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  • CLASSES

    Nitrogen Mustard Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Polyfunctional alkylating agent; activity as an antineoplastic and immunosuppressant
    Active against a variety of solid tumors, NHL, Hodgkin lymphoma, and ALL
    Also used in nephrotic syndrome, RA, Wegener's granulomatosis and other immune disorders

    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 (hazard ratio = 0.74; 2-sided 95% CI = 0.6, 0.92, stratified log rank p = 0.0047). 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 III 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 %, p = 0.012). Overall survival at 5 years was also increased by FEC-D (90.7% vs. 86.7%, p = 0.017). Grade 3/4 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 III 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%; p = 0.015). Extended follow-up after 7 years continued to show a significant benefit for DFS (81% vs. 75%, p = 0.033) and overall survival (87% vs. 82%, p = 0.032). 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 5-fluorouracil (5-FU) 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 5-FU (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 III 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 III 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 5-fluorouracil (CMF)†.
    Oral dosage
    Adults

    100 mg/m2 orally on days 1 through 14, in combination with methotrexate 40 mg/m2 IV and 5-fluorouracil 600 mg/m2 IV on day 1 and day 8, repeated every 28 days for 6 cycles.

    Intravenous dosage
    Adults

    500 to 1000 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's 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 1500 mg/m2 IV. In the ProMACE-CytaBOM regimen for Burkitt's lymphoma, 650 mg/m2 is given once every 21 days. In the M-BACOD regimen for Burkitt's 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 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 II 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 II 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 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. Hepatic impairment may reduce the rate at which the active metabolites of cyclophosphamide are formed.

    Renal Impairment

    Although patients with renal impairment may demonstrate measurable changes in cyclophosphamide pharmacokinetics, the need for dosage adjustment is controversial.
    CrCl > 55 mL/min: No change needed.
    CrCl 21—55 mL/min: Some experts recommend no change; others recommend a 10% dosage reduction.
    CrCl 11—20 mL/min: Some experts recommend no change; others recommend a 20% dosage reduction.
    CrCl <= 10 mL/min: Some experts recommend no change; others recommend a 50% dosage reduction.
     
    Intermittent hemodialysis
    Cyclophosphamide should be given after dialysis. If cyclophosphamide is given prior to dialysis, a supplemental dosage corresponding to the amount loss during dialysis (about 35% of the dose) may be required at the end of dialysis. However, the amount of cyclophosphamide and its metabolites removed during dialysis varies depending upon the dialysis system used. (written communication, Bristol-Myers Squibb)

    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

    Do not cut, crush, or chew tablets.
    Wash hands immediately if contact with broken tablets occur.

    Extemporaneous Compounding-Oral

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

    Injectable Administration
    Intravenous Administration

    Reconstitution:
    Add the appropriate amount of 0.9% Sodium Chloride Injection or Sterile Water for Injection, diluent to the vial to a final cyclophosphamide concentration of 20 mg/mL (2%).
    Swirl the vial gently to dissolve the drug completely.
    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.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use vials that show signs of melting (i.e., clear or yellowish viscous liquid typically found as a connected phase or in droplets).
     
    Direct Intravenous Injection:
    Cyclophosphamide for injection may be administered as direct IV injection only when reconstituted with 0.9% Sodium Chloride injection. Do not directly inject cyclophosphamide reconstituted with Sterile water for injection as this solution is hypotonic.
    Inject slowly to avoid rate-dependent adverse events.
     
    Intravenous Infusion:
    Cyclophosphamide for injection may be administered as an IV infusion when reconstituted with 0.9% Sodium Chloride injection or Sterile Water for injection and further diluted in 5% Dextrose Injection USP, 5% Dextrose and 0.9% Sodium Chloride injection USP, or 0.45% sterile sodium chloride to a minimum concentration of 2 mg/mL.
    Infuse slowly to avoid rate-dependent adverse events; infusion duration depends on the infusion volume and fluid type.
    After dilution in 0.45% Sodium Chloride injection, the solution may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator.
    After dilution in 5% Dextrose for injection or 5% Dextrose and 0.9% Sodium Chloride for injection, the solution may be stored at room temperature for up to 24 hours or for up to 36 hours in the refrigerator.
    The final storage time includes reconstitution time.

