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    Cyclophosphamide

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    Jun.20.2024

    cycloPHOSphamide

    Indications/Dosage

    Labeled

    • acute lymphocytic leukemia (ALL)
    • acute myelogenous leukemia (AML)
    • breast cancer
    • Burkitt lymphoma
    • chronic lymphocytic leukemia (CLL)
    • chronic myelogenous leukemia (CML)
    • cutaneous T-cell lymphoma (CTCL)
    • Hodgkin lymphoma
    • multiple myeloma
    • mycosis fungoides
    • nephrotic syndrome
    • neuroblastoma
    • non-Hodgkin's lymphoma (NHL)
    • ovarian cancer
    • retinoblastoma

    Off-Label

    • acute disseminated encephalomyelitis
    • amyloidosis
    • aplastic anemia
    • Behcet's syndrome
    • Churg-Strauss syndrome
    • dermatomyositis
    • encephalitis
    • granulomatosis with polyangiitis
    • heart transplant rejection
    • heart transplant rejection prophylaxis
    • immune thrombocytopenic purpura (ITP)
    • juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)
    • Kawasaki disease
    • kidney transplant rejection
    • kidney transplant rejection prophylaxis
    • liver transplant rejection
    • liver transplant rejection prophylaxis
    • lung transplant rejection
    • lupus nephritis
    • macroglobulinemia
    • osteogenic sarcoma
    • peripheral blood stem cell (PBSC) mobilization
    • peripheral T-cell lymphoma (PTCL)
    • pneumonitis
    • polyarteritis nodosa
    • polymyositis
    • pulmonary fibrosis
    • rheumatoid arthritis
    • scleroderma (systemic sclerosis)
    • small cell lung cancer (SCLC)
    • stem cell transplant preparation
    • systemic anaplastic large-cell lymphoma
    • systemic lupus erythematosus (SLE)
    • thymoma
    • trophoblastic disease
    • uveitis
    • warm autoimmune hemolytic anemia
    • rhabdomyosarcoma
    † Off-label indication

    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.[61450]

    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.[61451]

    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.[49907] 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.[49910]

    For the treatment of breast cancer

    Intravenous dosage

    Adults

    500 to 1,000 mg/m2 intravenous on day 1 in combination with fluorouracil and methotrexate (CMF), with fluorouracil and doxorubicin (CAF), or with doxorubicin (AC). Additionally, cyclophosphamide 600 mg/m2 may be given in a dose-dense fashion on day 1 of every 14 days with doxorubicin (60 mg/m2) along with growth-factor support, which must be given to prevent neutropenia.[33122]

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

    Intravenous dosage

    Adults

    600 mg/m2 IV in combination with doxorubicin (60 mg/m2 IV) every 2 weeks (dose-dense AC) and atezolizumab (840 mg IV every 2 weeks) for 8 weeks, followed by surgery. Begin dose-dense AC plus atezolizumab after completion of neoadjuvant nab-paclitaxel (125 mg/m2 once weekly) plus atezolizumab (840 mg IV every 2 weeks) for 12 weeks. After surgery, continue atezolizumab 1,200 mg IV every 3 weeks for 11 cycles to complete approximately 12 months of atezolizumab therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial (IMpassion031), neoadjuvant treatment with atezolizumab plus sequential nab-paclitaxel and AC chemotherapy significantly improved pCR compared with neoadjuvant placebo plus sequential nab-paclitaxel and AC chemotherapy in patients with early TNBC, regardless of PD-L1 status.[66038]

    for the neoadjuvant treatment of high-risk, early-stage, hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with doxorubicin and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab

    Intravenous dosage

    Adults

    600 mg/m2 IV every 3 weeks in combination with doxorubicin (60 mg/m2 IV every 3 weeks) [AC] for 4 cycles, followed by surgery; administer AC in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks). Begin AC plus pembrolizumab after the completion of 12 weeks of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly), and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. Administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV repeated every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy in patients with high-risk TNBC (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement) in a phase 3 trial (KEYNOTE-522). The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.[66036] [57889]

    for the neoadjuvant treatment of high-risk, early-stage, hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with epirubicin and pembrolizumab, after completion of neoadjuvant paclitaxel/carboplatin/pembrolizumab

    Intravenous dosage

    Adults

    600 mg/m2 IV every 3 weeks in combination with epirubicin (90 mg/m2 IV every 3 weeks) for 4 cycles, followed by surgery; administer epirubicin/cyclophosphamide in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks). Begin epirubicin/cyclophosphamide plus pembrolizumab after the completion of 12 weeks of neoadjuvant carboplatin (AUC 5 IV on day 1 every 3 weeks), paclitaxel (80 mg/m2 IV once weekly), and pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks); alternatively, carboplatin may be dosed once weekly at an AUC of 1.5 IV for 12 weeks. Administer pembrolizumab prior to chemotherapy when given on the same day. After surgery, administer pembrolizumab 200 mg IV every 3 weeks for up to 9 doses OR 400 mg IV repeated every 6 weeks for up to 5 doses or until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Neoadjuvant treatment with pembrolizumab in combination with carboplatin and paclitaxel, followed by neoadjuvant pembrolizumab plus anthracycline and cyclophosphamide significantly improved the rate of pathologic complete response (pCR) (63% vs. 55.6%) compared with placebo plus chemotherapy in patients with high-risk TNBC (tumor size more than 1 cm but up to and including 2 cm in diameter with nodal involvement; or tumor size more than 2 cm in diameter regardless of nodal involvement) in a phase 3 trial (KEYNOTE-522). The median event-free survival (EFS) was not reached in either arm, although EFS at 18 months was 91.3% in patients who received pembrolizumab compared with 85.3% in those who received placebo (HR 0.63; 95% CI, 0.43 to 0.93); overall survival results are immature.[66036] [57889]

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

    Intravenous dosage

    Adults

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

    for the adjuvant treatment of early breast cancer, in combination with methotrexate and fluorouracil (CMF)

    Oral dosage

    Adults

    100 mg/m2 orally on days 1 through 14, in combination with methotrexate 40 mg/m2 IV and fluorouracil 600 mg/m2 IV on day 1 and day 8, repeated every 28 days for 6 cycles.[61185] [47962] [47985] [51607]

    for adjuvant treatment of patients with operable node-positive breast cancer, in combination with docetaxel and doxorubicin (TAC)

    Intravenous dosage

    Adults

    500 mg/m2 IV plus doxorubicin (50 mg/m2 IV) then docetaxel (75 mg/m2 IV administered 1 hour later) every 3 weeks for 6 courses. Prophylactic colony stimulating factor support has been recommended to mitigate the risk of hematologic toxicities. Dosages should be adjusted based on toxicity. In an open-label randomized trial, 1,491 patients (stratified based on number of positive lymph nodes) were randomized to receive either docetaxel, doxorubicin, and cyclophosphamide (TAC regimen) or doxorubicin, fluorouracil, and cyclophosphamide (FAC regimen) every 3 weeks for 6 cycles. Results from the second interim analysis (median follow-up 55 months) indicated that the disease-free survival was significantly longer for the TAC regimen versus the FAC regimen. Grade 3 or 4 neutropenia was significantly greater with TAC (65.5% vs. 49.3%) as was febrile neutropenia (24.7% vs. 2.5%).[33124]

    for the treatment of breast cancer in patients with evidence of axillary node involvement following resection of the primary tumor, in combination with epirubicin and fluorouracil

