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  • CLASSES

    Nitrogen Mustard Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Alkylating agent; has activity as both an antineoplastic and immunosuppressant
    Used for the treatment of a variety of solid tumors, NHL, Hodgkin lymphoma, and ALL; oral cyclophosphamide used for nephrotic syndrome in pediatric patients; several off-label uses
    Contraindicated in patients with urinary outflow obstruction

    COMMON BRAND NAMES

    Cytoxan, Neosar

    HOW SUPPLIED

    Cyclophosphamide Oral Cap: 25mg, 50mg
    Cyclophosphamide/Cytoxan Oral Tab: 25mg, 50mg
    Cyclophosphamide/Cytoxan/Neosar Intravenous Inj Pwd F/Sol: 1g, 2g, 500mg

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    For the treatment of nodular or diffuse ALL.
    Oral dosage
    Adults, Adolescents, and Children

    1 to 5 mg/kg orally daily for both initial and maintenance dosing. Other oral regimens have been studied. Adjust dosage in response to tumor activity and/or leukopenia. Additionally, drug dosages may need to be reduced when cyclophosphamide is administered in combination with other cytotoxic regimens.

    Intravenous dosage
    Adults, Adolescents, and Children

    40 to 50 mg/kg IV (total course dose) in divided doses given over 2 to 5 days. Other regimens include cyclophosphamide 10 to 15 mg/kg IV every 7 to 10 days or cyclophosphamide 3 to 5 mg/kg twice weekly.

    For the treatment of relapsed or refractory ALL, in combination with etoposide and clofarabine†.
    Intravenous dosage
    Adults aged 21 years or less, Adolescents, and Children

    400 mg/m2 daily IV over 1 hour on days 1 to 5 in combination with etoposide 150 mg/m2 daily IV over 2 hours on days 1 to 5 and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 were given in a clinical study. Clofarabine was administered before cyclophosphamide and etoposide. In patients with a blast count greater than 30 x 109 cells/L, prophylactic steroids were given. Alternately, etoposide 100 mg/m2 daily IV over 2 hours on days 1 to 5 in combination with cyclophosphamide 440 mg/m2 daily IV over 1 hour on days 1 to 5, and clofarabine 40 mg/m2 daily IV over 2 hours on days 1 to 5 has been studied. Each drug was given daily for 4 days if administered as consolidation treatment.

    For the treatment of breast cancer.
    For adjuvant treatment of patients with operable node-positive breast cancer, in combination with docetaxel and doxorubicin (TAC).
    Intravenous dosage
    Adults

    500 mg/m2 IV plus doxorubicin (50 mg/m2 IV) then docetaxel (75 mg/m2 IV administered 1 hour later) every 3 weeks for 6 courses. Prophylactic colony stimulating factor support has been recommended to mitigate the risk of hematologic toxicities. Dosages should be adjusted based on toxicity. In an open-label randomized trial, 1,491 patients (stratified based on number of positive lymph nodes) were randomized to receive either docetaxel, doxorubicin, and cyclophosphamide (TAC regimen) or doxorubicin, fluorouracil, and cyclophosphamide (FAC regimen) every 3 weeks for 6 cycles. Results from the second interim analysis (median follow-up 55 months) indicated that the disease-free survival was significantly longer for the TAC regimen versus the FAC regimen. Grade 3 or 4 neutropenia was significantly greater with TAC (65.5% vs. 49.3%) as was febrile neutropenia (24.7% vs. 2.5%).

    For the treatment of breast cancer in patients with evidence of axillary node involvement following resection of the primary tumor, in combination with epirubicin and fluorouracil.
    Intravenous dosage
    Adults

    500 mg/m2 IV on day 1 in combination with fluorouracil (500 mg/m2 IV) and epirubicin (100 mg/m2 IV) (FEC regimen) every 21 days for 6 cycles. Alternatively, FEC may be administered for 3 cycles, then followed by docetaxel (100 mg/m2 IV) given every 21 days for 3 cycles (FEC-D regimen). A phase 3 trial of 1,944 patients with node-positive breast cancer compared the FEC-D regimen for 3 cycles to FEC for 6 cycles. The primary endpoint, 5-year disease-free survival, was significantly longer in the FEC-D arm (78.4% vs. 73.2 %); overall survival at 5 years was also significantly increased by FEC-D (90.7% vs. 86.7%). Grade 3 or 4 neutropenia and the incidence of nausea/vomiting were higher with FEC, whereas stomatitis, edema, and nail changes were more common with FEC-D.

    For adjuvant treatment of patients with operable stage I to III invasive breast cancer, in combination with docetaxel (TC).
    Intravenous dosage
    Adults

    A phase 3 study compared docetaxel (75 mg/m2) and cyclophosphamide 600 mg/m2 (TC regimen) given every 21 days for 4 cycles versus doxorubicin (60 mg/m2) and cyclophosphamide 600 mg/m2 (AC regimen) given every 21 days for 4 cycles. The primary endpoint of disease-free survival showed a significant advantage for the TC regimen at 5 years (86% vs. 80%). Extended follow-up after 7 years continued to show a significant benefit for DFS (81% vs. 75%) and overall survival (87% vs. 82%). Edema, myalgia and arthralgia were seen more frequently with the TC regimen and nausea and vomiting were seen more frequently with the AC regimen. No formal cardiac function comparison was performed.

    For the neoadjuvant treatment of HER2-positive breast cancer in combination with fluorouracil and cyclophosphamide (FEC-75), followed by paclitaxel and trastuzumab.
    Intravenous dosage
    Adults

    500 mg/m2 IV in combination with epirubicin (75 mg/m2 IV) and fluorouracil (500 mg/m2 IV) on day 1, every 21 days for 4 cycles (FEC-75).[63560] [63561] Epirubicin dose adjustments for subsequent cycles are recommended by the manufacturer based on nadir platelet counts, ANC, or grade 3 to 4 toxicity.[41751] After completion of 4 cycles of FEC-75, administer paclitaxel 80 mg/m2 IV once weekly in combination with trastuzumab (4 mg/kg IV over 90 minutes on week 1, then 2 mg/kg IV over 30 minutes once weekly), every 21 days for 4 cycles (12 weeks). Surgery should be performed after completion of paclitaxel plus trastuzumab therapy, followed by trastuzumab 6 mg/kg IV every 3 weeks for a total of 52 weeks from the first preoperative dose. In a randomized, phase 3 clinical trial, neoadjuvant treatment with FEC-75 followed by paclitaxel plus trastuzumab (sequential therapy) resulted in similar rates of pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) compared with paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent therapy). Sequential therapy was better tolerated and had a lower incidence of cardiac adverse reactions.[63560] [63561]

    For the treatment of metastatic breast cancer, in combination with epirubicin.
    Intravenous dosage
    Adults

    600 mg/m2 IV on day 1 in combination with epirubicin 75 mg/m2 IV on day 1, every 3 weeks for 6 cycles. In a phase 3 trial, progression-free survival and overall survival were similar when compared to patients on epirubicin and paclitaxel.

    For the treatment of metastatic breast cancer, in combination with fluorouracil and epirubicin.
    Intravenous dosage
    Adults

    500 mg/m2 IV on days 1 and 8 in combination with epirubicin 50 mg/m2 IV on days 1 and 8, plus fluorouracil 400 mg/m2 IV on days 1 and 8, every 3 to 4 weeks depending on patient recovery. In a phase 3 clinical trial, treatment was planned for 6 cycles, but was given up to 9 cycles in patients with a partial or complete response.

    For the adjuvant treatment of early breast cancer, in combination with methotrexate and fluorouracil (CMF)†.
    Oral dosage
    Adults

    100 mg/m2 orally on days 1 through 14, in combination with methotrexate 40 mg/m2 IV and fluorouracil 600 mg/m2 IV on day 1 and day 8, repeated every 28 days for 6 cycles.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with doxorubicin (AC) and atezolizumab, after completion of neoadjuvant nab-paclitaxel and atezolizumab.
    Intravenous dosage
    Adults

    600 mg/m2 IV in combination with doxorubicin (60 mg/m2 IV) every 2 weeks (dose-dense AC) and atezolizumab (840 mg IV every 2 weeks) for 8 weeks, followed by surgery. Begin dose-dense AC plus atezolizumab after completion of neoadjuvant nab-paclitaxel (125 mg/m2 once weekly) plus atezolizumab (840 mg IV every 2 weeks) for 12 weeks. After surgery, continue atezolizumab 1,200 mg IV every 3 weeks for 11 cycles to complete approximately 12 months of atezolizumab therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial (IMpassion031), neoadjuvant treatment with atezolizumab plus sequential nab-paclitaxel and AC chemotherapy significantly improved pCR compared with neoadjuvant placebo plus sequential nab-paclitaxel and AC chemotherapy in patients with early TNBC, regardless of PD-L1 status.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with doxorubicin and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab.
    Intravenous dosage
    Adults

    600 mg/m2 IV in combination with doxorubicin (60 mg/m2 IV) (AC) and pembrolizumab (200 mg IV) every 3 weeks for 4 cycles, followed by surgery. Begin AC plus pembrolizumab after completion of 4 cycles of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly) and pembrolizumab (200 mg IV every 3 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After surgery, patients received adjuvant pembrolizumab every 3 weeks for up to 9 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved pCR in patients with PD-L1 positive TNBC compared with placebo plus chemotherapy in another phase 3 trial (KEYNOTE-522); patients with PD-L1 negative TNBC numerically benefited from pembrolizumab but the results were not statistically significant.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with epirubicin and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab.
    Intravenous dosage
    Adults

    600 mg/m2 IV in combination with epirubicin (90 mg/m2 IV) (AC) and pembrolizumab (200 mg IV) every 3 weeks for 4 cycles, followed by surgery. Begin AC plus pembrolizumab after completion of 4 cycles of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly) and pembrolizumab (200 mg IV every 3 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. After surgery, patients received adjuvant pembrolizumab every 3 weeks for up to 9 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved pCR in patients with PD-L1 positive TNBC compared with placebo plus chemotherapy in another phase 3 trial (KEYNOTE-522); patients with PD-L1 negative TNBC numerically benefited from pembrolizumab but the results were not statistically significant.