    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

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

    Bladder obstruction, dialysis, hematuria, hemorrhagic cystitis, renal impairment, urinary tract infection (UTI), urinary tract obstruction

    Urinary tract and renal toxicities have been reported with cyclophosphamide therapy, including hemorrhagic cystitis requiring medical and/or surgical intervention. Urotoxicity may occur with short- or long-term therapy and may be fatal. Use is contraindicated in patients with urinary outflow obstruction (bladder obstruction/urinary tract obstruction). Use cyclophosphamide with caution in patients with an urinary tract infection (UTI) or with severe renal impairment (creatinine clearance < 25 mL/min). Cyclophosphamide is dialyzable; therefore, administer cyclophosphamide at a consistent interval from dialysis. Maintain adequate hydration to ensure forced diuresis and frequent bladder emptying; mesna administration may also help to prevent severe bladder toxicity. Correct any urinary tract obstructions prior to starting cyclophosphamide and regularly monitor for urotoxicity (e.g., urinalysis for erythrocytes/hematuria) and nephrotoxicity (e.g., serum creatinine concentration). Therapy interruption or cystectomy may be required in patients who develop urotoxicity (e.g., bladder ulceration, necrosis, fibrosis, contracture, secondary cancer); discontinue therapy for severe hemorrhagic cystitis.

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

    Myelosuppression (e.g., anemia, leukopenia, neutropenia, thrombocytopenia) has been reported with cyclophosphamide therapy; bone marrow suppression and/or failure has also occurred. Patients pretreated with or who are receiving concomitant chemotherapy and/or radiation may be at increased risk for myelosuppression. Monitor complete blood and platelets during cyclophosphamide therapy. Do not administer cyclophosphamide if the neutrophil count is 1,500/mm3 or less and the platelet count is less than 50,000/mm3. Cyclophosphamide therapy may also result in severe immunosuppression. Infection (e.g, viral infection such as varicella and herpes infection, bacterial infection, fungal infection) has occurred during treatment, including fatal cases of sepsis and septic shock. Latent infections may be reactivated. Discontinue, hold, or dose reduce therapy in patients who have or develop a serious infection. 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.

    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

    Patients with severe liver impairment may have reduced cyclophosphamide conversion to its active 4-hydroxyl metabolite. Additionally, cases of veno-occlusive disease (VOD) have developed gradually with long-term cyclophosphamide therapy given at low, immunosuppressive doses. The risk of VOD may be higher if cyclophosphamide is used in combination with whole body radiation, busulfan, or other agents as a preparative regimen for bone morrow transplantation or in patients with hepatic disease, prior radiation therapy to the abdomen, or a low performance status.

    Surgery

    If a patient has been treated with cyclophosphamide within 10 days of a procedure or surgery requiring depolarizing muscle relaxants (e.g., succinylcholine), the anesthesiologist should be notified because cyclophosphamide may cause marked and persistent inhibition of cholinesterase activity resulting in prolonged apnea. In addition, cyclophosphamide may interfere with normal wound healing.

    Geriatric, hyponatremia

    Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported in patients receiving cyclophosphamide; the older or geriatric adult is generally more susceptible to hyponatremia. Geriatric patients may also be at increased risk of cyclophosphamide-associated cardiotoxicity.

    Cardiac arrhythmias, cardiac disease, cardiac tamponade, heart failure, myocarditis, pericardial effusion, pericarditis, QT prolongation, ventricular arrhythmias

    Serious cardiotoxicity (e.g., myocarditis, myo-pericarditis, pericardial effusion, cardiac tamponade, and congestive heart failure) has 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 higher with high doses of cyclophosphamide and in patients with advanced age, other risk factors for cardiac toxicity including cardiac disease, prior radiation therapy to the cardiac region, or previous or concomitant treatment with other cardiotoxic agents. Monitor patients with risk factors for cardiac toxicity or cardiac disease.

    Pneumonitis, pulmonary fibrosis

    Serious pulmonary toxicity (e.g., pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, respiratory failure) has been reported with cyclophosphamide use. Toxicity may occur during or after treatment with cyclophosphamide; some cases of pneumonitis have occurred years after treatment. Late-onset pneumonitis occurring greater than 6 months after starting cyclophosphamide therapy is associated with an increased risk of death. 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, urinary tract cancer, and bladder cancer. Taking measures to prevent hemorrhagic cystitis may reduce the risk of bladder cancer.