    Intravenous dosage

    Adults

    500 mg/m2 IV on day 1 in combination with fluorouracil (500 mg/m2 IV) and epirubicin (100 mg/m2 IV) (FEC regimen) every 21 days for 6 cycles. Alternatively, FEC may be administered for 3 cycles, then followed by docetaxel (100 mg/m2 IV) given every 21 days for 3 cycles (FEC-D regimen). A phase 3 trial of 1,944 patients with node-positive breast cancer compared the FEC-D regimen for 3 cycles to FEC for 6 cycles. The primary endpoint, 5-year disease-free survival, was significantly longer in the FEC-D arm (78.4% vs. 73.2 %); overall survival at 5 years was also significantly increased by FEC-D (90.7% vs. 86.7%). Grade 3 or 4 neutropenia and the incidence of nausea/vomiting were higher with FEC, whereas stomatitis, edema, and nail changes were more common with FEC-D.[34268]

    for adjuvant treatment of patients with operable stage I to III invasive breast cancer, in combination with docetaxel (TC)

    Intravenous dosage

    Adults

    A phase 3 study compared docetaxel (75 mg/m2) and cyclophosphamide 600 mg/m2 (TC regimen) given every 21 days for 4 cycles versus doxorubicin (60 mg/m2) and cyclophosphamide 600 mg/m2 (AC regimen) given every 21 days for 4 cycles. The primary endpoint of disease-free survival showed a significant advantage for the TC regimen at 5 years (86% vs. 80%). Extended follow-up after 7 years continued to show a significant benefit for DFS (81% vs. 75%) and overall survival (87% vs. 82%).[35039] 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.[33123]

    for the treatment of metastatic breast cancer, in combination with epirubicin

    Intravenous dosage

    Adults

    600 mg/m2 IV on day 1 in combination with epirubicin 75 mg/m2 IV on day 1, every 3 weeks for 6 cycles. In a phase 3 trial, progression-free survival and overall survival were similar when compared to patients on epirubicin and paclitaxel.[49168]

    for the treatment of metastatic breast cancer, in combination with fluorouracil and epirubicin

    Intravenous dosage

    Adults

    500 mg/m2 IV on days 1 and 8 in combination with epirubicin 50 mg/m2 IV on days 1 and 8, plus fluorouracil 400 mg/m2 IV on days 1 and 8, every 3 to 4 weeks depending on patient recovery. In a phase 3 clinical trial, treatment was planned for 6 cycles, but was given up to 9 cycles in patients with a partial or complete response.[49142]

    For the treatment of Hodgkin lymphoma

    For the treatment of Hodgkin lymphoma, 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 Hodgkin lymphoma as part of the BEACOPP regimen

    Intravenous dosage

    Adolescents 15 years and older and Adults

    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.[12501][40572] 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.[12501][40572] The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials.[12501][40572][40568] 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.[49830] 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.[40568]

    for the treatment of previously untreated, high-risk classical Hodgkin lymphoma, in combination with brentuximab vedotin, doxorubicin, vincristine, etoposide, and prednisone

    Intravenous dosage

    Children 2 years and older and Adolescents

    600 mg/m2 IV on days 1 and 2 in combination with brentuximab vedotin 1.8 mg/kg (not to exceed 180 mg/dose) IV on day 1; doxorubicin 25 mg/m2 IV on days 1 and 2; vincristine 1.4 mg/m2 IV on day 8; etoposide 125 mg/m2 IV on days 1, 2, and 3; and prednisone 20 mg/m2 PO twice daily on days 1 to 7 repeated every 3 weeks for up to 5 cycles. Administer primary prophylaxis with a granulocyte colony-stimulating factor starting in cycle 1 due to the high incidence of febrile neutropenia.[45378]At a median follow-up time of 42.1 (range, 0.1 to 80.9) months, the 3-year event-free survival rate was significantly improved in patients (median age, 15.6 years; range, 3.4 to 21.99 years) with newly diagnosed, stage IIB with bulk tumor or stage IIIB, IVA, or IVB classic Hodgkin lymphoma who received brentuximab vedotin plus AVEPC compared with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) (92.1% vs. 82.5%; hazard ratio = 0.41; 95% CI, 0.25 to 0.67) in a multicenter, randomized, phase 3 trial (n = 587). The 3-year overall survival rates were 99.3% and 98.5% in the brentuximab vedotin plus AVEPC and ABVE-PC arms, respectively.[68172]

    For the treatment of non-Hodgkin's lymphoma (NHL) including Burkitt lymphoma and cutaneous T-cell lymphoma (CTCL) (mycosis fungoides)

    Intravenous dosage

    Adults, Adolescents and Children

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

    for the treatment of 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.[52334]

    for the treatment of follicular NHL, in combination with rituximab, doxorubicin, vincristine, and prednisone (R-CHOP)

    Intravenous dosage

    Adults

    750 mg/m2 IV on day 1, rituximab 375 mg/m2 IV given on day 1 (or day 0), in combination with  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, 2, 3, 4, and 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 3 trials.[47202] [47203] [47204]

    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

    750 mg/m2 IV on day 1, rituximab 375 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 PO daily on days 1, 2, 3, 4, and 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.[34649][31968] In a randomized, phase 3 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).[34649] In another randomized trial, the median progression-free survival (PFS) (4.8 vs. 1.2 years; p less than 0.0001) and OS (8.4 vs. 3.5 years; p less than 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.[47312]

    for the treatment of previously untreated diffuse large B-cell lymphoma (not otherwise specified) or high-grade B-cell lymphoma in patients who have an International Prognostic Index score of 2 or greater, in combination with polatuzumab vedotin, rituximab, doxorubicin, and prednisone

    Intravenous dosage

    Adults

    750 mg/m2 IV on day 1 in combination with polatuzumab vedotin 1.8 mg/kg IV, rituximab 375 mg/m2 IV, and doxorubicin 50 mg/m2 IV on day 1 plus prednisone 100 mg orally daily on days 1, 2, 3, 4, and 5 repeated every 21 days for 6 cycles has been evaluated in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 879; the POLARIX trial). Rituximab 375 mg/m2 IV was continued for 2 additional cycles of therapy (cycles 7 and 8).[67350]

    For the treatment of chronic lymphocytic leukemia (CLL)

    NOTE: Cyclophosphamide is approved for the treatment of CLL[49678]; 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.[50268] [41970] In 1 study, patients with severe lymphopenia for longer than 7 days received prophylactic antibiotics.[41970] 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.[50268]

    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.[50268] 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.[50269]

    for the treatment of CD20-positive CLL, in combination with fludarabine and rituximab

    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.[41970] 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).[40235]

    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[43762] and cyclophosphamide 650 mg/m2 IV on day 1 plus cladribine repeated every 28 days for a median of 3 cycles[50166] 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.[50166]

    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.[36901][50242] 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[36901] and another study administering rituximab 100 mg/m2 on day 8 and 275 mg/m2 on day 9 on cycle 1.[50242] 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 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.[33966] [33967]

    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.[34600] 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.[34668] 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.[34621]

    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.[28682] 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).[43256]

    For the treatment of neuroblastoma

    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.[33842]

    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.[33843]

    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%.[33844]

    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%.[33844]

    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.[49848]

    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.[51164] 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.[51165] 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.[51166]

    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.[51057][50310]

    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.[49936]

    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.[50099]

    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.[50307]

    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.[44348]

    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.[26863] 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.[24152]

    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.[23970]

    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.[24153]

    for the treatment of 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.[52522] 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.[24884]

    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.[52522]

    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.[24884]

    for the treatment of 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.[26574] 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.[32354]

    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

    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.[49678]

    For the treatment of rheumatoid arthritis† with or without Sjogren's syndrome† and juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)†

    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.

