support the use of cyclophosphamide (in combination with dactinomycin and vincristine) in the management of malignant ovarian germ cell tumors following optimal surgical debulking Slayton 1985.

Pheochromocytoma (malignant)c

Data from a limited number of patients in a small nonrandomized study suggest that cyclophosphamide (in combination with dacarbazine and vincristine) may be beneficial for the treatment of malignant pheochromocytoma Huang 2008.

Pure red cell aplasia (antibody-induced)c

Data from a retrospective review of erythropoietin-related pure red cell aplasia (PRCA) suggest cyclophosphamide (in combination with prednisone) may be utilized for management of antibody-induced PRCA Bennett 2005. Clinical experience also suggests the utility of cyclophosphamide (in combination with prednisone) in the management of antibody-induced PRCA Verhelst 2004.

Rhabdomyosarcomab

Data from a study which included a small number of adults <50 years of age support the use of cyclophosphamide (in combination with mesna, vincristine, and dactinomycin) for low-risk rhabdomyosarcoma Walterhouse 2014. Data from another study which also included patients <50 years of age support the use of cyclophosphamide (in combination with mesna, vincristine, and dactinomycin) for intermediate-risk rhabdomyosarcoma Arndt 2009.

Small cell lung cancer (refractory)b

Data from a non-inferiority study support the use of cyclophosphamide (in combination with doxorubicin and vincristine) in the management of refractory small cell lung cancer von Pawel 1999.

Uveitisc

Results from retrospective case studies indicate that cyclophosphamide is generally effective in treating uveitis Durrani 2004, Pujari 2010. However, no prospective studies or controlled clinical trials have been performed. Cyclophosphamide has several safety concerns, including GI toxicity and risk of opportunistic infections. An expert review states that cyclophosphamide should be reserved for refractory cases unresponsive to other treatment options Díaz-Llopis 2009.

Waldenström macroglobulinemiabyes

Data from a multicenter phase II study support the use of cyclophosphamide (in combination with dexamethasone and rituximab) for the treatment of symptomatic Waldenström macroglobulinemia Dimopoulos 2007. Data from a small multicenter study supports the use of cyclophosphamide (in combination with fludarabine and rituximab) for the treatment of symptomatic Waldenström macroglobulinemia Tedeschi 2012.

Based on recommendations from the Eighth International Workshop on Waldenström Macroglobulinemia (IWWM), cyclophosphamide (in combination with dexamethasone and rituximab) may be used for the treatment of Waldenström macroglobulinemia.

Contraindications

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

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

Dosage and Administration

Dosing: Adult

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

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

Hyper-CVAD regimen: IV: 300 mg/m² over 3 hours (with mesna) every 12 hours for 6 doses on days 1, 2, and 3 during odd-numbered cycles (cycles 1, 3, 5, 7) of an 8-cycle phase (Kantarjian 2000).

CALGB8811 regimen: IV:

Adults <60 years: 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: 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).

Autoimmune hemolytic anemia, relapsed or refractory (off-label use; based on limited data):

Oral (low-dose therapy): 1 to 2 mg/kg once daily or 50 to 150 mg once daily (Go 2017) or 1 to 2 mg/kg once daily (in combination with corticosteroids); response has been observed within 2 to 4 weeks (Salama 2015).

IV (high-dose therapy): 50 mg/kg/day (based on ideal body weight) on days 1 to 4 (in combination with mesna and G-CSF); RBC transfusion independence occurred at a median of 19 days (Moyo 2002) or 50 mg/kg/day on days 1 to 4 (in combination with mesna and G-CSF) (Go 2017) or 1,000 mg once a week for 4 doses (Go 2017).

Breast cancer (off-label dosing):

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

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

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

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

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

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

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

Pulse: IV: 15 mg/kg (maximum dose: 1,200 mg) every 2 weeks for 3 doses, followed by maintenance pulses of either 15 mg/kg IV (maximum dose: 1,200 mg) every 3 weeks or 2.5 to 5 mg/kg/day orally on days 1, 2, and 3 every 3 weeks for 3 months after remission achieved (de Groot 2009; Harper 2012).

Hematopoietic stem cell transplant conditioning (off-label use): IV:

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

Myeloablative transplant:

100 mg/kg (based on 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).

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

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

Hodgkin lymphoma (off-label dosing): IV:

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

BEACOPP escalated regimen: 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).

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

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

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

Lupus nephritis (off-label use): IV: 500 mg once every 2 weeks for 6 doses or 500 to 1,000 mg/m² once every month for 6 doses (Hahn 2012) or 500 to 1,000 mg/m² every month for 6 months, then every 3 months for a total of at least 2.5 years (Austin 1986; Gourley 1996).

Malignancy: Manufacturer’s labeling: Dosing in the manufacturer’s labeling may not reflect current clinical practice.