    Radiation therapy

    Use caution if cyclophosphamide is administered to patient with past or concomitant radiation therapy, as has this been associated with an increased risk of hemorrhagic cystitis as well as increased cardiotoxicity if radiation was received in the cardiac/chest region. Additionally, patients pretreated with or who are receiving concomitant radiation may be at increased risk for myelosuppression.

    Children

    Pre-pubescent children who received cyclophosphamide typically develop secondary sexual characteristics normally. However, ovarian fibrosis with complete loss of germ cells has been reported in pre-pubescent girls who received prolonged cyclophosphamide therapy. There appears to be an increased risk of premature menopause after completing cyclophosphamide therapy in girls who retain ovarian function. Oligospermia or azoospermia, increased gonadotropin secretion, and testicular atrophy have occurred in pre-pubescent boys who received cyclophosphamide therapy. Azoospermia may be reversible in some cases. Additionally, cyclophosphamide treatment exceeding 90 days increases the probability of sterility in male pediatric patients with minimal change nephrotic syndrome.

    Infertility, male-mediated teratogenicity, pregnancy

    Cyclophosphamide is classified as FDA pregnancy risk category D. When administered to a pregnant woman, cyclophosphamide can cause fetal harm including birth defects, miscarriage, fetal growth retardation, and fetotoxic effects. If cyclophosphamide is used during pregnancy or the patient becomes pregnant while receiving cyclophosphamide, she should be appraised of the potential risks to the fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during and for up to 1 year after completion of cyclophosphamide therapy. There is a potential for male-mediated teratogenicity with cyclophosphamide use; therefore, a male patient must use a latex condom during sexual intercourse with a woman of reproductive potential while on therapy and for at least 4 months after discontinuing cyclophosphamide. Infertility and sterility in males and females have been reported with cyclophosphamide use. Sterility may be irreversible and appears to be dependent on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment.

    Breast-feeding

    According to the manufacturer, cyclophosphamide or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from cyclophosphamide; neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in breastfed infants in women treated with cyclophosphamide. Cyclophosphamide is excreted into breast milk. The American Academy of Pediatrics considers cyclophosphamide a cytotoxic drug that may interfere with the cellular metabolism of a nursing infant. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Vaccination

    Vaccination during chemotherapy (such as cyclophosphamide) or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by at least 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    thrombotic microangiopathy / Delayed / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    cardiac tamponade / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / 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
    thromboembolism / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known