    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.[26575] [26576]

    For the treatment of systemic vasculitis syndromes† including Behcet's syndrome†, Churg-Strauss syndrome†, polyarteritis nodosa†, uveitis†, or granulomatosis with polyangiitis†

    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.[24154]

    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.[26496]

    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.[26496]

    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 [41507] 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[47366] 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.[41508]

    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.[41511]

    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.[61073]

    For the treatment of amyloidosis†

    for the treatment of systemic amyloid light-chain amyloidosis, in combination with lenalidomide and dexamethasone†

    Oral dosage

    Adults

    Oral cyclophosphamide in combination with lenalidomide (15 mg PO daily on days 1 to 21) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) repeated every 28 days has been evaluated in nonrandomized, phase 2 studies. Treatment duration, the cyclophosphamide dosage, and thromboprophylaxis recommendations varied in these studies.[61322] [61323] 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).[61322] 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.[61323]

    Intravenous dosage

    Adults

    300 mg/m2 IV on days 1 and 8 for cycles 1 to 6, then cyclophosphamide 300 mg/m2 IV on day 1 for cycles 7 to 12 in combination with lenalidomide (15 mg PO daily on days 1 to 21 for 12 cycles) and dexamethasone (20 mg PO on days 1, 2, 3, 4, 9, 10, 11, and 12 for cycles 1 to 6; then 20 mg PO on days 1, 2, 3, and 4 for cycles 7 to 12) repeated every 28 days was evaluated in a nonrandomized, phase 2 trial. Maintenance therapy with lenalidomide and dexamethasone was administered for 3 additional years or until disease progression. Patients with cardiac stage III had an upfront dose modification of dexamethasone.[61321]

    for the treatment of newly diagnosed light-chain amyloidosis, in combination with daratumumab; hyaluronidase, bortezomib, and dexamethasone†

    Intravenous or Oral dosage

    Adults

    300 mg/m2 (maximum dose of 500 mg) IV or PO in combination with bortezomib 1.3 mg/m2 subcutaneously and dexamethasone 40 mg IV/PO each given weekly on days 1, 8, 15, and 22 repeated every 28 days for a maximum of 6 cycles (VCd) plus up to 2 years of subcutaneous daratumumab; hyaluronidase (D-VCd) was evaluated in transplant eligible, newly diagnosed light-chain amyloidosis patients in a randomized, phase 3 trial (n = 388; the ANDROMEDA trial). The dose of dexamethasone was reduced to 20 mg in patients older than 70 years or who had a body mass index less than 18.5, hypervolemia, poorly controlled diabetes mellitus, or prior intolerance to steroid therapy. Daratumumab; hyaluronidase was administered as follows: 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 8 (8 doses), 1,800 mg daratumumab and 30,000 units hyaluronidase every 2 weeks on weeks 9 to 24 (8 doses), and then 1,800 mg daratumumab and 30,000 units hyaluronidase every 4 weeks starting on week 25 until disease progression or for a maximum of 2 years.[65366] At a median follow-up time of 11.4 (range, 0.03 to 21.3) months, the hematologic complete response (hemCR) rate was significantly improved (53.3% vs. 18.1%; relative risk ratio = 2.9; 95% CI, 2.1 to 4.1; p less than 0.001) in patients who received D-VCd compared with VCd in the ANDROMEDA trial. The median time to hemCR was 60 and 85 days in the D-VCd and VCd arms, respectively.[66968]

    For the treatment of highly refractory Kawasaki disease†

    Intravenous dosage

    Infants, Children, and Adolescents

    2 mg/kg/dose IV once daily may be considered in highly refractory children who have failed to respond to a second IVIG infusion, an extended course of steroids, or infliximab.[17314] [61950]

    for the treatment of systemic anaplastic large-cell lymphoma (sALCL)†

    for the treatment of previously untreated sALCL, in combination with brentuximab vedotin, doxorubicin, and prednisone†

    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†

    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%)).[45378]

    For the treatment of immune-mediated encephalitis†, including acute disseminated encephalomyelitis† (ADEM)

    Intravenous dosage

    Adults

    600 mg to 1 g/m2 IV as a single dose or once monthly for up to 6 months.[67800] [67918] [67919] [67920] [67921]

    Infants, Children, and Adolescents

    500 mg to 1 g/m2 (Max: 1.5 g/dose) IV once monthly for up to 6 months.[67917]

    For the treatment of refractory or severe dermatomyositis† and polymyositis†

    Oral dosage

    Adults

    1.5 to 2 mg/kg/dose PO once daily or 50 to 100 mg/day PO in 1 or 2 divided doses for several months.[68308] [68322] [70295]

    Children and Adolescents

    1.5 to 2 mg/kg/dose PO once daily for several months.[68308] [68313] [68314] [68317] [68322] [70295]

    Intravenous dosage

    Adults

    500 to 1,000 mg/m2/dose IV every 4 weeks for several months.[68308] [68311] [68322] [70295]

    Children and Adolescents

    500 to 1,000 mg/m2/dose IV every 4 weeks for several months.[68308] [68311] [68313] [68314] [68317] [68322] [68338] [68339] [70295]

    For the treatment of warm autoimmune hemolytic anemia†

    Oral dosage

    Adults

    50 to 100 mg PO once daily or 1 to 2 mg/kg/dose PO once daily.[70696]

    Intravenous dosage

    Adults

    50 mg/kg/dose IV once daily for 4 days or 1 g IV once monthly for 4 months. Use ideal body weight to calculate weight-based dose.[70696]

    Therapeutic Drug Monitoring

    Management of Treatment-Related Toxicities

     

    Hematologic Toxicity

    • ANC 1,500 cells/mm3 or less or platelets less than 50,000 cells/mm3: Do not administer cyclophosphamide.[65780][65781][65782]

     

    Hemorrhagic Cystitis

    • Discontinue cyclophosphamide therapy for severe hemorrhagic cystitis.[65780][65781][65782]

    Maximum Dosage Limits

    • 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.

    Patients with Hepatic Impairment Dosing

    According to the manufacturer, no dosage adjustment is necessary. However, hepatic impairment may reduce the conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy.[65780] [65781] [65782]

    Recommendations to reduce doses in hepatic impairment have been suggested as follows, but are not established.

    Total bilirubin 3.1 to 5 mg/dL: Administer 75% of the dose.[53549][67269]

    Total bilirubin greater than 5 mg/dL: Do not administer.[53549][67269][67270]

    Aminotransferase concentrations greater than 3 times the ULN: Administer 75% of the dose.[53549][67270]

    AST greater than 180 International Units/L: Administer 75% of the dose.[67270]

    Patients with Renal Impairment Dosing

    Mild or moderate renal impairment: Dose adjustments are not recommended for patients with mild or moderate renal impairment.[65780][65781][65782]

    Severe renal impairment (CrCl less than 24 mL/min): Monitor patients for signs and symptoms of toxicity.[65780][65781][65782] For CrCl less than 10 mL/min, it has been suggested to administer 50% of the dose.[67270]

     

    Intermittent hemodialysis

    Reduce dose by 25% and administer after hemodialysis.[64121] The amount of cyclophosphamide and its metabolites removed during hemodialysis varies depending upon the dialysis system used. Consider the use of a consistent interval between cyclophosphamide administration and hemodialysis to reduce variability in exposure.[65780][65781][65782]

    † Off-label indication
    Revision Date: 06/20/2024, 11:18:17 AM

    References

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    Cyclophosphamide 25mg Capsule (54879-0021) (STI Pharma LLC) null

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (62332-0619) (Alembic Pharmaceuticals, Inc.) nullCyclophosphamide 50mg Capsule package photo

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (43975-0308) (Amerigen Pharmaceuticals Inc) null

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (62559-0931) (ANI Pharmaceuticals, Inc.) null

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (69097-0517) (Cipla USA, Inc) null

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (00054-0383) (Hikma Pharmaceuticals USA Inc.) null

    Cyclophosphamide Oral capsule

    Cyclophosphamide 50mg Capsule (54879-0022) (STI Pharma LLC) null

    Cyclophosphamide Oral tablet

    Cyclophosphamide 25mg Tablet (10019-0982) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Oral tablet

    Cyclophosphamide 25mg Tablet (00054-4129) (Hikma Pharmaceuticals USA Inc.) (off market)