    Intravenous dosage
    Adults

    500 to 1,000 mg/m2 intravenous on day 1 in combination with fluorouracil and methotrexate (CMF), with fluorouracil and doxorubicin (CAF), or with doxorubicin (AC). Additionally, cyclophosphamide 600 mg/m2 may be given in a dose-dense fashion on day 1 of every 14 days with doxorubicin (60 mg/m2) along with growth-factor support, which must be given to prevent neutropenia.

    For the treatment of Hodgkin lymphoma.
    For the treatment of Hodgkin lymphoma as part of the BEACOPP regimen.
    Intravenous dosage
    Adults and Adolescents >=15 years

    650 mg/m2 IV on day 1 in combination with bleomycin (10 units/m2 IV on day 8), etoposide (100 mg/m2/day IV on days 1, 2, and 3), doxorubicin (25 mg/m2 IV on day 1), vincristine (1.4 mg/m2 (max: 2 mg) IV on day 8), procarbazine (100 mg/m2/day PO on days 1 through 7), and prednisone (40 mg/m2 PO on days 1 through 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The escalated dose BEACOPP regimen includes cyclophosphamide 1200 mg/m2 IV on day 1 in combination with bleomycin (10 units/m2 IV on day 8), etoposide (200 mg/m2/day IV on days 1—3), doxorubicin (35 mg/m2 IV on day 1), vincristine (1.4 mg/m2 (max: 2 mg) IV on day 8), procarbazine (100 mg/m2/day PO on days 1 through 7), and prednisone (40 mg/m2 PO on days 1 through 14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials. Escalated dose BEACOPP has shown a significantly better freedom from treatment failure at 10 years (82% vs. 70%, p < 0.0001) and overall survival at 10 years (86% vs. 80%, p = 0.0053) compared to standard dose BEACOPP. A regimen of 4 cycles of escalated dose BEACOPP followed by 4 cycles of standard dose BEACOPP has also been used in patients who achieve a complete response after the initial 4 cycles of escalated dose BEACOPP.

    In combination with other regimens.
    Intravenous dosage
    Adults, Adolescents, and Children

    Cyclophosphamide has been included in various regimens. Dosages in combination with various other agents include 300 mg/m2 IV on days 1 and 8; 600 mg/m2 IV on day 1; 650 mg/m2 IV on days 1 and 8.

    Oral dosage
    Adults, Adolescents, and Children

    As part of a combination regimen, cyclophosphamide 70 mg/m2 PO every other day with vinblastine, procarbazine, and prednisone (PCVP).

    For the treatment of non-Hodgkin's lymphoma (NHL) including Burkitt lymphoma and cutaneous T-cell lymphoma (CTCL) (mycosis fungoides).
    For the treatment of elderly patients with NHL in combination with doxorubicin, vincristine, and prednisone.
    Intravenous dosage
    Geriatric patients

    750 mg/m2 IV on day 1 in combination with doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV on day 1 (maximum dosage is 2 mg), and prednisone 50 mg/m2 PO once daily on days 1 to 5, repeated every 21 days. After 3 cycles, patients with a complete response received 3 additional cycles, patients with a partial response received 5 additional cycles, and patients with progressive disease discontinued treatment.

    For the treatment of follicular NHL, in combination with rituximab, doxorubicin, vincristine, and prednisone (R-CHOP).
    Intravenous dosage
    Adults

    Rituximab 375 mg/m2 IV given on day 1 (or day 0) in combination with cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV (maximum dosage is 2 mg), and prednisone 100 mg/m2 PO on days 1 to 5 (R-CHOP regimen) repeated every 3 weeks for 6 to 8 cycles has been studied in previously untreated and previously treated patients with follicular lymphoma (FL) in randomized, phase III trials.

    For the first-line treatment of diffuse large B-cell, CD20-positive NHL, in combination with rituximab, doxorubicin, vincristine, and prednisone (R-CHOP).
    Intravenous dosage
    Adults and Geriatric patients 60 years and older

    Rituximab 375 mg/m2 IV on day 1 has been studied in combination with cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 (maximum dosage is 2 mg) IV on day 1, and prednisone 40 or 100 mg/m2/day PO on days 1 to 5 (R-CHOP) repeated every 21 days for up to 8 cycles in patients aged 60 years and older with previously untreated diffuse large B-cell lymphoma in randomized, clinical trials. In a randomized, phase III study in 632 patients aged 60 years or older (range 60 to 92 years), the 3-year failure-free survival rate was significantly higher with R-CHOP compared with CHOP (53% vs. 46%; hazard ratio [HR] = 0.78; 95% CI, 0.61 to 0.99; p = 0.04) at a median follow-up of 3.5 years. Overall survival (OS) was not significantly improved in the R-CHOP arm (HR = 0.83; 95% CI, 0.63 to 1.09). In another randomized trial, the median progression-free survival (PFS) (4.8 vs. 1.2 years; p < 0.0001) and OS (8.4 vs. 3.5 years; p < 0.0001) times were significantly improved with R-CHOP compared with CHOP in 399 patients aged 60 to 75 years. The 10-year PFS rates were 36.5% and 20.1% in the R-CHOP and CHOP arms, respectively, and the 10-year OS rates were 43.5% and 27.6%, respectively.

    Intravenous dosage
    Adults, Adolescents and Children

    Most commonly, cyclophosphamide is given as part of combination regimens with total doses of up to 1,500 mg/m2 IV. In the ProMACE-CytaBOM regimen for Burkitt lymphoma, 650 mg/m2 is given once every 21 days. In the M-BACOD regimen for Burkitt lymphoma, 600 mg/m2 is given once every 21 days.

    For the treatment of chronic lymphocytic leukemia (CLL).
    NOTE: Cyclophosphamide is approved for the treatment of CLL; however, all components of combination regimens may not have been evaluated by the FDA for the treatment of CLL.
    For the first-line treatment of CLL, in combination with fludarabine.
    Intravenous dosage
    Adults

    250 mg/m2/day IV on days 1 to 3 in combination with fludarabine 25 mg/m2/day IV on days 1 to 3 repeated every 28 days for up to 6 cycles was evaluated in randomized, phase III studies. In 1 study, patients with severe lymphopenia for longer than 7 days received prophylactic antibiotics. In another study, patients received prophylactic antibiotic therapy with cotrimoxazole for 6 months after treatment and allopurinol daily for 7 days during the first 2 to 3 courses; prophylactic antiviral therapy was recommended.

    Oral dosage
    Adults

    150 mg/m2/day PO on days 1 to 5 plus fludarabine 24 mg/m2/day PO on days 1 to 5 repeated every month for up to 6 cycles was evaluated in a randomized, phase III study. Patients received prophylactic antibiotic therapy with cotrimoxazole for 6 months after treatment and allopurinol daily for 7 days during the first 2 to 3 courses; prophylactic antiviral therapy was recommended. No significant differences in efficacy was found between patients who received PO or IV cyclophosphamide plus fludarabine therapy in a retrospective analysis in 65 patients.

    For the treatment of CD20-positive CLL, in combination with fludarabine and rituximab.
    NOTE: Rituximab is FDA approved in combination with cyclophosphamide and fludarabine for the treatment of CD20+ CLL.
    Intravenous dosage
    Adults

    250 mg/m2/day on days 1 to 3 in combination with fludarabine 25 mg/m2/day on days 1 to 3 and rituximab 375 mg/m2 IV on day 0 (the day prior to fludarabine and cyclophosphamide (FC) on cycle 1, then 500 mg/m2 IV on day 1 on cycles 2 to 6 repeated every 28 days (R-FC) for 6 cycles has been studied in randomized, phase III trials. The addition of rituximab to fludarabine and cyclophosphamide (mean of 5.2 cycles) resulted in a significantly improved progression-free survival (PFS) time (primary endpoint) compared with FC alone (51.8 vs. 32.8 months; p < 0.0001) in 817 previously untreated CLL patients in a multinational, randomized, phase III trial. The 3-year PFS (65% vs. 45% hazard ratio (HR) = 0.56; 95% CI, 0.46 to 0.69) and overall survival (OS) (87% vs. 83%; HR = 0.67; 95% CI, 0.48 to 0.92) rates were also significantly improved with R-FC. Grade 3 or 4 neutropenia and leukopenia occurred significantly more often with R-FC therapy. The median PFS time (primary endpoint) was 30.6 months with R-FC compared with 20.6 months with FC (HR = 0.65; 95% CI, 0.51 to 0.82; p < 0.001) in another multinational, randomized, phase III trial in 552 CLL patients who had relapsed or refractory disease following 1 prior line of therapy. All patients in this study received tumor lysis and antibiotic/antiviral prophylaxis. At a median follow-up time of 25 months, the median OS was not significantly different between treatment arms (R-FC, median time not reached; FC, 52 months). There were more treatment-related deaths reported with R-FC therapy (19 vs. 14 deaths).