    Moderate

    hematuria / Delayed / Incidence not known
    bladder spasm / Early / Incidence not known
    testicular atrophy / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    parotitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    erythema / Early / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    hot flashes / Early / Incidence not known
    immunosuppression / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    ascites / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    nausea / Early / 10.0
    vomiting / Early / 10.0
    amenorrhea / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    cough / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    dizziness / Early / Incidence not known
    dysesthesia / Delayed / Incidence not known
    tremor / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    infection / Delayed / Incidence not known
    malaise / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Use caution if cyclophosphamide is used concomitantly with zidovudine, ZDV, as increased or additive hemotoxicity and/or immunosuppression may occur.
    Abatacept: (Moderate) Concomitant use of immunosuppressives may potentially 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.
    Acetaminophen; Butalbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Acetaminophen; Butalbital; Caffeine: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving cyclophosphamide along with adalimumab may be at a greater risk of developing an infection.
    Alefacept: (Severe) Patients receiving other immunosuppressives should not receive concurrent therapy with alefacept; there is the possibility of excessive immunosuppression and subsequent risks of infection and other serious side effects.
    Amiodarone: (Moderate) Use caution if cyclophosphamide is used concomitantly with amiodarone, as there may be an increased risk of pulmonary toxicity.
    Amlodipine; Benazepril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Amobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Use caution if cyclophosphamide is used concomitantly with amphotericin B, as there may be an increased risk of nephrotoxicity.
    Amphotericin B lipid complex (ABLC): (Moderate) Use caution if cyclophosphamide is used concomitantly with amphotericin B, as there may be an increased risk of nephrotoxicity.
    Amphotericin B liposomal (LAmB): (Moderate) Use caution if cyclophosphamide is used concomitantly with amphotericin B, as there may be an increased risk of nephrotoxicity.
    Amphotericin B: (Moderate) Use caution if cyclophosphamide is used concomitantly with amphotericin B, as there may be an increased risk of nephrotoxicity.
    Angiotensin-converting enzyme inhibitors: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Anthracyclines: (Major) Use caution if cyclophosphamide is used concomitantly with anthracyclines, as there may be an increased risk of cardiotoxicity. Concurrent administration of cyclophosphamide and doxorubicin has resulted in an increase in exposure to doxorubicinol, a more cardiotoxic metabolite of doxorubicin. Additionally, concurrent treatment with doxorubicin (including doxorubicin liposomal) has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive effects may be seen with other immunosuppressives or antineoplastic agents, such as cyclophosphamide. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects. Some protocols recommend decreasing the dosage of the standard immunosuppressive agents during treatment with antithymocyte globulin. Carefully observe patients for new adverse effects if the dose of cyclophosphamide is reduced, as adverse effects of antithymocyte globulin may have been masked.
    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.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) In vitro studies have shown that orphenadrine, a CYP2B6 inhibitor, inhibited the microsomal activation of cyclophosphamide. Theoretically, such inhibition of CYP2B6 would interfere with the effectiveness of cyclophosphamide by limiting the drug's bio-activation.
    Atracurium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Azathioprine: (Moderate) Use caution if cyclophosphamide is used concomitantly with azathioprine, as there may be an increased risk of hepatotoxicity (liver necrosis).
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Barbiturates: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Basiliximab: (Minor) Because basiliximab is an immunosuppressant, additive effects may be seen with other immunosuppressives.
    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.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Benazepril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Use caution if cyclophosphamide is used concomitantly with metronidazole, as animal studies found the combination to be associated with an increased risk of cyclophosphamide-related toxicities. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, but the causal association is unclear.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Use caution if cyclophosphamide is used concomitantly with metronidazole, as animal studies found the combination to be associated with an increased risk of cyclophosphamide-related toxicities. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, but the causal association is unclear.
    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: (Minor) Use busulfan and cyclophosphamide together with caution. Concomitant use may result in increased busulfan levels and increased busulfan toxicity; additionally, myelosuppressive toxicity may be additive. An increased incidence of hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease, and mucositis has been reported; additionally, there may be an increased risk of pulmonary toxicity. Busulfan and cyclophosphamide are both metabolized in the liver through conjugation with glutathione; so these drugs may compete for elimination which may reduce the clearance of busulfan.
    Butabarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Captopril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Carbamazepine: (Minor) Use caution if cyclophosphamide is used concomitantly with carbamazepine, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Carbamazepine is a strong CYP3A4 inducer, as well as an inducer of CYP2A6, 2C9, and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
    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.