    Cyclophosphamide Oral tablet

    Cyclophosphamide 25mg Tablet (00054-8089) (Hikma Pharmaceuticals USA Inc.) (off market)

    Cyclophosphamide Oral tablet

    Cytoxan 25mg Tablet (00015-0504) (Bristol Myers Squibb Oncology Products) (off market)

    Cyclophosphamide Oral tablet

    Cyclophosphamide 50mg Tablet (10019-0984) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Oral tablet

    Cyclophosphamide 50mg Tablet (00054-4130) (Hikma Pharmaceuticals USA Inc.) (off market)

    Cyclophosphamide Oral tablet

    Cyclophosphamide 50mg Tablet (00054-8130) (Hikma Pharmaceuticals USA Inc.) (off market)

    Cyclophosphamide Oral tablet

    Cytoxan 50mg Tablet (00015-0503) (Bristol Myers Squibb Oncology Products) (off market)

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (72603-0326) (Aisling Pharma) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (70121-1239) (Amneal Biosciences) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (10019-0956) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (68001-0371) (BluePoint Laboratories) (off market)

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (68001-0443) (BluePoint Laboratories) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (72572-0085) (Civica, Inc.) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (65219-0131) (Fresenius Kabi USA, LLC) nullCyclophosphamide 1g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (81298-8112) (Long Grove Pharmaceuticals, LLC) nullCyclophosphamide 1g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (16714-0857) (NorthStar Rx LLC) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (25021-0248) (Sagent Pharmaceuticals) nullCyclophosphamide 1g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (00781-3244) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (39822-0255) (XGen Pharmaceuticals DJB) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (Amerinet) (10019-0936) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (NOVAPLUS) (10019-0939) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 1g Powder for Injection (PREMIER ProRx) (10019-0944) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (70121-1240) (Amneal Biosciences) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (10019-0957) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (68001-0372) (BluePoint Laboratories) (off market)

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (68001-0444) (BluePoint Laboratories) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (72572-0083) (Civica, Inc.) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (65219-0133) (Fresenius Kabi USA, LLC) nullCyclophosphamide 2g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (81298-8114) (Long Grove Pharmaceuticals, LLC) nullCyclophosphamide 2g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (16714-0858) (NorthStar Rx LLC) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (25021-0249) (Sagent Pharmaceuticals) nullCyclophosphamide 2g Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (00781-3255) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (39822-0260) (XGen Pharmaceuticals DJB) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (Amerinet) (10019-0937) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (NOVAPLUS) (10019-0942) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 2g Powder for Injection (PREMIER ProRx) (10019-0945) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (72603-0104) (Aisling Pharma) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (70121-1238) (Amneal Biosciences) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (10019-0955) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (68001-0370) (BluePoint Laboratories) (off market)

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (68001-0442) (BluePoint Laboratories) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (72572-0087) (Civica, Inc.) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (65219-0135) (Fresenius Kabi USA, LLC) nullCyclophosphamide 500mg Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (81298-8110) (Long Grove Pharmaceuticals, LLC) nullCyclophosphamide 500mg Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (16714-0859) (NorthStar Rx LLC) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (25021-0247) (Sagent Pharmaceuticals) nullCyclophosphamide 500mg Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (00781-3233) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (39822-0250) (XGen Pharmaceuticals DJB) nullCyclophosphamide 500mg Powder for Injection package photo

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (Amerinet) (10019-0935) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (NOVAPLUS) (10019-0938) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Powder for solution for injection

    Cyclophosphamide 500mg Powder for Injection (PREMIER ProRx) (10019-0943) (Baxter Anesthesia/Critical Care Oncology) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/10mL Solution for Injection (00781-3529) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (00781-3530) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/5mL Solution for Injection (00781-3528) (Sandoz Inc. a Novartis Company) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (70860-0218) (Athenex Pharmaceutical Division LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (68001-0564) (BluePoint Lab Injectables) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (75907-0190) (Dr. Reddy's Laboratories, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (55150-0271) (Eugia US LLC fka AuroMedics Pharma LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (55150-0271) (Eugia US LLC fka AuroMedics Pharma LLC) nullCyclophosphamide 1g/5mL Solution for Injection package photo

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (51407-0749) (Golden State Medical Supply, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/5mL Solution for Injection (50742-0520) (Ingenus Pharmaceuticals, LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (68001-0565) (BluePoint Lab Injectables) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (75907-0189) (Dr. Reddy's Laboratories, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (55150-0272) (Eugia US LLC fka AuroMedics Pharma LLC) nullCyclophosphamide 2g/10mL Solution for Injection package photo

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (51407-0750) (Golden State Medical Supply, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/10mL Solution for Injection (50742-0521) (Ingenus Pharmaceuticals, LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (70860-0218) (Athenex Pharmaceutical Division LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (75907-0191) (Dr. Reddy's Laboratories, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (55150-0270) (Eugia US LLC fka AuroMedics Pharma LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (55150-0270) (Eugia US LLC fka AuroMedics Pharma LLC) nullCyclophosphamide 500mg/2.5mL Solution for Injection package photo

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (51407-0748) (Golden State Medical Supply, Inc.) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/2.5mL Solution for Injection (50742-0519) (Ingenus Pharmaceuticals, LLC) null

    Cyclophosphamide Solution for injection

    Cyclophosphamide 1g/2mL Solution for Injection (43598-0661) (Dr. Reddy's Laboratories, Inc.) (off market)

    Cyclophosphamide Solution for injection

    Cyclophosphamide 2g/4mL Solution for Injection (43598-0662) (Dr. Reddy's Laboratories, Inc.) (off market)

    Cyclophosphamide Solution for injection

    Cyclophosphamide 500mg/mL Solution for Injection (43598-0660) (Dr. Reddy's Laboratories, Inc.) (off market)

    Description/Classification

    Description

    Cyclophosphamide is a bifunctional alkylating agent related to mechlorethamine (nitrogen mustard). Cyclophosphamide has activity against many neoplastic diseases including Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphocytic leukemia, breast carcinoma, ovarian carcinoma, lung cancers, multiple myeloma, sarcomas, chronic lymphocytic leukemia, mycosis fungoides, neuroblastoma, and retinoblastoma.[65780][65781][65782] Oral cyclophosphamide is also FDA approved for the treatment of minimal change nephrotic syndrome in pediatric patients who are unable to receive adrenocorticosteroid therapy.[65781] The drug has also been used to treat immunologic disorders such as lupus nephritis, nephrotic syndrome, granulomatosis with polyangiitis, rheumatoid arthritis, and graft-versus-host disease or graft rejection. Oral or intermittent intravenous cyclophosphamide has become the standard treatment for diffuse proliferative lupus nephritis; the drug has been shown to prevent progressive scarring within the kidney, preserve renal function, induce renal remission, and reduce the risk of end-stage renal failure requiring dialysis or transplantation.[24884] Due to the risk of urotoxicity including hemorrhagic cystitis, the use of cyclophosphamide is contraindicated in patients with urinary outflow obstruction. Myelosuppression is common and requires close monitoring of complete blood counts during therapy.[65780][65781][65782]

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Alkylating Agents
          • Nitrogen Mustard Analogs
    Revision Date: 06/20/2024, 11:18:17 AM

    References

    24884 - Ortmann RA, Klippel JH. Update on cyclophosphamide for systemic lupus erythematosus. Rheum Dis Clin North Am 2000;26:363-75.65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    • 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.[65780][65781][65782]

    Hazardous Drugs Classification

    • NIOSH 2016 List: Group 1 [63664]
    • NIOSH (Draft) 2020 List: Table 1
    • Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    • Oral Tablets/Capsules: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    • Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.[63664]

    Emetic Risk

    Pediatrics:

    • IV Doses of 1,200 mg/m2 or higher: High
    • IV Doses of 1,000 mg/m2: Moderate
    • IV Doses of 500 mg/m2: Low
    • Oral Doses of 2 to 3 mg/kg: Low

    Adults:

    • IV Doses of 1,500 mg/m2 or higher: High
    • IV Doses of less than 1,500 mg/m2: Moderate
    • Any IV dose of cyclophosphamide when used in combination with an anthracycline: High
    • Oral Doses: Moderate/High

    Administer routine antiemetic prophylaxis prior to treatment.[67392][67389]

    Extravasation Risk

    • Nonvesicant [67387]

    Route-Specific Administration

    Oral Administration

    Oral Solid Formulations

    • Swallow capsules whole; do not open, crush, or chew capsules.
    • Avoid contact with broken capsules; if contact with broken capsules occurs, wash hands immediately and thoroughly.[65781]

    Extemporaneous Compounding-Oral

    Extemporaneous 10 mg/mL Oral Suspension

    • Prior to compounding, reconstitute a 2 g vial of cyclophosphamide injection with 100 mL 0.9% Sodium Chloride Injection for a final concentration of 20 mg/mL.
    • Mix the injectable solution in a 1:1 ratio with either Simple Syrup or Ora-Plus for a final concentration of 10 mg/mL.
    • Shake well prior to administration.
    • Storage: Store refrigerated (4 to 22 degrees C) and protected from light in amber polypropylene oral syringes for up to 56 days.[67156]

    Extemporaneous Oral Liquid Preparation

    • Dissolve cyclophosphamide for injection (reconstituted powder for solution) in Aromatic Elixir, NF.
    • Storage: Store refrigerated in glass containers for up to 14 days.[65782]

    Injectable Administration

    Intravenous Administration

    Reconstitution, Powder for Injection

    • Do not use cyclophosphamide powder for injection vials if there are signs of melting. Melted cyclophosphamide powder is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.
    • For patients receiving a direct IV injection of cyclophosphamide, reconstitute using 0.9% Sodium Chloride Injection only.
    • For patients receiving an IV infusion of cyclophosphamide, reconstitute using either 0.9% Sodium Chloride Injection or Sterile Water for Injection.
    • 500 mg vial: Add 25 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    • 1 g vial: Add 50 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    • 2 g vial: Add 100 mL of diluent for a concentration of 20 mg/mL. Gently swirl to dissolve.
    • Storage: Vials reconstituted with 0.9% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator; immediately use vials reconstituted with Sterile Water for Injection (do not store).[65782]

    Dilution, Reconstituted Powder for Injection

    • For administration as a direct IV injection, further dilution is not necessary.
    • For administration as an IV infusion, dilute reconstituted powder for injection (20 mg/mL) to a minimum concentration of 2 mg/mL in 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose Injection and 0.9% Sodium Chloride Injection.
    • Solutions diluted in 0.45% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 6 days in the refrigerator including the time for reconstitution.
    • Solutions diluted in 5% Dextrose Injection or 5% Dextrose Injection and 0.9% Sodium Chloride Injection may be stored at room temperature for up to 24 hours or for up to 36 hours in the refrigerator including the time for reconstitution.[65782]

    Dilution, Solution for Injection

    • For administration as a direct IV injection, dilute to a concentration of 20 mg/mL using any of the following diluents: 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection.
    • For administration as an IV infusion, dilute to a concentration of 2 mg/mL using any of the following IV fluids: 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose Injection and 0.9% Sodium Chloride Injection.
    • Storage of multiple-dose vial: After the first use, store the partially used vial in the original carton in the refrigerator (2 to 8 C or 36 to 46 F); discard unused portion after 28 days.
    • Storage of diluted infusion solution: Store at room temperature for up to 24 hours or in the refrigerator for up to 6 days.[65780]

    Administration

    • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    • For direct IV injection, diluted cyclophosphamide powder for injection may be only be administered when reconstituted with 0.9% Sodium Chloride Injection. Do not directly inject cyclophosphamide powder that was reconstituted with Sterile Water for Injection as this solution is hypotonic.[65782]
    • Inject or infuse slowly to avoid rate-dependent adverse events (e.g., facial swelling, headache, nasal congestion, scalp burning); duration depends on the infusion volume and fluid type.[65780][65782]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Cyclophosphamide