    For the first-line treatment of CLL, in combination with cladribine.
    Intravenous dosage
    Adults

    250 mg/m2/day IV over 30 to 60 minutes on days 1 to 3 plus cladribine repeated every 28 days for a median of 6 cycles and cyclophosphamide 650 mg/m2 IV on day 1 plus cladribine repeated every 28 days for a median of 3 cycles were evaluated in 2 randomized, phase III trials. The cladribine dosage was 0.12 mg/kg/day IV on days 1 to 3 in both studies.

    For the first-line treatment of CLL, in combination with cladribine and mitoxantrone.
    Intravenous dosage
    Adults

    650 mg/m2 IV on day 1 in combination with cladribine 0.12 mg/kg/day IV over 2 hours on days 1 to 3 and mitoxantrone 10 mg/m2 IV on day 1 repeated every 28 days for up to 6 cycles (median, 3 cycles) has been evaluated in a randomized, phase III trial.

    For the treatment of CLL, in combination with pentostatin and rituximab.
    Intravenous dosage
    Adults

    600 mg/m2 IV on day 1 in combination with pentostatin (2 mg/m2 or 4 mg/m2 IV on day 1) and rituximab (375 mg/m2 IV on day 1) repeated every 21 days for 6 or 8 cycles has been studied in clinical trials. The first cycle rituximab administration varied in these studies with 1 study giving rituximab 100 mg/m2 on day 1 and 375 mg/m2 on days 3 and 5 on cycle 1 and another study administering rituximab 100 mg/m2 on day 8 and 275 mg/m2 on day 9 on cycle 1. Patients received prophylactic antibiotic and/or antiviral therapy in these studies.

    For the treatment of multiple myeloma.
    Intravenous dosage
    Adults

    200 to 300 mg/m2 IV on day 1 in combination with carmustine, prednisone, and either doxorubicin or cisplatin. As part of the M-2 protocol, cyclophosphamide is given as 10 mg/kg IV on day 1 in combination with vincristine, carmustine, melphalan, and prednisone.

    Oral dosage
    Adults

    Cyclophosphamide 125 mg/m2 PO on days 1 to 4 has been given in combination with vincristine, melphalan, and prednisone (VMCP regimen).

    For the treatment of ovarian cancer.
    Intravenous dosage
    Adults

    Total doses of 600 to 1000 mg/m2 IV in combination with doxorubicin, cisplatin, and/or other agents.

    Oral dosage
    Adults

    100 to 150 mg/m2 PO once daily for 14 days in combination with doxorubicin, cisplatin, fluorouracil, or other agents.

    For the treatment of retinoblastoma.
    Intravenous dosage
    Children

    40 mg/kg IV and vincristine (0.05 mg/kg IV) every 3 weeks for 57 weeks. Cyclophosphamide has been used in various combination regimens with doxorubicin, cisplatin, etoposide, and/or vincristine.

    For the treatment of acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML).
    Intravenous dosage
    Adults, Adolescents and Children

    Although FDA-approved for AML and CML, cyclophosphamide does not have extensive activity in primary myeloid malignancies and has generally been replaced with more effective agents (e.g., cytarabine/anthracyclines for AML and hydroxyurea/interferon alfa for CML). Cyclophosphamide may be used as part of conditioning regimens prior to bone marrow transplantation (BMT) in patients with AML or CML. Common doses of cyclophosphamide for conditioning regimens include 120 to 200 mg/kg IV divided as 60 mg/kg/day IV for 2 days or 50 mg/kg/day IV for 4 days or 3.6 to 6 g/m2 IV divided over 3 to 4 days. Doses greater than 120 mg/kg over 2 days (i.e., more than 60 mg/kg/day for 2 days) are associated with an increased risk of severe cardiac toxicity.

    For the treatment of neuroblastoma.
    For the treatment of intermediate-risk neuroblastoma in combination with carboplatin/doxorubicin/etoposide†.
    Intravenous dosage
    Infants and Children

    Cyclophosphamide has been given in combination with etoposide, carboplatin, and doxorubicin in the following fashion. Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, and 3 (4 mg/kg/day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, and 3 (4 mg/kg/day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, and 3 (4 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). All cycles given at 3 week intervals. Patients with favorable biologic features received 4 cycles; if incomplete response after 4 cycles, patients given an additional 4 cycles. Patients with unfavorable biologic features received 8 cycles. Infants younger than 60 days received granulocyte colony-stimulating factor after each cycle.

    Oral dosage
    Infants and Children

    150 mg/m2/day PO days 1 to 7 in combination with doxorubicin (35 mg/m2 IV on day 8) every 21 days for 5 cycles. In a clinical trial, 135 patients with hyperdiploid tumors exhibited a complete response rate of 67%. Patients with diploid tumors or patients with hyperdiploid tumors who had a suboptimal response to treatment were switched to cisplatin and etoposide.

    Intravenous dosage
    Children

    70 mg/kg/day IV infusion with hydration on days 1 and 2 in combination with doxorubicin and vincristine every 21 days for courses 1, 2, 4, and 6; alternating with cisplatin and etoposide every 21 days for courses 3, 5, and 7. Mesna may be given as 24-hour infusions to start with cyclophosphamide at an equal dose. This dose of cyclophosphamide was studied in 86 patients with high-risk neuroblastoma. Complete responses or very good partial responses were seen in 79% of patients. Comparable response rates were seen between patients who received 5 or 7 cycles of treatment.

    Infants

    10 mg/kg/day IV on days 1 to 5 in combination with doxorubicin and vincristine given every 21 days for 2 courses; preceded by 2 courses of carboplatin and etoposide. NOTE: Final doses of all agents should be reduced by 30% in neonates (see below). In a study of 52 patients with unresectable localized neuroblastoma, an overall response rate of 66% was observed. Surgical resection was attempted in all patients and considered complete in 66%.

    Neonates

    7 mg/kg/day IV on days 1 to 5 in combination with doxorubicin and vincristine given every 21 days for 2 courses; preceded by 2 courses of carboplatin and etoposide. In a study of 52 patients with unresectable localized neuroblastoma, an overall response rate of 66% was observed. Surgical resection was attempted in all patients and considered complete in 66%.

    For the treatment of minimal change nephrotic syndrome, in patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
    Oral dosage

    The safety and effectiveness of cyclophosphamide have not been established for the treatment of nephrotic syndrome in adults or other renal disease.

    Children and Adolescents

    2 mg/kg/day orally for 8 to 12 weeks; the maximum cumulative dose is 168 mg/kg. Treatment beyond 90 days increases the probability of sterility in males.

    For the treatment of high-risk gestational trophoblastic disease†.
    Intravenous dosage
    Adults

    600 mg/m2 IV on day 8 in combination with etoposide, methotrexate, leucovorin, actinomycin D, and vincristine (EMA-CO regimen), repeated every 2 to 3 weeks depending on toxicity. Multiple studies have been reported with cure rates ranging from 70% to 90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as 3 consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2 to 3 additional courses after complete hCG response.

    For the treatment of osteogenic sarcoma† in combination with bleomycin and dactinomycin.
    Intravenous dosage
    Adults, Adolescents, and Children

    600 mg/m2/day IV on days 1 and 2, or on days 1, 2, and 3 in combination with bleomycin and dactinomycin (BCD regimen) has been incorporated into multiple treatment protocols for osteogenic sarcoma. In the POG-8651 protocol, 106 patients (younger than 30 years old) with previously untreated nonmetastatic high-grade osteogenic sarcoma were randomized to receive multiagent chemotherapy either before or after surgical resection. Multiagent chemotherapy consisted of 3 days of BCD each cycle in sequence with doxorubicin and cisplatin, and high-dose methotrexate. Event-free survival (EFS), the primary endpoint, was not significantly different between the treatment arms and reached 69% at 5 years in the postoperative group. In a comparison of the Memorial Sloan-Kettering Cancer Center T-10 and T-12 protocols, 73 patients (ages 4.6 to 36.4 years) with previously untreated, high-grade osteogenic sarcoma received BCD on days 1 and 2 of each cycle as part of a multiagent chemotherapy regimen in sequence with doxorubicin and cisplatin, high-dose methotrexate, and surgical resection. The 5-year EFS was 78% and 73% in the T-12 and T-10 protocols, respectively. The use of BCD alone has also been studied in 8 pediatric patients (ages 9.1 to 16.4 years old) with previously treated metastatic osteogenic sarcoma. Patients received 1 to 5 courses of BCD. No tumor regression could be measured for any of the patients, and progressive tumor enlargement was demonstrated in 2 patients.