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

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

Microscopic polyangiitis (off-label use; in combination with glucocorticoids):

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

Pulse: IV: 15 mg/kg (maximum dose: 1,200 mg) every 2 weeks for 3 doses, followed by maintenance pulses of either 15 mg/kg (maximum dose: 1,200 mg) IV every 3 weeks or 2.5 to 5 mg/kg/day orally on days 1, 2, and 3 every 3 weeks until remission and then for 3 additional months (de Groot 2009; Harper 2012).

Multiple myeloma (off-label dosing): Oral: CyBorD regimen: 300 mg/m² on days 1, 8, 15, and 22 every 4 weeks (in combination with bortezomib and dexamethasone) for 4 cycles; may continue beyond 4 cycles (Khan 2012) or 500 mg/m² on days 1, 8, and 15 every 3 weeks (in combination with bortezomib and dexamethasone) for 8 cycles (Kumar 2012).

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

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

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

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

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

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

Pure red cell aplasia, antibody-induced (off-label use; based on limited data): Oral: 50 to 100 mg daily (in combination with prednisone); hematologic response was observed after a median of 3 months (Bennett 2005).

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

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

Intermediate risk: 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).

Uveitis (off-label use):

Oral: 20 to 100 mg daily (Diaz-Llopis 2009) or 100 to 150 mg daily (Purjari 2010) or 1 to 3 mg/kg/day (Jabs 2000); adjust dose based on response or toxicity. May use IV dosing for more resistant cases (Diaz-Llopis 2009).

IV: 750 to 1,000 mg every 4 weeks (Diaz-Llopis 2009).

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).

Dosing: Geriatric

Refer to adult dosing; adjust for renal clearance.

Dosing: Pediatric

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 (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2013; Roila 2010). 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).

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

Hematologic toxicity: May require dose reduction or treatment interruption.

Hemorrhagic cystitis, severe: Discontinue treatment.

Dosing: Adjustment for Toxicity

Hematologic toxicity: May require dose reduction or treatment interruption

Hemorrhagic cystitis, severe: Discontinue treatment.

Dosing: Obesity

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

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

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

Cy120 (cyclophosphamide total dose of 120 mg/kg): Use either IBW (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)]

Reconstitution

Injection powder for reconstitution: Reconstitute with 25 mL for a 500 mg vial, 50 mL for a 1,000 mg vial, or 100 mL for a 2,000 mg vial to a concentration of 20 mg/mL using NS or SWFI. Solutions reconstituted in SWFI are hypotonic and should not be used for direct IV push administration. May reconstitute with NS or SWFI for solutions that will be further diluted for IV infusion. Swirl gently to mix. For IV infusion (according to the manufacturer), further dilute for infusion in D5W, ¹/₂NS, or D5NS, to a minimum concentration of 2 mg/mL. May also dilute for infusion in NS at concentrations of 0.24 to 20 mg/mL.

Extemporaneously Prepared

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

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

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

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

Administration

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics may be recommended to prevent nausea and vomiting (Hesketh 2017; Paw Cho Sing 2019; Roila 2016).

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

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

Hematopoietic stem cell transplant (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: Tablets are not scored and should not be cut, chewed, or crushed. Swallow capsules whole; do not open, crush, or chew. To minimize bladder toxicity, increase normal fluid intake. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer tablets/capsules at bedtime. Avoid exposure to broken capsules; if contact occurs, wash hands immediately and thoroughly.

Storage

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

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

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

Drug Interactions

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

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

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

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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

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

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

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). 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. Consider therapy modification

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

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

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

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

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

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

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

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

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. Consider therapy modification

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

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

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

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

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

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

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

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

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

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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

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

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

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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

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

Adverse Reactions

Frequency not defined.

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

Endocrine & metabolic: Altered hormone level (increased gonadotropin secretion), amenorrhea