    Ciprofloxacin: (Moderate) Use caution if cyclophosphamide is used concomitantly with ciprofloxacin, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. It is not yet completely clear what effect inhibitors of CYP2B6 or CYP3A4 have on the activation and/or toxicity of cyclophosphamide; it has 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. In vitro, coadministration with a CYP3A4 inhibitor had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with both strong and moderate CYP3A4 inhibitors in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cisatracurium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Clopidogrel: (Moderate) Monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide during coadministration with clopidogrel. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6. Clopidogrel is a weak CYP2B6 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cytarabine, ARA-C: (Major) Use caution if cyclophosphamide is used concomitantly with cytarabine, Ara-C, as there may be an increased risk of cardiotoxicity.
    Darunavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with darunavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Darunavir is a strong CYP2B6 and 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Darunavir; Cobicistat: (Moderate) Use caution if cyclophosphamide is used concomitantly with darunavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Darunavir is a strong CYP2B6 and 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with darunavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Darunavir is a strong CYP2B6 and 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with ritonavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ritonavir is a strong CYP3A4 inhibitor as well as a moderate inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Daunorubicin Liposomal: (Moderate) Concurrent use of liposomal daunorubicin with immunosuppressives, other bone marrow depressants or agents that cause mucositis may result in additive effects. Dosage reductions may be required.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Moderate) Concurrent use of liposomal daunorubicin with immunosuppressives, other bone marrow depressants or agents that cause mucositis may result in additive effects. Dosage reductions may be required.
    Doxacurium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Doxorubicin Liposomal: (Major) Cyclophosphamide has been reported to potentiate anthracycline-induced cardiotoxicity. Concurrent administration of cyclophosphamide and conventional doxorubicin may result in an increase in exposure to doxorubicinol, a metabolite of doxorubicin that appears to be a more potent cardiotoxin than doxorubicin. Concurrent treatment with conventional doxorubicin has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis. Data examining the concurrent use of pegylated liposomal doxorubicin (Doxil) and cyclophosphamide are not available. In addition, exacerbation of cyclophosphamide-induced hemorrhagic cystitis by the doxorubicin in Doxil has been reported.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efalizumab: (Major) Cyclophosphamide exhibits significant immunosuppressive activity and myelosuppression that may be additive to other immunosuppressives, such as efalizumab. While therapy is designed to take advantage of this effect, clinicians should be alert for over-immunosuppression or myelosuppression. LFTs should be monitored in patients receiving both agents concomitantly.
    Efavirenz: (Moderate) Use caution if cyclophosphamide is used concomitantly with efavirenz, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Efavirenz is a moderate CYP2B6 and 3A4 inducer, as well as a moderate in vitro inhibitor of CYP2C9 and 2C19; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 or 2C19 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution if cyclophosphamide is used concomitantly with efavirenz, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Efavirenz is a moderate CYP2B6 and 3A4 inducer, as well as a moderate in vitro inhibitor of CYP2C9 and 2C19; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 or 2C19 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if cyclophosphamide is used concomitantly with efavirenz, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Efavirenz is a moderate CYP2B6 and 3A4 inducer, as well as a moderate in vitro inhibitor of CYP2C9 and 2C19; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 or 2C19 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Enalapril, Enalaprilat: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Enalapril; Felodipine: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    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.
    Ethotoin: (Minor) Since cyclophosphamide is activated in the liver, enzyme inducers such as the hydantoins can increase the clinical and/or toxic effects of these chemotherapy agents.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Fosinopril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Golimumab: (Severe) The safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Imatinib: (Moderate) Use caution if cyclophosphamide is used concomitantly with imatinib and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide, including neutropenia, neurotoxicity, and risk of infection. Imatinib is a moderate 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites or to its neurotoxic metabolites may be affected. The significance of this potential interaction is not clear given the complexity of cyclophosphamide pharmacokinetics. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional CYP450 enzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites of cyclophosphamide are then inactivated by aldehyde dehydrogenase-mediated oxidation.
    Indomethacin: (Minor) Use caution if cyclophosphamide is used concomitantly with indomethacin, as there may be an increased risk of nephrotoxicity; additionally, acute water intoxication has been reported with concomitant use of cyclophosphamide and indomethacin.
    Influenza Virus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifampin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifampin is a strong CYP3A4 inducer, as well as a moderate inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Isoniazid, INH; Rifampin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifampin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifampin is a strong CYP3A4 inducer, as well as a moderate inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Use caution if cyclophosphamide is used concomitantly with zidovudine, ZDV, as increased or additive hemotoxicity and/or immunosuppression may occur.
    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.