    For the treatment of metastatic rhabdomyosarcoma† in combination with topotecan and vincristine alternating with VAC.
    Intravenous dosage
    Adults

    Dosage is not established. In a phase II trial of newly diagnosed metastatic rhabdomyosarcoma, 61 patients younger than 21 years received cyclophosphamide 250 mg/m2/day IV on days 1 to 5 immediately followed by topotecan (0.75 mg/m2/day IV on days 1 to 5) (TC); repeated every 21 days for 2 cycles. To prevent hemorrhagic cystitis, mesna 250 mg/m2/day IV on days 1 to 5 was given immediately prior to cyclophosphamide administration. If objective improvement occurred (CR or PR), patients continued to receive TC in combination with vincristine (VTC) alternating with vincristine, dactinomycin, and cyclophosphamide (VAC) during weeks 6 to 41. The overall response rate to TC was 46% (3% CR, 43% PR, 23% objective improvement, and 10% no response). Of treated patients, 70% were considered responders and received alternating VTC/VAC therapy. After 41 weeks of therapy, 34% achieved a CR. Disease-free survival at 3 years was 10%, while 3-year overall survival was 20%. No unexpected toxicities occurred during treatment. In a phase III clinical trial, VAC/VTC was compared to VAC in 617 patients with previously untreated intermediate-risk rhabdomyosarcoma. The primary endpoint, failure-free survival (FFS), was not significantly different between the 2 treatment arms (68% VAC/VTG vs. 73% VAC, p = 0.3) when measured at 4 years. In addition, the estimated overall survival (OS) at 4 years was 79% for both treatment groups. Neutropenia occurred more significantly more often in patients who received VAC only (78% vs. 85%, p = 0.04).

    For the treatment of small cell lung cancer (SCLC)†.
    For the treatment of newly-diagnosed small cell lung cancer (SCLC) in combination with doxorubicin and vincristine†.
    Intravenous dosage
    Adults

    Multiple dosage regimens have been studied. Cyclophosphamide 750 mg/m2 IV on day 1 in combination with doxorubicin 40 mg/m2 IV on day 1 and vincristine 1.2 mg/m2 (maximum dose is 2 mg) IV on day 1, every 4 weeks for 4 cycles. Cyclophosphamide 800 mg/m2 IV on day 1 in combination with doxorubicin 50 mg/m2 IV on day 1 and vincristine 1.4 mg/m2 (maximum dosage is 2 mg) IV on day 1, every 3 to 4 weeks for 4 cycles. Cyclophosphamide 1,000 mg/m2 IV on day 1 in combination with doxorubicin 40 mg/m2 IV on day 1 and vincristine 1 mg/m2 (maximum dosage is  2 mg) IV on day 1, every 3 weeks for 6 cycles.

    For the treatment of newly-diagnosed small cell lung cancer (SCLC) in combination with doxorubicin and etoposide†.
    Intravenous dosage
    Adults

    Cyclophosphamide 1,000 mg/m2 IV on day 1 in combination with doxorubicin 45 mg/m2 IV on day 1 and etoposide 100 mg/m2/day IV on days 1, 2, and 3 every 3 weeks for 5 cycles.

    For peripheral blood stem cell (PBSC) mobilization†.
    Intravenous dosage
    Adults

    4 g/m2 IV over 6 hours on day 1 along with mesna 3 g/m2 IV, then 500 mg every 3 hours PO/IV for 8 doses and prednisone 2 mg/kg orally on days 1 to 4. At 36 to 48 hours after completion of cyclophosphamide, patients began G-CSF 10 mg/kg subcutaneously per day until recovery.

    For stem cell transplant preparation†.
    For stem cell transplant preparation prior to nonmyeloablative allogeneic hematopoietic stem cell transplant in combination with fludarabine†.
    Intravenous dosage
    Adults

    Cyclophosphamide 60 mg/kg/day IV on 2 consecutive days (days -7 and -6) in combination with fludarabine 25 mg/m2/day IV for 5 consecutive days (days -5 to -1). Cyclosporine alone or in combination with mycophenolate was used for GVHD prevention. For obese patients (more than 120% ideal body weight), chemotherapy dosing weight was calculated by using the formula: dosing weight = ideal body weight + (actual/ideal weight)/2.

    For stem cell transplant preparation, in combination with fludarabine, prior to reduced intensity allogeneic hematopoietic stem cell transplantation for advanced indolent B cell malignancies†.
    Intravenous dosage
    Adults

    Fludarabine 30 mg/m2/day IV for 5 consecutive days (days -7 to -3) in combination with cyclophosphamide 1 g/m2/day IV on 3 consecutive days (days -5 to -3). Low dose methotrexate was given in combination with tacrolimus or cyclosporine for the prevention of GVHD. Infection prophylaxis with fluconazole, acyclovir, and TMP/SMX was given per institutional standards.

    For stem cell transplant preparation prior to allogeneic hematopoietic stem cell transplant in combination with busulfan†.
    Intravenous dosage
    Adults

    Busulfan 1 mg/kg PO 4 times a day on days -7 to -4 (16 mg/kg PO total dose) in combination with cyclophosphamide 60 mg/kg/day IV on days -3 and -2 (120 mg/kg IV total dose). Cyclosporine and prednisone were used for the prevention of GVHD. Cyclophosphamide was dosed on ideal weight, all other agents were dosed on actual weight.

    For solid organ transplant rejection prophylaxis† (e.g., heart transplant rejection prophylaxis†, kidney transplant rejection prophylaxis†, or liver transplant rejection prophylaxis†) or treatment of acute or chronic solid organ transplant rejection† (e.g., heart transplant rejection†, liver transplant rejection†, lung transplant rejection†, or kidney transplant rejection†).
    Oral dosage
    Adults

    Doses of 1 to 2 mg/kg/day PO have been given for periods as long as 2 years. Cyclophosphamide is usually used as a second-line agent in patients who have failed other immunosuppressant therapy.

    For the treatment of aplastic anemia†.
    Intravenous dosage
    Adults

    45 to 50 mg/kg IV divided over 4 days has been used without bone marrow transplantation with a response rate similar to cyclosporine (CSA) and antithymocyte globulin (ATG). In a small trial of 19 patients, the probability of survival at 2 years was 84% and the probability of independence from transfusion at 4 years was 73% in patients treated with high-dose cyclophosphamide. However, a phase III trial comparing cyclophosphamide to CSA/ATG was terminated early due to excess early mortality in the cyclophosphamide group (3 deaths within 3 months with cyclophosphamide vs. no CSA/ATG deaths). Recovery of WBC was significantly delayed in patients treated with cyclophosphamide, despite treatment with hematopoietic growth factors.

    For the treatment of corticosteroid-resistant chronic immune thrombocytopenic purpura (ITP)†.
    Oral dosage
    Adults

    2 mg/kg PO once daily has been recommended in patients who fail initial treatment with prednisone or do not tolerate corticosteroid treatment. Dosage is adjusted according to WBC count. Treatment is indicated in symptomatic patients with a platelet count less than 50,000/mm3.

    Intravenous dosage
    Adults

    500 mg IV every 3 to 4 weeks. Cyclophosphamide has also been used as part of combination chemotherapy with prednisone and etoposide or vincristine with or without procarbazine in patients with severe refractory ITP.

    For the treatment of dermatomyositis†, pneumonitis†, or polymyositis† related to autoimmune diseases (i.e., systemic lupus erythematosus (SLE)† or scleroderma (systemic sclerosis)†).
    For SLE† including neuropsychiatric, hematologic, lupus nephritis†, and other severe manifestations of SLE.
    Oral dosage
    Adults, Adolescents, and Children

    Guidelines do not mention the use of oral cyclophosphamide for lupus nephritis. 1 to 3 mg/kg PO once daily in combination with corticosteroids. Regimens should be adjusted based on hematologic toxicity. Duration of therapy has not been established. In lupus nephritis, cyclophosphamide is given for 1 year after the nephritis is in remission; however, there are no data to support this recommendation. In some patients, prolonged continuous therapy for up to 2 years does not control the disease. Factors associated with a poor response to cyclophosphamide include African American race, elevated creatinine clearance, or advanced interstitial fibrosis at the initiation of cyclophosphamide treatment. Cyclophosphamide has also been used in combination with other immunosuppressants such as azathioprine, methotrexate, and fludarabine.

    Intravenous dosage
    Adults

    500 mg IV every 2 weeks for 6 doses then daily oral mycophenolate mofetil (MMF) or azathioprine plus methylprednisolone 500 to 1,000 mg/day IV for 3 days then prednisone 0.5 to 1 mg/kg/day (1 mg/kg/day recommended if crescents seen) tapered after a few weeks to lowest effective dose for class III/IV disease either for initial induction therapy or for induction therapy after lack of improvement with MMF. An alternative regimen is the same except the cyclophosphamide dose is 500 to 1,000 mg/m2 IV every month for 6 months and no MMF or azathioprine is used; the alternative regimen is also recommended for patients with class V disease without proliferative changes and with proteinuria greater than 3 g/24 hours who do NOT improve with MMF and prednisone. The first regimen is preferred for white patients with European background; the 2 regimens have not been compared in nonwhite racial groups. MMF and cyclophosphamide are considered equivalent for induction, but MMF is preferred for African American and Hispanic patients, and MMF is preferred for patients who express a major concern with fertility preservation; high-dose cyclophosphamide can cause permanent infertility in both women and men. Guidelines recommend that most patients be followed for 6 months after induction initiation before making major treatment changes unless 50% or more worsening of proteinuria or serum creatinine at 3 months exists.