    pH Range
    pH 3 to 9 (Reconstituted solution) Measured pH of 6.87 at 22 mg/mL.
    ReferencesAnon. The United States Pharmacopeia. Rockville, Maryland: The United States Pharmacopeial Convention. Current edition.
    ReferencesBrooke D, Scott JA, Bequette RJ. Effect of briefly heating cyclophosphamide solutions. Am J Hosp Pharm. 1975; 32
    Osmolality/Osmolarity
    Cytoxan New Formulation: Reconstitution with normal saline to a cyclophosphamide concentration of 20 mg/mL provides an acceptable osmolality for direct injection of 374 mOsm/L. Reconstitution with sterile water for injection results in a very hypotonic solution with an osmolality of 74 mOsm/L. Sterile water for injection should only be used if the dose will be diluted for infusion in a solution with a sufficient osmolality. Cytoxan Former Formulation: Reconstitution of the former formulation of cyclophosphamide with sterile water for injection results in solutions of 20 and 25 mg/mL that are hypotonic having osmolarities of 172 mOsm/L and 219 mOsm/L, respectively.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    Stability
    Cyclophosphamide in intact containers stored as directed by the manufacturer is stable until the labeled expiration date. Martel et al. reported that the stability of cyclophosphamide in intact containers stored at an elevated temperature of 33 degree C protected from exposure to light for 12 months exhibited little or no loss of drug when tested by stability-indicating HPLC analysis. The authors stated such temperatures might be reached during transportation of the vials during summer months. The manufacturer states that cyclophosphamide reconstituted with sodium chloride 0.9% is stable for 24 hours at room temperature or 6 days refrigerated. Kirk et al. reported cyclophosphamide 20 mg/mL in sterile water for injection exhibited 13% and 35% loss of cyclophosphamide in 1 and 4 weeks, respectively, stored at room temperature. If refrigerated or frozen, less than 3% loss occurred in 4 weeks. Mittner et al. reported similar stability for cyclophosphamide at 20 mg/mL in sterile water for injection with HPLC analysis finding about 10% loss in 4 days at room temperature and 6% loss in 52 days and 10 to 12% loss in 119 days refrigerated. Brooke et al. reported that cyclophosphamide 21 mg/mL reconstituted with paraben-preserved bacteriostatic water for injection exhibited less than 1.5% loss in 8 hours at room temperature and within 6 days refrigerated. Decomposition proceeded more rapidly if benzyl alcohol-preserved diluent was used, and the authors suggested the benzyl alcohol should be avoided because it may catalyze cyclophosphamide decomposition. Cyclophosphamide 21 mg/mL solutions subjected to temperatures of 50 to 60 degree C for 15 minutes remained stable but at 70 and 80 degree C 10% and 23% loss of cyclophosphamide, respectively, occurred in 15 minutes. Infusion Solutions: The manufacturer indicates that reconstituted cyclophosphamide may be diluted in the following solutions to a minimum concentration of 2 mg/mL (0.2%) for administration by intravenous infusion and are stable for the time periods noted: Dextrose 5%- Stable for 24 hours at room temperature and 36 hours refrigerated Dextrose 5% in sodium chloride 0.9%- Stable for 24 hours at room temperature and 36 hours refrigerated Sodium chloride 0.45%- Stable for 24 hours at room temperature and 6 days refrigerated Kirk et al. reported that cyclophosphamide 4 mg/mL in sodium chloride 0.9% in polyvinyl chloride (PVC) plastic bags exhibited no loss in 4 weeks and about 8% loss in 19 weeks refrigerated or frozen. Beijnen et al. reported that cyclophosphamide 1 mg/mL in either dextrose 5% or in sodium chloride 0.9% was stable for up to 7 days exhibiting losses of 10% or less at room temperature and less than 5% loss under refrigeration. Ostermann-Kraljevic et al. reported the stability of cyclophosphamide 0.24 and 6.4 mg/mL in dextrose 5% and sodium chloride 0.9% in glass and polyethylene containers. The solutions were physically stable, and HPLC analysis found less than 10% loss of cyclophosphamide within 7 days at room temperature of 22 to 24 degree C. Dine et al. reported that cyclophosphamide 10 mg/mL in dextrose 5% and in sodium chloride 0.9% in polyvinyl chloride (PVC) plastic bags lost less than 10% of the drug concentration in 30 days stored refrigerated at 4 degree C and protected from exposure to light. Packaged in Syringes: Kirk et al. reported that cyclophosphamide 20 mg/mL in PlastiPak polypropylene syringes with sealed tips exhibited 10% loss of drug concentration in about 11 to 14 weeks under refrigeration. When frozen, the drug precipitated and solution seeped past the plunger tips that had contracted in the cold resulting in a microbiological contamination hazard.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesBeijnen JH, van Gijn R, Challa EE, et al. Chemical stability of two sterile parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids. J Parenter Sci Tech. 1992; 46
    ReferencesBrooke D, Bequette RJ, Davis RE. Chemical stability of cyclophosphamide in parenteral solutions. Am J Hosp Pharm. 1973; 30
    ReferencesBrooke D, Scott JA, Bequette RJ. Effect of briefly heating cyclophosphamide solutions. Am J Hosp Pharm. 1975; 32
    ReferencesDine T, Lebegue S, Benaji B, et al. Stability and compatibility studies of four cytostatic agents (fluorouracil, dacarbazine, cyclophosphamide and ifosfamide) with PVC infusion bags. Pharm Sci Commun. 1994; 4
    ReferencesKirk B, Melia CD, Wilson JV, et al. Chemical stability of cyclophosphamide injection. Br J Parenter Ther. 1984; 5
    ReferencesMartel P, Pinguet F, Petit I, et al. Stability of the principal cytostatic agents during storage at unusual temperatures. Int J Pharm. 1997; 149
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    ReferencesMittner A, Vincze Z, Jemnitz K. Stability of cyclophosphamide containing infusions. Pharmazie. 1999; 54
    ReferencesOstermann-Kraljevic S, Berger M, Voeffray M, et al. Stability and compatibility studies of antineoplastic agents in glass and polyethylene containers. Eur J Hosp Pharm. 1999; 5
    pH Effects
    Cyclophosphamide stability in aqueous solution is independent of pH in the range of pH 2 to 10 or 11; the drug exhibits maximum stability throughout this wide pH range. However, at extreme pH values above 11 and below 2, increased rates of decomposition occur.
    ReferencesAllwood M, Stanley A, Wright P. The cytotoxics handbook, 3rd ed., Oxford, England: Radcliffe Medical Press, 1997.
    ReferencesBeijnen JH, van Gijn R, Challa EE, et al. Chemical stability of two sterile parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids. J Parenter Sci Tech. 1992; 46
    ReferencesKaijser GP, Aalbers T, Beijnen JH, et al. Chemical stability of cyclophosphamide, trofosfamide, and 2- and 3-dechloroethylfosfamide. J Oncol Pharm Pract. 1996; 2
    Light Exposure
    No unacceptable adverse effect on drug concentration due to normal fluorescent light exposure was observed in stability studies of cyclophosphamide in infusion solutions.
    ReferencesBeijnen JH, van Gijn R, Challa EE, et al. Chemical stability of two sterile parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids. J Parenter Sci Tech. 1992; 46
    ReferencesBenvenuto JA, Adams SC, Vyas HM, et al. Pharmaceutical issues in infusion chemotherapy stability and compatibility. in Lokich JJ (ed), Cancer chemotherapy by infusion. Chicago: Precept Press. 1987;
    Freezing
    Kirk et al. reported that freezing cyclophosphamide 20 mg/mL in sterile water for injection in PlastiPak polypropylene syringes sealed with tip caps resulted in precipitate formation during microwave thawing that required vigorous shaking to redissolve. In the frozen syringes, solution seeped past the plunger tips that had contracted in the cold resulting in a microbiological contamination hazard. Kirk et al. also reported that freezing did not cause precipitation to occur in solutions with a concentration less than 8 mg/mL. Cyclophosphamide 4 mg/mL in sodium chloride 0.9% in polyvinyl chloride (PVC) plastic bags exhibited no loss in 4 weeks and about 8% loss in 19 weeks refrigerated or frozen.
    ReferencesKirk B, Melia CD, Wilson JV, et al. Chemical stability of cyclophosphamide injection. Br J Parenter Ther. 1984; 5
    Sorption Leaching
    Cyclophosphamide has not been found in stability studies to undergo substantial sorption to polyvinyl chloride (PVC) containers, PVC administration set tubing, polypropylene (in syringes), polyethylene containers, other polyolefin containers, or glass containers, or to elastomeric pump reservoirs. In addition, Xu et al. reported no sorption occurred to a polyurethane central catheter from Arrow International as well as no leaching of the chlorhexidine antimicrobial in it.
    ReferencesAnon. Drug stability data for Intermate and Infusor portable elastomeric infusion devices. Round Lake, IL: Baxter Healthcare Corporation.. 2008;
    ReferencesAnon. Guidelines for the administration of drugs using the Homepump Eclipse and C-Series disposable elastomeric infusion systems. Lake Forest, CA: I-Flow Corporation. 2004;
    ReferencesBenvenuto JA, Anderson RW, Kerkof K, et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm. 1981; 38
    ReferencesBenvenuto JA, Adams SC, Vyas HM, et al. Pharmaceutical issues in infusion chemotherapy stability and compatibility. in Lokich JJ (ed), Cancer chemotherapy by infusion. Chicago: Precept Press. 1987;
    ReferencesBeijnen JH, van Gijn R, Challa EE, et al. Chemical stability of two sterile parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids. J Parenter Sci Tech. 1992; 46
    ReferencesDine T, Lebegue S, Benaji B, et al. Stability and compatibility studies of four cytostatic agents (fluorouracil, dacarbazine, cyclophosphamide and ifosfamide) with PVC infusion bags. Pharm Sci Commun. 1994; 4
    ReferencesKirk B, Melia CD, Wilson JV, et al. Chemical stability of cyclophosphamide injection. Br J Parenter Ther. 1984; 5
    ReferencesOstermann-Kraljevic S, Berger M, Voeffray M, et al. Stability and compatibility studies of antineoplastic agents in glass and polyethylene containers. Eur J Hosp Pharm. 1999; 5
    Other Information
    Cyclophosphamide is cited by NIOSH as a drug that should be handled as hazardous. Aluminum: Ogawa et al. reported that an aluminum needle immersed in Adria cyclophosphamide 20 mg/mL resulted in darkening of the needle and release of a gas after a few days at room temperature protected from light. Other Drugs: Dorr reported that mesna is stable for 24 hours admixed with cyclophosphamide in dextrose 5% or in lactated Ringer's injection. However, Menard et al. reported that storage temperature and drug concentrations influence the stability of the two drugs. At higher concentrations of the drugs, such as cyclophosphamide 10.8 mg/mL and mesna 3.2 mg/mL in dextrose 5%, both drugs exhibit less than 10% loss in 24 hours at room temperature and 72 hours refrigerated. However, at lower concentrations, such as cyclophosphamide 1.8 mg/mL and mesna 0.54 mg/mL in dextrose 5%, the room temperature stability was reduced to only 12 hours with 10% loss of both drugs at that time. Cyclophosphamide and dacarbazine mixed in solution did not display altered ultraviolet and visible light spectral changes. This is suggestive of but not definitive evidence of stability of the combination. Microbial Growth Potential: Hamilton-Miller reported that cyclophosphamide exhibited no antimicrobial activity against 28 strains of microbes including Gram-positive aerobic bacterial, Gram-negative aerobic bacteria, anaerobic bacteria, and yeasts. Kramer and Wenchel also found no antimicrobial activity of cyclophosphamide 0.77 mg/mL against Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans. Favier et al. evaluated the antimicrobial effects of cyclophosphamide 5 mg/mL in dextrose 5% against five microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. Test samples were packaged in plastic bags and were stored at room temperature and refrigerated at 4 to 8 degree C for up to 98 hours. Cyclophosphamide did not demonstrate increased antimicrobial activity compared to the negative controls. Quality Control: Lelievre et al. described an approach to quality control and accuracy assessment for 22 cancer chemotherapy drugs, including cyclophosphamide, which is designed to reduce the risk of erroneously prepared doses reaching patients. The technique utilized an ultraviolet (UV)-visible and infrared (IR) scanning analysis (Multispec, Microdom) of the finished dosage forms to verify the right molecule, concentration, and solution. Of 3149 doses of the 22 drugs tested, 7.82% varied by more than 10% from the intended concentration.
    ReferencesAnon. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH Publication No. 2004-165. 2004; 165
    ReferencesDorr RT. Mesnex dosing and administration guide. Evansville, IN: Bristol-Myers Company. Data on file. 1989;
    ReferencesFavier B, Latour JF, Fuhrmann C. Viability of microorganisms in bags of cytotoxic drugs. J Oncol Pharm Pract. 2001; 6
    ReferencesHamilton-Miller JMY. Antimicrobial activity of 21 anti-neoplastic agents. Br J Cancer. 1984; 49
    ReferencesHorton JK, Stevens MFG. Search for drug interactions between the anti-tumor agent DTIC and other cytotoxic agents. J Pharm Pharmacol (Supplement). 1979; 31
    ReferencesKramer I, Wenchel HM. Wachstumsverhalten ausgewahlter mikroorganismen in zytostatika-zuberreitungen [Growth behavior of selected microorganisms in solutions of cytostatic drugs]. Krankenhauspharmazie. 1988; 11
    ReferencesLelievre B, Devys C, Daouphars M, et al. Qualitative and quantitative analysis of chemotherapy preparations. Eur J Hosp Pharm Pract. 2010; 16
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    ReferencesMenard C, Bourguignon C, Schlatter J, et al. Stability of cyclophosphamide and mesna admixtures in polyethylene infusion bags. Ann Pharmacother. 2003; 37
    ReferencesOgawa GS, Young R, Munar M. Dispensing-pin problems. Am J Hosp Pharm. 1985; 42
    Stability Max
    Maximum reported stability periods: Reconstituted- 5 days at room temperature and about 90 days refrigerated. In D5W- 7 days at room temperature and 30 days refrigerated. In NS- 7 days at room temperature and 19 weeks refrigerated.
    ReferencesAnon. Guidelines for the administration of drugs using the Homepump Eclipse and C-Series disposable elastomeric infusion systems. Lake Forest, CA: I-Flow Corporation. 2004;
    ReferencesBeijnen JH, van Gijn R, Challa EE, et al. Chemical stability of two sterile parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids. J Parenter Sci Tech. 1992; 46
    ReferencesBenvenuto JA, Anderson RW, Kerkof K, et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm. 1981; 38
    ReferencesBenvenuto JA, Adams SC, Vyas HM, et al. Pharmaceutical issues in infusion chemotherapy stability and compatibility. in Lokich JJ (ed), Cancer chemotherapy by infusion. Chicago: Precept Press. 1987;
    ReferencesBrooke D, Bequette RJ, Davis RE. Chemical stability of cyclophosphamide in parenteral solutions. Am J Hosp Pharm. 1973; 30
    ReferencesDine T, Lebegue S, Benaji B, et al. Stability and compatibility studies of four cytostatic agents (fluorouracil, dacarbazine, cyclophosphamide and ifosfamide) with PVC infusion bags. Pharm Sci Commun. 1994; 4
    ReferencesGallelli JF. Stability studies of drugs used in intravenous solutions part one. Am J Hosp Pharm. 1967; 24
    ReferencesKirk B, Melia CD, Wilson JV, et al. Chemical stability of cyclophosphamide injection. Br J Parenter Ther. 1984; 5
    ReferencesMittner A, Vincze Z, Jemnitz K. Stability of cyclophosphamide containing infusions. Pharmazie. 1999; 54
    ReferencesOstermann-Kraljevic S, Berger M, Voeffray M, et al. Stability and compatibility studies of antineoplastic agents in glass and polyethylene containers. Eur J Hosp Pharm. 1999; 5
    Revision Date: 06/20/2024, 11:18:17 AMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