    Lisinopril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lopinavir; Ritonavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with ritonavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ritonavir is a strong CYP3A4 inhibitor as well as a moderate inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of cyclophosphamide, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of cyclophosphamide, such as neurotoxicity. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may increase the clinical and/or toxic effects of cyclophosphamide due to a potential for increased conversion of cyclophosphamide to its metabolites. If used together, monitor patients closely for cyclophosphamide efficacy and/or toxicity. The extensive P-450 catalyzed metabolism of cyclophosphamide yields both therapeutically active (N-hydroxylated) and therapeutically inactive but neurotoxic (N-dechlorethylated) metabolites. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Cyclophosphamide is primarily metabolized by CYP2B6, and to a lesser extent by CYP3A4, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Chronic administration of high doses of phenobarbital, another strong CYP3A inducer, has been reported to increase the rate of metabolism and the leukopenic activity of cyclophosphamide.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may increase the clinical and/or toxic effects of cyclophosphamide due to a potential for increased conversion of cyclophosphamide to its metabolites. If used together, monitor patients closely for cyclophosphamide efficacy and/or toxicity. The extensive P-450 catalyzed metabolism of cyclophosphamide yields both therapeutically active (N-hydroxylated) and therapeutically inactive but neurotoxic (N-dechlorethylated) metabolites. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Cyclophosphamide is primarily metabolized by CYP2B6, and to a lesser extent by CYP3A4, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. It is not yet completely clear what effect inducers of the CYP450 isoenzymes have on the activation and/or toxicity of cyclophosphamide. Chronic administration of high doses of phenobarbital, another strong CYP3A inducer, has been reported to increase the rate of metabolism and the leukopenic activity of cyclophosphamide.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Mephobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    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.
    Methohexital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Metronidazole: (Moderate) Use caution if cyclophosphamide is used concomitantly with metronidazole, as animal studies found the combination to be associated with an increased risk of cyclophosphamide-related toxicities. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, but the causal association is unclear.
    Mifepristone: (Moderate) Use caution and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. Co-use may increase the risk of infection or neutropenia, or other side effects such as neurotoxicity, from cyclophosphamide. Mifepristone, when used chronically for hormonal conditions, such as Cushing's syndrome, is a CYP3A4 inhibitor as well as an inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional CYP450 enzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation of cyclophosphamide to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites of cyclophosphamide are then inactivated by aldehyde dehydrogenase-mediated oxidation.
    Mitotane: (Major) Use caution if cyclophosphamide is used concomitantly with mitotane, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Mitotane is a strong CYP3A4 inducer. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Mivacurium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Modafinil: (Minor) Use caution if cyclophosphamide is used concomitantly with modafinil, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Modafinil is a moderate CYP2C19 inhibitor, a moderate CYP3A4 inducer, and a weak inhibitor of CYP2C9; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 or 2C19 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Moexipril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Nafcillin: (Minor) Use caution if cyclophosphamide is used concomitantly with nafcillin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Nafcillin is a moderate CYP3A4 inducer in vitro. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Natalizumab: (Major) 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 an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as cyclophosphamide. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
    Nefazodone: (Moderate) Use caution if cyclophosphamide is used concomitantly with nefazodone, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Nefazodone is a strong CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Nelfinavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with nelfinavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Nelfinavir is a moderate CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Netupitant, Fosnetupitant; Palonosetron: (Minor) Netupitant; palonosetron is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting in patients receiving cyclophosphamide-based chemotherapy. However, theoretically it could cause possible changes in the efficacy or toxicity profile of cyclophosphamide. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Netupitant is a moderate CYP3A4 inhibitor; the inhibitory effect of netupitant on CYP3A4 can last for multiple days. Conversion of cyclophosphamide to its active metabolites may be affected. When coadministered with netupitant; palonosetron, the mean Cmax and AUC for cyclophosphamide was 27% and 20% higher, respectively, than when coadministered with palonosetron alone. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197). However, in cancer patients who received a single dose of netupitant; palonosetron 1 hour prior to chemotherapy (docetaxel, etoposide, or cyclophosphamide), the Cmax and AUC of netupitant and its metabolites, as well as palonosetron, were similar to those in healthy subjects.
    Neuromuscular blockers: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Nevirapine: (Minor) Use caution if cyclophosphamide is used concomitantly with nevirapine, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Nevirapine is a moderate CYP3A4 inducer. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Nicardipine: (Moderate) Use caution if cyclophosphamide is used concomitantly with nicardipine, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Nicardipine is a moderate in vitro CYP2C19 and 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Octreotide: (Moderate) Use caution if cyclophosphamide is used concomitantly with octreotide, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Octreotide is a moderate CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with ritonavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ritonavir is a strong CYP3A4 inhibitor as well as a moderate inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Omeprazole; Amoxicillin; Rifabutin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifabutin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifabutin is a moderate CYP3A4 inducer. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Ondansetron: (Minor) Ondansetron may cause a decrease in the serum concentration of cyclophosphamide if the two drugs are coadministered. It is unknown if patients receiving ondansetron continuous infusions would experience lowered tumor responses to cyclophosphamide treatment.