    Use of high-dose myeloablative therapy† in patients with advanced, refractory SLE†.
    Intravenous dosage
    Adults

    Higher doses of cyclophosphamide have a long-lasting effect on the disease course of SLE. Autologous stem cell transplantation incorporating cyclophosphamide in the mobilization (2 g/m2 IV) and conditioning regimens (200 mg/kg IV over 3 to 4 days) has been studied and shows stabilization or marked improvement in patients with severe, advanced disease refractory to standard doses of cyclophosphamide.

    For pneumonitis†/alveolitis† in patients with scleroderma (systemic sclerosis)†.
    Oral or Intravenous dosage
    Adults

    Initially, 1 to 1.5 mg/kg/day PO; may increase in 25 mg increments every 3 to 4 weeks up to 2 mg/kg/day. Alternatively, 800 to 1,400 mg IV monthly with IV hydration for 6 to 9 months. The goal is to avoid neutropenia. In 1 series, compared with patients who did not receive cyclophosphamide for alveolitis, patients treated with cyclophosphamide had improvement in FVC and diffusing capacity and an increased survival. In another study, receipt of cyclophosphamide 1 mg/kg/day PO initially, then increased monthly by 25 mg up to 2 mg/kg/day, for 12 months led to a percent of predicted FVC difference of -1 +/- 0.92 from baseline in patients with limited or diffuse systemic scleroderma. In contrast, the percent of predicted FVC difference for placebo recipients was -2.6 +/- 0.9 from baseline. Survival or long-term adverse effects such as malignancy were not determined.

    For the treatment of rheumatoid arthritis† with or without Sjogren's syndrome† and juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)†.
    Use of high-dose myeloablative therapy† in patients with severe, active rheumatoid arthritis†.
    Intravenous dosage
    Adults

    Doses of cyclophosphamide 200 mg/kg (total dose) IV or 4 g/m2 IV followed by hematopoietic growth factors and peripheral stem cell transplantation have been studied in small phase I/II trials. Responses have been noted for more than 19 months.

    Oral dosage
    Adults, Adolescents, and Children

    1.5 to 2.5 mg/kg/day PO in combination with other agents; however, doses of less than 1.0 mg/kg/day have not been consistently effective.

    Intravenous dosage
    Adults, Adolescents, and Children

    0.5 to 1 g/m2 IV monthly for 6 months then every 2 to 3 months in combination with other agents.

    For the treatment of systemic vasculitis syndromes† including Behcet's syndrome†, Churg-Strauss syndrome†, polyarteritis nodosa†, uveitis†, or Wegener's granulomatosis†.
    Oral dosage
    Adults

    1 to 2 mg/kg/day PO in addition to corticosteroids, especially if there is major organ system involvement. Doses can be increased by 25 mg/day every 2 weeks until clinical response or toxicity is seen. Therapy should be continued for 12 to 18 months following complete remission. Early addition of cyclophosphamide is appropriate in Wegener's granulomatosis and polyarteritis nodosa.

    Intravenous dosage
    Adults

    0.5 to 1 g/m2 IV monthly in addition to corticosteroids, especially if there is major organ system involvement. Early addition of cyclophosphamide is appropriate in Wegener's granulomatosis and polyarteritis nodosa. Other studies have described lower pulse doses of cyclophosphamide 500 mg IV weekly (250 mg IV in patients with creatinine clearance less than 30 mL/min) in combination with mesna.

    For the treatment of idiopathic pulmonary fibrosis†.
    Oral dosage
    Adults

    2 mg/kg/day PO to a maximum dose of 150 mg/day PO. Dosing should begin at 25 to 50 mg/day PO. Increase gradually, by 25-mg increments, every 7 to 14 days until the maximum dose is reached. Guidelines suggest treatment should be in combination with corticosteroids and for a minimum duration of 6 months. Objective responses may not be noted until the patient has received 3 months or more of therapy. Exact duration of treatment and need for long-term maintenance should be individualized based on clinical response and tolerance to therapy.

    Intravenous dosage
    Adults

    500 to 1,800 mg IV given every 2 to 4 weeks has been tried in open trials of refractory patients with generally unimpressive results. The poor results in these trials may reflect the late course disease when treatment was started rather than a failure of cyclophosphamide therapy.

    For the treatment of unresectable, advanced thymoma†.
    In combination with cisplatin and doxorubicin†.
    Intravenous dosage
    Adults

    500 mg/m2 IV on day 1 plus doxorubicin 50 mg/m2 IV on day 1 and cisplatin 50 mg/m2 IV on day 1 (with 1 L hydration before and after chemotherapy) repeated every 21 days (PAC regimen) for up to 8 cycles (median of 7 cycles) in patients with previously untreated, unresectable, extensive-stage thymoma or for 2 or 4 cycles (median of 4 cycles; range, 1-7 cycles) followed by radiotherapy in patients with previously untreated, unresectable, limited-stage thymoma who had stable disease or better have been evaluated in nonrandomized studies with favorable overall response rates and overall survival rates. Additionally, multimodality treatment with 3 cycles of cyclophosphamide 500 mg/m2 IV on day 1, cisplatin 30 mg/m2/day IV on days 1 to 3, doxorubicin 30 mg/m2/day continuous IV infusion over 24 hours on days 1 to 3, and prednisone 100 mg PO on days 1 to 5 repeated every 3 to 4 weeks followed by surgery and radiation therapy and then consolidation chemotherapy with cyclophosphamide, cisplatin, and doxorubicin given at 80% of the original doses and prednisone (given at 100%) repeated every 3 to 4 weeks for 3 cycles has also been evaluated in another nonrandomized study.

    In combination with cisplatin, doxorubicin, and vincristine†.
    Intravenous dosage
    Adults

    700 mg/m2 IV on day 4 plus cisplatin 50 mg/m2 IV on day 1, doxorubicin 40 mg/m2 IV on day 1, and vincristine 0.6 mg/m2 IV on day 3 repeated every 3 weeks (median of 5 cycles, range, 3-7 cycles) resulted in a favorable overall response rate in a nonrandomized study of 37 patients.

    For the treatment of Waldenstrom macroglobulinemia†.
    For the treatment of newly diagnosed Waldenstrom macroglobulinemia, in combination with rituximab and dexamethasone†.
    Oral dosage
    Adults

    100 mg/m2 orally twice daily on days 1 to 5 (total dose of 1,000 mg/m2/cycle) in combination with rituximab 375 mg/m2 IV on day 1 and dexamethasone 20 mg IV on day 1 repeated every 21 days for 6 cycles was evaluated in a single-arm, phase II trial.

    For the treatment of amyloidosis†.
    For the treatment of systemic amyloid light-chain amyloidosis, in combination with lenalidomide and dexamethasone†.
    Oral dosage
    Adults

    Oral cyclophosphamide in combination with lenalidomide (15 mg PO daily on days 1 to 21) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) repeated every 28 days has been evaluated in nonrandomized, phase 2 studies. Treatment duration, the cyclophosphamide dosage, and thromboprophylaxis recommendations varied in these studies. In 1 study, cyclophosphamide (500 mg PO on days 1, 8, and 15), lenalidomide, and dexamethasone therapy was given for a maximum of 9 cycles; treatment was discontinued after cycle 6 if a complete response or partial response/very good partial response plus organ response was obtained. In this study, patients with fluid retention over 3% of body weight despite optimal diuretic use received a lower dose of dexamethasone (20 mg once weekly). In another study, cycles of cyclophosphamide (300 mg/m2 PO on days 1, 8, and 15), lenalidomide, and dexamethasone were continued until disease progression, unacceptable toxicity, or up to 2 years; however, cyclophosphamide was given for up to a maximum of 12 cycles only.

    Intravenous dosage
    Adults

    300 mg/m2 IV on days 1 and 8 for cycles 1 to 6, then cyclophosphamide 300 mg/m2 IV on day 1 for cycles 7 to 12 in combination with lenalidomide (15 mg PO daily on days 1 to 21 for 12 cycles) and dexamethasone (20 mg PO on days 1, 2, 3, 4, 9, 10, 11, and 12 for cycles 1 to 6; then 20 mg PO on days 1, 2, 3, and 4 for cycles 7 to 12) repeated every 28 days was evaluated in a nonrandomized, phase 2 trial. Maintenance therapy with lenalidomide and dexamethasone was administered for 3 additional years or until disease progression. Patients with cardiac stage III had an upfront dose modification of dexamethasone.