    References

    63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616165780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.67156 - Kennedy R, Groepper D, Tagen M, et al. Stability of cyclophosphamide in extemporaneous oral suspensions. Ann Pharmacother 2010;44:295-301.67387 - Perez Fidalgo, JA, Garcia Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol. 2012 Oct;23 Suppl; vii167-73.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.67392 - Paw Cho Sing E, Robinson P, Flank J, et al. Classification of the acute emetogenicity of chemotherapy in pediatric patients: A clinical practice guideline. Pediatr Blood Cancer. 2019 May;66(5):e27646. Doi: 10.1002/pbc.27646. Epub 2019 Feb 7.

    Adverse Reactions

    Mild

    • abdominal pain
    • alopecia
    • amenorrhea
    • anorexia
    • arthralgia
    • asthenia
    • azoospermia
    • chills
    • cough
    • diarrhea
    • dizziness
    • dysesthesia
    • dysgeusia
    • fatigue
    • fever
    • flushing
    • gonadal suppression
    • headache
    • hyperhidrosis
    • hypoesthesia
    • infection
    • influenza
    • lacrimation
    • malaise
    • muscle cramps
    • myalgia
    • nasal congestion
    • nausea
    • oligospermia
    • paresthesias
    • parosmia
    • pruritus
    • rash
    • rhinorrhea
    • skin hyperpigmentation
    • tinnitus
    • tremor
    • urticaria
    • vomiting

    Moderate

    • anemia
    • ascites
    • bladder spasm
    • bone marrow suppression
    • chest pain (unspecified)
    • cholestasis
    • colitis
    • confusion
    • conjunctivitis
    • constipation
    • dyspnea
    • edema
    • elevated hepatic enzymes
    • encephalopathy
    • erythema
    • hematuria
    • hepatitis
    • hepatomegaly
    • hot flashes
    • hyperbilirubinemia
    • hyperglycemia
    • hypertension
    • hyperuricemia
    • hypoglycemia
    • hyponatremia
    • hypotension
    • hypoxia
    • immunosuppression
    • impaired wound healing
    • infertility
    • interstitial lung disease
    • jaundice
    • leukopenia
    • neurotoxicity
    • neutropenia
    • oral ulceration
    • palmar-plantar erythrodysesthesia (hand and foot syndrome)
    • palpitations
    • parotitis
    • peripheral neuropathy
    • pneumonitis
    • QT prolongation
    • radiation recall reaction
    • stomatitis
    • supraventricular tachycardia (SVT)
    • testicular atrophy
    • thrombocytopenia