    Orphenadrine: (Minor) In vitro studies have shown that orphenadrine, a CYP2B6 inhibitor, inhibited the microsomal activation of cyclophosphamide. Theoretically, such inhibition of CYP2B6 would interfere with the effectiveness of cyclophosphamide by limiting the drug's bio-activation.
    Paclitaxel: (Minor) Use caution if cyclophosphamide is used concomitantly with paclitaxel; increased hemotoxicity 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.
    Pancuronium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    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 either filgrastim or sargramostim; theoretically, this could also occur with pegfilgrastim.
    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.
    Pentobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Pentostatin: (Major) Use caution if cyclophosphamide is used concomitantly with pentostatin, as there may be an increased risk of cardiotoxicity.
    Perindopril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Perindopril; Amlodipine: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Phenobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Phenytoin: (Minor) Use caution if cyclophosphamide is used concomitantly with phenytoin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Phenytoin is a strong CYP3A4 inducer, as well as an inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Posaconazole: (Moderate) Use caution if cyclophosphamide is used concomitantly with posaconazole, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Posaconazole is a strong CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    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.
    Primidone: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Quinapril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Ramipril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Rapacuronium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Rifabutin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifabutin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifabutin is a moderate CYP3A4 inducer. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Rifampin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifampin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifampin is a strong CYP3A4 inducer, as well as a moderate inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Rifapentine: (Minor) Use caution if cyclophosphamide is used concomitantly with rifapentine, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. CYP2C9 is also involved in the activation of cyclophosphamide. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifapentine is a moderate CYP3A4 and CYP2C9 inducer. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Rifaximin: (Minor) Use caution if cyclophosphamide is used concomitantly with rifaximin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Rifaximin can be a moderate CYP3A4 inducer in vitro; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Ritonavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with ritonavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ritonavir is a strong CYP3A4 inhibitor as well as a moderate inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Rituximab: (Moderate) These drugs are commonly used together in various treatment regimens for cancer or other diseases. However, the use of these drugs together may cause additive immunosuppression and increase the risk for infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of cyclophosphamide did not alter the pharmacokinetics of rituximab.
    Rituximab; Hyaluronidase: (Moderate) These drugs are commonly used together in various treatment regimens for cancer or other diseases. However, the use of these drugs together may cause additive immunosuppression and increase the risk for infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of cyclophosphamide did not alter the pharmacokinetics of rituximab.
    Rocuronium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    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.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Saquinavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with saquinavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Saquinavir is a strong CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Secobarbital: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cyclophosphamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of cyclophosphamide, such as neurotoxicity.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    St. John's Wort, Hypericum perforatum: (Minor) Use caution if cyclophosphamide is used concomitantly with St. John's Wort, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. St. John's Wort is a strong CYP3A4 inducer and a moderate inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Succinylcholine: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    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.
    Telithromycin: (Moderate) Use caution if cyclophosphamide is used concomitantly with telithromycin, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Telithromycin is a strong CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and cyclophosphamide is necessary, as the systemic exposure of cyclophosphamide may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of cyclophosphamide. Cyclophosphamide is a prodrug that is partially (10% to 35%) activated by CYP3A4. However, the N-dechloroethylation process, which produces a therapeutically inactive but neurotoxic metabolite, appears to be primarily catalyzed by CYP3A4. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temozolomide: (Minor) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    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) Coadministration of thiazide diuretics and antineoplastic agents such as cyclophosphamide may result in reduced renal excretion of the antineoplastic agent and therefore increased myelosuppressive effects.
    Thiopental: (Minor) Use caution if cyclophosphamide is used concomitantly with barbiturates, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Barbiturates are CYP3A4 inducers, as well as inducers of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    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.