    For the treatment of newly diagnosed light-chain amyloidosis, in combination with daratumumab; hyaluronidase, bortezomib, and dexamethasone†.
    Daratumumab; hyaluronidase is FDA approved in combination with bortezomib, cyclophosphamide, and dexamethasone for the treatment of newly diagnosed light-chain amyloidosis.
    Intravenous or Oral dosage
    Adults

    300 mg/m2 (maximum dose of 500 mg) IV or PO in combination with bortezomib 1.3 mg/m2 subcutaneously and dexamethasone 40 mg IV/PO each given weekly on days 1, 8, 15, and 22 repeated every 28 days for a maximum of 6 cycles (VCd) plus up to 2 years of subcutaneous daratumumab; hyaluronidase (D-VCd) was evaluated in transplant eligible, newly diagnosed light-chain amyloidosis patients in a randomized, phase 3 trial (n = 388; the ANDROMEDA trial). The dose of dexamethasone was reduced to 20 mg in patients older than 70 years or who had a body mass index less than 18.5, hypervolemia, poorly controlled diabetes mellitus, or prior intolerance to steroid therapy. Daratumumab; hyaluronidase was administered as follows: 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every 2 weeks on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression or for a maximum of 2 years. In the phase 3 trial, the hematologic complete response rate was significantly improved (42% vs. 13%; p less than 0.0001) in patients (median age, 64 years; range, 34 to 87 years) who received D-VCd compared with VCd.

    For the treatment of highly refractory Kawasaki disease†.
    Intravenous dosage
    Children and Adolescents

    2 mg/kg/day IV may be considered in highly refractory patients who have failed to respond to a second IVIG infusion, an extended course of steroids, or infliximab.[61950]

    For the treatment of systemic anaplastic large-cell lymphoma (sALCL)†.
    For the treatment of previously untreated sALCL, in combination with brentuximab vedotin, doxorubicin, and prednisone†.
    NOTE: Brentuximab vedotin is FDA approved in combination with cyclophosphamide, doxorubicin, and prednisone for this indication.
    Intravenous dosage
    Adults

    750 mg/m2 IV on day 1 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1, doxorubicin 50 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 given every 21 days for 6 to 8 cycles of therapy. The progression-free survival (PFS) time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing sALCL or peripheral T-cell lymphoma who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In patients with sALCL (n = 314; anaplastic lymphoma kinase (ALK)-negative sALCL, 48%; ALK-positive sALCL, 22%), the PFS times were 55.7 months and 54.2 months in patients who received brentuximab vedotin plus CHP and CHOP, respectively (HR = 0.59; 95% CI, 0.42 to 0.84).[45378]

    For the treatment of peripheral T-cell lymphoma (PTCL)†.
    For the treatment of previously untreated CD30-expressing PTCL, in combination with brentuximab vedotin, doxorubicin, and prednisone†.
    NOTE: Brentuximab vedotin is FDA approved in combination with cyclophosphamide, doxorubicin, and prednisone for this indication.
    Intravenous dosage
    Adults

    750 mg/m2 IV on day 1 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1, doxorubicin 50 mg/m2 IV on day 1, and prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 given every 21 days for 6 to 8 cycles of therapy. The progression-free survival time (evaluated via an independent review facility) was significantly improved in patients with CD30-expressing systemic anaplastic large-cell lymphoma (sALCL) or PTCL who received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (48.2 months vs. 20.8 months; hazard ratio (HR) = 0.71; 95% CI, 0.54 to 0.93) in a multicenter, randomized, double-blind, phase 3 trial (the ECHELON-2 trial; n = 452). Overall survival was also significantly improved in the brentuximab vedotin-containing arm (HR = 0.66; 95% CI, 0.46 to 0.95). In this trial, 70% of patients had sALCL and 30% of patients had PTCL (e.g., including PTCL not otherwise specified (16%), angioimmunoblastic T-cell lymphoma (12%), adult T-cell leukemia/lymphoma (2%), and enteropathy-associated T-cell lymphoma (less than 1%)).

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for cyclophosphamide is dependent on the disease state, performance status, and other chemotherapy agents or radiation therapy given in combination.

    Adults

    In conjunction with bone marrow transplantation, 240 mg/kg IV over a 4 day period (60 mg/kg/day IV) or 7 g/m2 (240 mg/kg) IV as a 96-hour continuous infusion have been reported as the MTD with acceptable myelosuppression and dose-limiting cardiotoxicity. Orally, 50 mg/m2/day PO for 14 days has been reported as the MTD.

    Elderly

    In conjunction with bone marrow transplantation, 240 mg/kg IV over a 4 day period (60 mg/kg/day IV) or 7 g/m2 (240 mg/kg) IV as a 96-hour continuous infusion have been reported as the MTD with acceptable myelosuppression and dose-limiting cardiotoxicity. Orally, 50 mg/m2/day PO for 14 days has been reported as the MTD.

    Adolescents

    50 mg/kg IV in divided doses over a period of 2—5 days; 5 mg/kg/day PO.

    Children

    50 mg/kg IV in divided doses over a period of 2—5 days; 5 mg/kg/day PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is necessary. However, hepatic impairment may reduce the conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy.

    Renal Impairment

    Dosage adjustments are not recommended for patients with renal impairment. However, patients with severe renal impairment (CrCl less than 24 mL/min) may have decreased renal excretion and increased plasma levels of cyclophosphamide and its metabolites. Monitor these patients for signs and symptoms of toxicity.
     
    Intermittent hemodialysis
    The amount of cyclophosphamide and its metabolites removed during hemodialysis varies depending upon the dialysis system used. Consider the use of a consistent interval between cyclophosphamide administration and hemodialysis to reduce variability in exposure.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering cytotoxic drugs.
     
    Administer cyclophosphamide in the morning.
    Maintain adequate fluid intake with cyclophosphamide therapy to ensure a high urine output and reduce the risk of urinary toxicity.

    Oral Administration
    Oral Solid Formulations

    Swallow capsules whole; do not open, crush, or chew capsules.
    Avoid contact with broken capsules; if contact with broken capsules occurs, wash hands immediately and thoroughly.

    Extemporaneous Compounding-Oral

    Cyclophosphamide powder for injection may be dissolved in Aromatic Elixir, NF to compound an oral liquid preparation.
    The resultant solution is stable for 14 days under refrigeration in glass containers.

    Injectable Administration
    Intravenous Administration

    Reconstitution, Powder for Injection
    Do not use cyclophosphamide powder for injection vials if there are signs of melting. Melted cyclophosphamide powder is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.
    For patients receiving a direct IV injection of cyclophosphamide, reconstitute using 0.9% Sodium Chloride Injection only.
    For patients receiving an IV infusion of cyclophosphamide, reconstitute using either 0.9% Sodium Chloride Injection or Sterile Water for Injection.
    500 mg vial: Add 25 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    1 g vial: Add 50 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    2 g vial: Add 100 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    Storage: Vials reconstituted with 0.9% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator; immediately use vials reconstituted with Sterile Water for Injection (do not store).
     
    Dilution, Reconstituted Powder for Injection
    For administration as a direct IV injection, further dilution is not necessary.
    For administration as an IV infusion, dilute reconstituted powder for injection (20 mg/mL) to a minimum concentration of 2 mg/mL in 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose Injection and 0.9% Sodium Chloride Injection.
    Solutions diluted in 0.45% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator including the time for reconstitution.
    Solutions diluted in 5% Dextrose Injection or 5% Dextrose Injection and 0.9% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 36 hours in the refrigerator including the time for reconstitution.
     
    Dilution, Solution for Injection
    For administration as a direct IV injection, dilute to a minimum concentration of 20 mg/mL using any of the following diluents: 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection.
    For administration as an IV infusion, dilute to a minimum concentration of 2 mg/mL using any of the following IV fluids: 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose Injection and 0.9% Sodium Chloride Injection.
    Diluted solutions may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator.
    After the first use, partially used vials should be stored in the refrigerator (2 to 8 C or 36 to 46 F) and used within 28 days.
     
    Administration
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    For direct IV injection, diluted cyclophosphamide powder for injection may be only be administered when reconstituted with 0.9% Sodium Chloride Injection. Do not directly inject cyclophosphamide powder that was reconstituted with Sterile Water for Injection as this solution is hypotonic.
    Inject or infuse slowly to avoid rate-dependent adverse events (e.g., facial swelling, headache, nasal congestion, scalp burning); duration depends on the infusion volume and fluid type.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Cytoxan:
    - Discard unused portion. Do not store for later use.
    - Store at or below 77 degrees F
    Neosar:
    - Discard unused portion. Do not store for later use.
    - Store at or below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Treatment with cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to cyclophosphamide or any component of the product. Hypersensitivity (e.g., anaphylactic reactions) has been reported with cyclophosphamide use; some cases were fatal. Cross-sensitivity with other alkylating agents is possible.

    Bladder obstruction, hemorrhagic cystitis, urinary tract infection (UTI), urinary tract obstruction

    Treatment with cyclophosphamide is contraindicated in patients with urinary outflow obstruction (e.g., bladder obstruction or urinary tract obstruction). Before starting treatment, any urinary tract obstructions must be either excluded or corrected. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Use cyclophosphamide with caution, if at all, in patients with an active urinary tract infection (UTI). Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Discontinue cyclophosphamide if severe hemorrhagic cystitis occurs; medical and/or surgical supportive treatment may be required for prolonged cases. Urotoxicity including bladder ulceration, necrosis, fibrosis, contracture, and secondary cancer may require an interruption of cyclophosphamide treatment or cystectomy; fatal cases of urotoxicity have occurred. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity; mesna has been used to prevent severe bladder toxicity.