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

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

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

Infection: Infection

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

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Leukopenia, neutropenia, thrombocytopenia, and anemia may commonly occur; may be dose related. Bone marrow failure has been reported. Bone marrow failure and severe immunosuppression may lead to serious (and fatal) infections, including sepsis and septic shock, or may reactive latent infections. Antimicrobial prophylaxis may be considered in appropriate patients. Initiate antibiotics for neutropenic fever; antifungal and antiviral medications may also be necessary. Monitor blood counts during treatment. Avoid use if neutrophils are ≤1,500/mm³ and platelets are <50,000/mm³. Consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia. Platelet and neutrophil nadirs are usually at weeks 1 and 2 of treatment and recovery is expected after ~20 days. Severe myelosuppression may be more prevalent in heavily pretreated patients or in patients receiving concomitant chemotherapy and/or radiation therapy.
• Cardiotoxicity: Cardiotoxicity has been reported (some fatal), usually with high doses associated with transplant conditioning regimens, although may rarely occur with lower doses. Cardiac abnormalities do not appear to persist. Cardiotoxicities reported have included arrhythmias (supraventricular and ventricular [some with QT prolongation]), congestive heart failure, heart block, hemopericardium (secondary to hemorrhagic myocarditis and myocardial necrosis), myocarditis (including hemorrhagic), pericarditis, pericardial effusion including cardiac tamponade, and tachyarrhythmias. Cardiotoxicity is related to endothelial capillary damage; symptoms may be managed with diuretics, ACE inhibitors, beta-blockers, or inotropics (Floyd 2005). The risk for cardiotoxicity may be increased with higher doses, advanced age, prior radiation to the cardiac region, and in patients who have received prior or concurrent cardiotoxic medication. Use with caution in patients with preexisting cardiovascular disease or those at risk for cardiotoxicity. For patients with cardiac risk factors or preexisting cardiac disease, monitor during treatment. 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]).
• Gastrointestinal adverse effects: Nausea and vomiting commonly occur. Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Paw Cho Sing 2019; Roila 2016). Stomatitis/mucositis may also occur.
• Hepatotoxicity: Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease (VOD), has been reported in patients receiving chemotherapy regimens containing cyclophosphamide. A major risk factor for SOS is cytoreductive conditioning transplantation regimens with cyclophosphamide used in combination with total body irradiation or busulfan (or other agents). Other risk factors include preexisting hepatic dysfunction, prior radiation to the abdominal area, and low performance status. Children <3 years of age are reported to be at increased risk for hepatic SOS; monitor for signs or symptoms of hepatic SOS, including bilirubin >1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, or unexplained right upper quadrant pain (Arndt 2004). SOS has also been reported in patients receiving long-term lower doses for immunosuppressive indications.
• Hypersensitivity: Anaphylactic reactions have been reported. Cross-sensitivity with other alkylating agents may occur.
• Hyponatremia: Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) has been reported; some have been fatal.
• Immunosuppression: Monitor for infections; immunosuppression and serious infections may occur. Serious infections may require dose reduction, or interruption or discontinuation of treatment.
• Pulmonary toxicities: Pulmonary toxicities, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. Monitor for signs/symptoms of pulmonary toxicity. Consider pulmonary function testing to assess the severity of pneumonitis (Morgan 2011). Cyclophosphamide-induced pneumonitis is rare and may present as early (within 1 to 6 months) or late onset (several months to years). Early onset may be reversible with discontinuation; late onset is associated with pleural thickening and may persist chronically (Malik 1996). In addition, late onset pneumonitis (>6 months after therapy initiation) may be associated with increased mortality.
• Secondary malignancies: Secondary malignancies (bladder cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported with both single-agent and with combination chemotherapy regimens; onset may be delayed (up to several years after treatment). Bladder cancer usually occurs in patients previously experiencing hemorrhagic cystitis; risk may be reduced by preventing hemorrhagic cystitis.
• Urinary/renal toxicity: Cyclophosphamide is associated with the development of hemorrhagic cystitis, pyelitis, ureteritis, and hematuria. Hemorrhagic cystitis may rarely be severe or fatal. Bladder fibrosis may also occur, either with or without cystitis. Urotoxicity is due to excretion of cyclophosphamide metabolites in the urine and appears to be dose- and treatment duration-dependent, although may occur with short-term use. Increased hydration and frequent voiding is recommended to help prevent cystitis; some protocols utilize mesna to protect against hemorrhagic cystitis. Monitor urinalysis for hematuria or other signs of urotoxicity. Severe or prolonged hemorrhagic cystitis may require medical or surgical treatment. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases. Discontinue cyclophosphamide with severe hemorrhagic cystitis. Exclude or correct any urinary tract obstructions prior to treatment initiation (use is contraindicated with bladder outlet obstruction). Use with caution (if at all) in patients with active urinary tract infection.
• Wound healing impairment: May interfere with wound healing.

Disease-related concerns:

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

Concurrent drug therapy issues:

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

Monitoring Parameters

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

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Cyclophosphamide crosses the placenta and can be detected in amniotic fluid (D'Incalci 1982). Birth defects (including malformations of the skeleton, palate, limbs, and eyes), miscarriage, fetal growth retardation, and fetotoxic effects in the newborn (including anemia, gastroenteritis leukopenia, pancytopenia, and severe bone marrow hypoplasia) have been reported.

Women of childbearing potential should avoid pregnancy while receiving cyclophosphamide and for up to 1 year after completion of treatment. Males with female partners who are or may become pregnant should use a condom during and for at least 4 months after cyclophosphamide treatment. Cyclophosphamide may cause sterility in males and females (may be irreversible) and amenorrhea in females. When treatment is needed for lupus nephritis, cyclophosphamide should be avoided in women who are pregnant or those who wish to preserve their fertility (Hahn 2012).

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

Patient Education

What is this drug used for?

• It is used to treat cancer.
• It is used to treat nephrotic syndrome.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Lack of appetite
• Diarrhea
• Hair loss
• Skin discoloration
• Nail changes
• Nausea
• Vomiting
• Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Low sodium like headache, difficulty focusing, trouble with memory, confusion, weakness, seizures, or change in balance.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Severe loss of strength and energy
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Dizziness
• Passing out
• Abnormal heartbeat
• Wound healing impairment
• Blood in the urine
• Painful urination
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.