    Ticlopidine: (Moderate) Use caution if cyclophosphamide is used concomitantly with ticlopidine, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ticlopidine is a strong CYP2B6 inhibitor in vitro, as well as a moderate inhibitor of CYP2C19; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Tipranavir: (Moderate) Use caution if cyclophosphamide is used concomitantly with tipranavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Tipranavir is a strong CYP3A4 inhibitor and a moderate inhibitor of CYP2C19; conversion of cyclophosphamide to its active or toxic metabolites may be affected. The 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 use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Trandolapril: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur.
    Trandolapril; Verapamil: (Moderate) Use caution if cyclophosphamide is used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors), as increased or additive leukopenia may occur. (Moderate) Use caution if cyclophosphamide is used concomitantly with verapamil, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide or a loss of blood pressure control. The clinical significance of this interaction is unknown. The absorption of verapamil can be reduced by the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Also, cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Verapamil is a moderate CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    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.
    Tubocurarine: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Valproic Acid, Divalproex Sodium: (Minor) Use caution if cyclophosphamide is used concomitantly with valproic acid, divalproex sodium, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Valproic acid is a moderate CYP2C9 inhibitor, a weak CYP2C19 inhibitor, and a weak inducer/inhibitor of CYP3A4; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9, 2C19, or 3A4 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Vecuronium: (Major) Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of depolarizing neuromuscular blockers, such as succinylcholine, and may cause prolonged apnea. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.
    Verapamil: (Moderate) Use caution if cyclophosphamide is used concomitantly with verapamil, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide or a loss of blood pressure control. The clinical significance of this interaction is unknown. The absorption of verapamil can be reduced by the cyclophosphamide, vincristine, procarbazine, prednisone (COPP) chemotherapeutic drug regimen. Also, cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Verapamil is a moderate CYP3A4 inhibitor; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Voriconazole: (Moderate) Use caution if cyclophosphamide is used concomitantly with voriconazole, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Voriconazole is a moderate CYP2C9 and 3A4 inhibitor, as well as a weak inhibitor of CYP2C19; conversion of cyclophosphamide to its active metabolites may be affected. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Warfarin: (Moderate) Use caution if cyclophosphamide is used concomitantly with warfarin, as both increased and decreased effects of warfarin have been reported when they are used together.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Zidovudine, ZDV: (Moderate) Use caution if cyclophosphamide is used concomitantly with zidovudine, ZDV, as increased or additive hemotoxicity and/or immunosuppression may occur.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, cyclophosphamide or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from cyclophosphamide; neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in breastfed infants in women treated with cyclophosphamide. Cyclophosphamide is excreted into breast milk. The American Academy of Pediatrics considers cyclophosphamide a cytotoxic drug that may interfere with the cellular metabolism of a nursing infant. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Cyclophosphamide is a prodrug that requires hepatic activation in order to be cytotoxic. Phosphoramide mustard and acrolein are formed following hepatic and cellular activation. Phosphoramide mustard is the active alkylating moiety responsible for the cytotoxic effects. As with other bifunctional alkylating agents, phosphoramide mustard forms intrastrand and interstrand DNA-DNA cross-links, which are responsible for the inactivation of the DNA. Acrolein binds to proteins but does not contribute to the anti-tumor effects. Acrolein is toxic to the bladder and is associated with the development 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 or intravenously (IV). It exhibits linear pharmacokinetics over the usual dosage range. Approximately 20% is bound to plasma proteins; binding is not dependent on dose. Some cyclophosphamide metabolites are greater than 60% protein bound. The approximate volume of distribution is 30—60 liters. Following IV administration, the elimination half-life is 3—12 hours and the total body clearance is 4—5.6 L/hr. Cyclophosphamide is a prodrug that undergoes activation and metabolism primarily in the liver. 4-hydroxycyclophosphamide is in equilibrium with its ring-open tautomer aldophosphamide and both of these undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide undergoes beta-elimination to form the 2 active metabolites, phosphoramide mustard and acrolein. This conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide is directly detoxified by side chain oxidation, leading to the formation of inactive metabolites. Cyclophosphamide may induce its own metabolism. This auto-induction results in an increase in the total clearance, an increased formation of 4-hydroxyl metabolites, and a shortened half-life following repeat administration at 12- to 24-hour intervals. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination. Saturable elimination in parallel with first-order renal elimination describe the kinetics of cyclophosphamide administered as 4 grams/m2 IV over 90 minutes. Following IV administration, 10—20% is excreted in the urine and 4% is excreted in feces, mostly as metabolites.
     
    Affected cytochrome P450 isoenzymes: CYP2A6, CYP2B6, CYP3A4/5, CYP2C9, CYP2C18, CYP2C19
    About 75% of the cyclophosphamide dose is activated to form 4-hydroxycyclophosphamide by hepatic cytochrome P450 isoenzymes including CYP2A6, CYP2B6, CYP3A4/5, CYP2C9, CYP2C18, and CYP2C19; CYP2B6 has the highest 4-hydroxylase activity. The contribution of CYP3A4 to the activation of cyclophosphamide is variable, from a low level of 5—10% 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. 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

    The AUC ratio for cyclophosphamide oral to IV administration ranges from 0.87—0.96:1. Following oral administration, the median time to peak plasma concentration (Tmax) is 1 hour.