    Dialysis, renal impairment

    Monitor patients with severe renal impairment (CrCl 10 to 24 mL/min) for signs and symptoms of toxicity during treatment with cyclophosphamide. Decreased renal excretion of cyclophosphamide may result in increased plasma levels of cyclophosphamide and its metabolites. Although cyclophosphamide and its metabolites are dialyzable, there are likely quantitative differences depending on the dialysis system being used. For patients with renal failure who require dialysis, consider using a consistent interval between cyclophosphamide administration and dialysis.

    Anemia, bone marrow suppression, infection, leukopenia, neutropenia, thrombocytopenia, viral infection

    Bone marrow suppression (e.g., anemia, leukopenia, neutropenia, thrombocytopenia) has been reported with cyclophosphamide therapy. Bone marrow failure and severe immunosuppression have also occurred, leading to serious and sometimes fatal infection; latent infections (e.g. viral infection) can be reactivated. Patients pretreated with or who are receiving concomitant chemotherapy and/or radiation may be at increased risk for myelosuppression. Monitor complete blood counts during treatment. Do not administer cyclophosphamide if the neutrophil count is 1,500 cells/mm3 or less and the platelet count is less than 50,000 cells/mm3. Consider primary and secondary prophylaxis with a granulocyte colony-stimulating factor in patients who have an increased risk of neutropenic complications. Prophylactic antimicrobial, antifungal, and/or antiviral therapy may be indicated in some patients. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients who develop a serious infection.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) may occur with cyclophosphamide therapy. Take appropriate measures (e.g. aggressive hydration, allopurinol) in patients with bulky chemosensitive tumors who are at high-risk for developing TLS.

    Hepatic disease, sinusoidal obstruction syndrome (SOS), veno-occlusive disease (VOD)

    Use cyclophosphamide with caution in patients with a history of hepatic disease, as they may be predisposed to the development of veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS); patients with low performance status and those who have received previous abdominal radiation may also be at increased risk. Veno-occlusive disease has been reported in patients treated with cyclophosphamide, including some cases with fatal outcome. A cytoreductive regimen in preparation for bone marrow transplant that includes cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. Veno-occlusive disease has also developed gradually in patients receiving long-term, low-dose cyclophosphamide for immunosuppression.

    Impaired wound healing, surgery

    Notify the anesthesiologist if a patient has been treated with cyclophosphamide within 10 days of surgery requiring general anesthesia. Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity; prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). Cyclophosphamide may also cause impaired wound healing.

    Cardiac disease, cardiotoxicity, geriatric

    Use cyclophosphamide with caution in patients with pre-existing cardiac disease and other risk factors for cardiotoxicity, as myocarditis, myopericarditis, pericardial effusion, cardiac tamponade, and congestive heart failure have been reported with cyclophosphamide use; some cases were fatal. Cardiac arrhythmias including supraventricular arrhythmias (e.g., atrial fibrillation, atrial flutter) and ventricular arrhythmias (e.g., QT prolongation associated with ventricular tachyarrhythmia) have also occurred following cyclophosphamide-containing therapy. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in geriatric patients, in patients who have received prior radiation to the cardiac region, and in those with previous or concomitant treatment with other cardiotoxic agents.

    Chronic lung disease (CLD), pneumonitis

    Use cyclophosphamide with caution in patients with a history of chronic lung disease (CLD) as pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity.

    New primary malignancy

    New primary malignancy has occurred following treatment with cyclophosphamide, including acute leukemias, myelodysplasia, lymphoma, thyroid cancer, sarcoma, and urinary tract cancer. Taking measures to prevent hemorrhagic cystitis may reduce the risk of bladder cancer.

    Radiation therapy

    Patients who were pretreated with and/or receiving concomitant radiation therapy with cyclophosphamide are at an increased risk of several treatment-related adverse reactions, including severe myelosuppression, cardiotoxicity (previous radiation treatment to the cardiac region), and veno-occlusive disease / sinusoidal obstructive syndrome (previous radiation therapy of the abdomen).

    Alcoholism, driving or operating machinery, ethanol ingestion

    Cyclophosphamide solution for injection contains ethanol to dissolve the active ingredients; take this into account for patients in whom ethanol ingestion should be avoided or minimized, including patients with alcoholism or hepatic impairment. The amount of alcohol may vary between products; consult individual product labeling for alcohol content. Patients should give consideration to the effect of the alcohol content in cyclophosphamide on driving or operating machinery immediately after the infusion.

    Children

    Prepubescent children treated with cyclophosphamide typically develop secondary sexual characteristics normally; prepubescent girls may have regular menses. However, ovarian fibrosis with complete loss of germ cells has been reported in prepubescent girls who received prolonged cyclophosphamide therapy in late pre-pubescence. Girls treated with cyclophosphamide who retain ovarian function are at an increased risk of premature menopause. Oligospermia or azoospermia, increased gonadotropin secretion, and testicular atrophy have occurred in prepubescent boys who received cyclophosphamide therapy; azoospermia may be reversible in some cases. Treatment beyond 90 days increases the probability of sterility in males.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during cyclophosphamide treatment and for at least 1 year after the last dose. Exposure to cyclophosphamide during pregnancy can cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Women who are pregnant or who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. Malformations of the skeleton, palate, limbs, and eyes as well as miscarriage have been reported after human fetal exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects in the newborn (e.g., leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis) have also been reported after exposure to cyclophosphamide during pregnancy. When administered to pregnant animals (mice, rats, rabbits, and monkeys) during organogenesis at doses at or below the dose used in humans based on body surface area, multiple malformations occurred including neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during cyclophosphamide treatment. Cyclophosphamide can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 year after treatment with cyclophosphamide. Females of reproductive potential should undergo pregnancy testing prior to initiation of cyclophosphamide. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for at least 4 months after treatment with cyclophosphamide. Women who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. The development of infertility or sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment; it may be irreversible in some patients. Amenorrhea (transient or permanent), associated with decreased estrogen and increased gonadotropin secretion, develops in a proportion of women treated with cyclophosphamide; patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from cyclophosphamide, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Cyclophosphamide is present in human milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast-fed by women treated with cyclophosphamide.

    ADVERSE REACTIONS

    Severe

    cardiotoxicity / Delayed / 0-45.0
    leukemia / Delayed / 0-2.0
    myocarditis / Delayed / 0-0.1
    hemorrhagic cystitis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    cardiac tamponade / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    premature labor / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombotic microangiopathy / Delayed / Incidence not known
    atrial flutter / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known

    Moderate

    bone marrow suppression / Delayed / 10.0
    hematuria / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    testicular atrophy / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    immunosuppression / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    edema / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    parotitis / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    erythema / Early / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hot flashes / Early / Incidence not known
    bladder spasm / Early / Incidence not known

    Mild

    amenorrhea / Delayed / 0-50.0
    abdominal pain / Early / 1.0-10.0
    diarrhea / Early / 1.0-10.0
    rash / Early / 1.0-10.0
    vomiting / Early / 30.0
    nausea / Early / 10.0
    alopecia / Delayed / 10.0
    azoospermia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    cough / Delayed / Incidence not known
    nasal congestion / Early / Incidence not known
    lacrimation / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    tremor / Early / Incidence not known
    dizziness / Early / Incidence not known
    infection / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    malaise / Early / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known
    dysgeusia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    parosmia / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    headache / Early / Incidence not known
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression.
    Abatacept: (Moderate) Concomitant use of immunosuppressives such as cyclophosphamide may increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients taking concomitant immunosuppressants have not been evaluated. Patients receiving cyclophosphamide along with adalimumab may be at a greater risk of developing an infection.
    Amiodarone: (Moderate) Use caution if cyclophosphamide is used concomitantly with amiodarone as there may be an increased risk of pulmonary toxicity.
    Amlodipine; Benazepril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity.
    Amphotericin B lipid complex (ABLC): (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity.
    Amphotericin B liposomal (LAmB): (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity.
    Amphotericin B: (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity.
    Amprenavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Angiotensin-converting enzyme inhibitors: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Anthracyclines: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Atazanavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Atazanavir; Cobicistat: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Azathioprine: (Moderate) Monitor hepatic function if coadministration of cyclophosphamide with azathioprine is necessary as there is an increased risk of hepatotoxicity (liver necrosis).
    Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as intravenous cyclophosphamide. Therefore, belimumab use is not recommended in combination with intravenous cyclophosphamide. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Benazepril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Busulfan: (Moderate) Monitor hepatic function if coadministration of cyclophosphamide with busulfan is necessary as there is an increased risk of hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD). An increased incidence of mucositis has also been reported with concomitant use.
    Captopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations if coadministration with cyclophosphamide is necessary. Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.
    Cytarabine, ARA-C: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with cytarabine is necessary as there is an increased risk of cardiotoxicity.
    Darunavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Enalapril, Enalaprilat: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Enalapril; Felodipine: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Etanercept: (Major) The concurrent use of cyclophosphamide and etanercept is not recommended. Patients with severe Wegener's granulomatosis who received cyclophosphamide, etanercept, and corticosteroids had more non-cutaneous solid malignancies as compared with patients who received only cyclophosphamide and corticosteroids. Also, concurrent use of myelosuppressive anti-rheumatic agents has been associated with pancytopenia, including aplastic anemia, in some patients treated with etanercept.
    Fam-Trastuzumab deruxtecan: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab deruxtecan is necessary as there is an increased risk of cardiotoxicity.
    Filgrastim, G-CSF: (Minor) Use caution if cyclophosphamide is used concomitantly with filgrastim, G-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF.
    Fosamprenavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Fosinopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Indinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Indomethacin: (Moderate) Use caution if coadministration of cyclophosphamide with indomethacin is necessary as acute water intoxication has been reported with concomitant use.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lisinopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Lopinavir; Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Metronidazole: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity.
    Moexipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as cyclophosphamide. Ordinarily, patients with multiple sclerosis who are receiving chronic immunosuppressant therapy (including with cyclophosphamide) should not be treated with natalizumab for similar reasons. The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with cyclophosphamide is also a risk factor for PML.
    Nelfinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Paclitaxel: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with paclitaxel is necessary. Increased hematologic toxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Minor) Use caution if cyclophosphamide is used concomitantly with pegfilgrastim; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GM-CSF.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Pentostatin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with pentostatin is necessary as there is an increased risk of cardiotoxicity.
    Perindopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Perindopril; Amlodipine: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Pertuzumab; Trastuzumab; Hyaluronidase: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Protease inhibitors: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Quinapril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Ramipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Saquinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Sargramostim, GM-CSF: (Minor) Use caution if cyclophosphamide is used concomitantly with sargramostim, GM-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and GM-CSF.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Succinylcholine: (Major) Notify the anesthesiologist if a patient has been treated with cyclophosphamide within 10 days of general anesthesia. Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity; prolonged apnea may occur with concurrent use of depolarizing muscle relaxants such as succinylcholine.
    Tamoxifen: (Moderate) Monitor for signs and symptoms of thrombosis if coadministration of cyclophosphamide with tamoxifen is necessary; concomitant use of tamoxifen with chemotherapy may increase the risk of thromboembolic complications.
    Tbo-Filgrastim: (Minor) Use caution if cyclophosphamide is used concomitantly with filgrastim, G-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF.
    Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Thiazide diuretics: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression.
    Thiotepa: (Moderate) The concomitant use of thiotepa and cyclophosphamide may reduce cyclophosphamide metabolism to its active metabolite resulting in decreased cyclophosphamide efficacy. Thiotepa is a CYP2B6 inhibitor in vitro. Cyclophosphamide is converted to the active metabolite, 4-hydroxycyclophosphamide, via CYP2B6 metabolism. This effect appears to be sequence dependent with a greater reduction in the conversion to the active metabolite when thiotepa is given 1.5 hours prior to the IV cyclophosphamide compared to when thiotepa is given after IV cyclophosphamide.
    Tipranavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Trandolapril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Trandolapril; Verapamil: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression.
    Trastuzumab: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
    Trastuzumab; Hyaluronidase: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vasopressin, ADH: (Minor) Use of vasopressin with drugs suspected of causing syndrome of inappropriate antidiuretic hormone secretion (SIADH), such as cyclophosphamide, may increase the pressor and antidiuretic effects of vasopressin.
    Warfarin: (Moderate) Monitor the PT/INR in patients receiving cyclophosphamide with warfarin therapy; both increased and decreased warfarin effect have been reported in patients receiving concomitant therapy.
    Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during cyclophosphamide treatment and for at least 1 year after the last dose. Exposure to cyclophosphamide during pregnancy can cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Women who are pregnant or who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. Malformations of the skeleton, palate, limbs, and eyes as well as miscarriage have been reported after human fetal exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects in the newborn (e.g., leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis) have also been reported after exposure to cyclophosphamide during pregnancy. When administered to pregnant animals (mice, rats, rabbits, and monkeys) during organogenesis at doses at or below the dose used in humans based on body surface area, multiple malformations occurred including neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

    Due to the potential for serious adverse reactions in nursing infants from cyclophosphamide, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Cyclophosphamide is present in human milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast-fed by women treated with cyclophosphamide.

    MECHANISM OF ACTION

    Cyclophosphamide is a synthetic alkylating agent that is chemically related to the nitrogen mustards. It is an inactive prodrug that requires activation to release the active metabolite, phosphoramide mustard. Hydroxylation of cyclophosphamide by the cytochrome P450 system generates 4-hydroxycyclophosphamide, which coexists in equilibrium with its tautomer, aldophosphamide. These metabolites are able to freely diffuse into cells, where aldophosphamide is decomposed into 2 compounds, phosphoramide mustard and acrolein. Phosphoramide mustard produces interstrand and intrastand DNA crosslinks, responsible for the cytotoxic properties of cyclophosphamide. Acrolein is the cause of hemorrhagic cystitis.
     
    Cyclophosphamide also has immunosuppressant effects. Cyclophosphamide causes lymphopenia (both B-cells and T-cells) and selective suppression of B-lymphocyte activity. Decreased immunoglobulin secretion has been described in patients treated with low-dose cyclophosphamide for autoimmune diseases. Cyclophosphamide also influences T-lymphocyte activity, although the exact mechanism has not been established. Cyclophosphamide can suppress some T-cell function (e.g., graft-versus-host response and delayed hypersensitivity). In addition, cyclophosphamide (or an activated analog, 4-hydroperoxycyclophosphamide) can enhance the immune response by inhibiting suppressor T-cells. Some studies have shown that cyclophosphamide can increase the efficacy of certain immunotherapy regimens by decreasing tumor-induced suppressor T-cells. Other data suggest that cyclophosphamide induces release of factors that enhance tumor-specific T-cells, specifically type I interferons.

    PHARMACOKINETICS

    Cyclophosphamide is administered orally and intravenously. The parent drug, cyclophosphamide, is approximately 20% protein-bound, with no dose-dependent changes in protein binding; some metabolites are protein-bound to an extent greater than 60%. The volume of distribution approximates total body water (30 to 50 liters). Following IV administration, the elimination half-life of cyclophosphamide ranges from 3 to 12 hours, with total body clearance ranging from 4 liters/hour to 5.6 liters/hour. Pharmacokinetics are linear over the dose range used clinically; however, at high doses, less of the parent compound is cleared by 4-hydroxylation, resulting in nonlinear elimination. When administered at a dose of 4 g/m2 over 90 minutes, cyclophosphamide exhibited saturable elimination in parallel with first-order renal elimination. Cyclophosphamide appears to induce its own metabolism, which results in an increase in the total clearance, increased formation of the 4-hydroxyl metabolites, and shortened half-life values following repeated administration at 12- to 24-hour intervals. Cyclophosphamide is primarily excreted as metabolites, with 10% to 20% excreted as unchanged drug in the urine and 4% in the bile following IV administration.
     
    Affected cytochrome P450 isoenzymes: CYP2A6, CYP2B6, CYP3A4/5, CYP2C9, CYP2C18, CYP2C19
    Cyclophosphamide is a prodrug that is primarily (75%) biotransformed in the liver to active alkylating metabolites by a mixed-function microsomal oxidase system including CYP2A6, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C18, and CYP2C19; CYP2B6 exhibits the highest 4-hydroxylase activity. The contribution of CYP3A4 to the activation of cyclophosphamide is variable, from a low level of 5% to 10% up to 35% of total enzyme activity. CYP3A5 and CYP2C9 might be important in extrahepatic activation of cyclophosphamide. The extensive P-450 catalyzed metabolism of cyclophosphamide yields both therapeutically active (N-hydroxylated) and therapeutically inactive but neurotoxic (N-dechlorethylated) metabolites. The hydroxylation and activation process for cyclophosphamide is catalyzed primarily by CYP2B6 as previously mentioned, whereas the N-dechloroethylation process for cyclophosphamide appears catalyzed primarily by CYP3A4. Cyclophosphamide, the parent compound, is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide; these active metabolites then undergo oxidation by aldehyde dehydrogenase to form inactive 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can also undergo beta-elimination to form other active metabolites, phosphoramide mustard, and acrolein; this spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of a dose of cyclophosphamide is directly detoxified by side-chain oxidation, leading to the formation of inactive metabolite 2-dechloroethylcyclophosphamide. It is not yet completely clear what effect inhibitors of CYP2B6 or CYP3A4 have on the activation and/or toxicity of cyclophosphamide. It would appear that inhibitors of CYP2B6 would interfere with the effectiveness of cyclophosphamide by limiting the drug's bioactivation. It has also been postulated that the use of CYP3A4 inhibitors might attenuate neurotoxic effects of the drug in some patients, but no clinically reliable data are available to support this hypothesis.

    Oral Route

    Peak concentrations of cyclophosphamide occurred 1 hour after oral administration (Tmax). The AUC ratio for cyclophosphamide after oral and IV administration (AUCPO to AUCIV) ranged from 0.87 to 0.96.