    Severe

    • acute respiratory distress syndrome (ARDS)
    • anaphylactic shock
    • atrial fibrillation
    • atrial flutter
    • bradycardia
    • bronchiolitis obliterans
    • bronchospasm
    • cardiac arrest
    • cardiac tamponade
    • cardiomyopathy
    • cardiotoxicity
    • diabetes insipidus
    • disseminated intravascular coagulation (DIC)
    • erythema multiforme
    • fetal death
    • GI bleeding
    • hearing loss
    • heart failure
    • hemolytic-uremic syndrome
    • hemorrhagic cystitis
    • hepatic encephalopathy
    • hepatic failure
    • hepatotoxicity
    • leukemia
    • leukoencephalopathy
    • myocardial infarction
    • myocarditis
    • new primary malignancy
    • pancreatitis
    • pericardial effusion
    • pericarditis
    • pleural effusion
    • premature labor
    • pulmonary edema
    • pulmonary embolism
    • pulmonary fibrosis
    • pulmonary hypertension
    • pulmonary toxicity
    • renal failure (unspecified)
    • renal tubular necrosis
    • rhabdomyolysis
    • seizures
    • SIADH
    • sinusoidal obstruction syndrome (SOS)
    • skin cancer
    • Stevens-Johnson syndrome
    • teratogenesis
    • thrombosis
    • thrombotic microangiopathy
    • toxic epidermal necrolysis
    • tumor lysis syndrome (TLS)
    • typhlitis
    • vasculitis
    • veno-occlusive disease (VOD)
    • ventricular fibrillation
    • ventricular tachycardia
    • visual impairment

    Bone marrow suppression (e.g., anemia, leukopenia, neutropenia, thrombocytopenia) is the most common cyclophosphamide toxicity. Neutropenia is dose-dependent, with patients receiving low-dose cyclophosphamide rarely developing significant neutropenia.[65804] Bone marrow failure and severe immunosuppression have occurred, leading to serious and sometimes fatal infections; neutropenic fever has also been reported. Leukocyte and platelet nadirs typically occur in weeks 1 and 2 of therapy; blood counts usually normalize after 20 days. Do not administer cyclophosphamide if the neutrophil count is 1,500 cells/mm3 or less and the platelet count is less than 50,000 cells/mm3. Granulocyte colony-stimulating factors may be considered as primary and secondary prophylaxis of neutropenic complications in high-risk patients.[65780] [65781] [65782]

    Hemorrhagic cystitis is the most common form of cyclophosphamide-related bladder toxicity, although pyelitis, ureteritis, and hematuria have also been reported.[65780] [65781] [65782] [65804] Early-onset hemorrhagic cystitis occurs within days of cyclophosphamide administration and is usually caused by the toxic metabolite, acrolein.[65804] Aggressive hydration before or immediately after cyclophosphamide and frequent bladder emptying may reduce the frequency and severity of acute bladder toxicity; administration of mesna has also been used.[65780] [65781] [65782] In 20% to 25% of patients who receive high-dose cyclophosphamide, hemorrhagic cystitis can develop weeks to months after treatment; most of these cases are related to reactivation of BK virus. Chronic low-dose cyclophosphamide has also been associated with late-onset hemorrhagic cystitis attributed to BK virus.[65804] In a study of patients receiving oral cyclophosphamide 2 mg/kg per day with prednisone, 50% developed non-glomerular hematuria; gross hematuria was present in 44% of these patients and microscopic hematuria in 56%. The median time to development of non-glomerular hematuria was 37 months (34 months in smokers and 56 months in nonsmokers), although it can develop years after cyclophosphamide therapy is discontinued. The median dose before the development of hematuria was 124 grams.[24578] Discontinue cyclophosphamide therapy in patients who develop severe hemorrhagic cystitis; medical and/or surgical supportive treatment may be required. Urotoxicity (e.g., bladder ulceration, necrosis, fibrosis, and contracture) may occur with short-term or long-term use of cyclophosphamide and may be fatal. Routinely monitor urinalyses for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity.[65780] [65781] [65782]

    Hyponatremia associated with increased total body water, acute water intoxication, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported in patients receiving cyclophosphamide; some cases were fatal.[65780] [65781] [65782]

    Infertility due to gonadal suppression can occur in men or women receiving cyclophosphamide. Cyclophosphamide interferes with oogenesis and spermatogenesis. Cyclophosphamide-induced sterility may be irreversible in some patients.[65780] [65781] [65782] Amenorrhea (transient or permanent) associated with decreased estrogen and increased gonadotropin secretion development has been reported in women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months of stopping therapy. Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and usually have regular menses. Ovarian fibrosis with apparent complete loss of germ cells after prolonged cyclophosphamide treatment during late prepubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause. In women, the risk of premature menopause increases with age.[65780] [65781] [65782] The risk for sustained amenorrhea in patients with lupus receiving monthly intermediate-dose cyclophosphamide is 12% for women younger than 25 years old and is greater than 50% for women over 30 years old. However, no ovarian failure was observed in women younger than 26 years old with aplastic anemia after receiving high-dose cyclophosphamide as part of a conditioning regimen for allogeneic bone marrow transplant.[65804] Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal testosterone secretion. Prepubescent boys treated with cyclophosphamide generally develop secondary sexual characteristics normally; however, some boys develop oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may also occur. Cyclophosphamide-induced azoospermia is sometimes reversible, although the reversibility may not occur until several years after stopping cyclophosphamide therapy. Other reproductive adverse events reported with cyclophosphamide therapy in postmarketing surveillance include ovarian failure, ovarian disorder, and oligomenorrhea.[65780] [65781] [65782]

    Teratogenesis including malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and additional toxic effects in the newborn include leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis. Fetal death has also been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    New primary malignancy has occurred with short-term or long-term cyclophosphamide treatment, most commonly acute leukemias, myelodysplasia, bladder cancer, and skin cancer.[65780] [65781] [65782] [65804] Therapy-related leukemia occurs in approximately 2% of patients treated with chronic cyclophosphamide, usually in patients who received treatment for more than 1 year; the time frame for the occurrence of a secondary leukemia is usually between 3 to 10 years after treatment. Most cases of cyclophosphamide-induced bladder cancer have been reported in patients who received the drug orally for more than 1 year, with a cumulative dose of more than 20 g as the primary risk factor.[65804] Routinely monitor urinalyses for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Taking measures to prevent hemorrhagic cystitis may reduce the risk of bladder cancer. Lymphoma, renal cell cancer, renal pelvis cancer, sarcoma, thyroid cancer, and ureteric cancer have also been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Cardiotoxicity is the dose-limiting toxicity of cyclophosphamide and is only observed after administration of high doses. Transient cardiotoxicity has been reported in up to 45% of patients receiving bone marrow transplantation, typically manifesting as subclinical left ventricular dysfunction; mild arrhythmias and small pleural and pericardial effusions can also occur. Pretreatment cardiac evaluations may help predict the reversibility of cardiac toxicity.[65804] Cardiomyopathy, myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure have all been reported with cyclophosphamide therapy; some cases have been fatal.[65780] [65781] [65782] Left ventricular dysfunction has been reported in 7% to 28% of patients treated with cyclophosphamide and appears to be related to a single dose rather than cumulative dosing. High-dose rapid administration of cyclophosphamide may induce lethal acute pericarditis and hemorrhagic myocarditis.[65787] Hemorrhagic myocarditis, which is fatal and occurs abruptly within days of cyclophosphamide administration, has been reported in less than 0.1% of patients in most transplant centers.[65804]

    Abdominal pain and diarrhea have been reported in patients treated with cyclophosphamide, although diarrhea is uncommon with oral cyclophosphamide.[65780] [65781] [65782] [65804] There have been isolated reports of hemorrhagic colitis in patients treated with cyclophosphamide. Cecitis (typhlitis), constipation, enteritis, and GI bleeding have also been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Anaphylactic shock and hypersensitivity reactions have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782] Some hypersensitivity reactions have occurred with oral therapy, but most have been associated with intravenous administration.[65796]

    Pulmonary toxicity including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of therapy) appears to be associated with increased mortality; pneumonitis may develop years after treatment with cyclophosphamide. Acute respiratory distress syndrome (ARDS), interstitial lung disease as manifested by respiratory failure, bronchiolitis obliterans, organizing pneumonia, allergic alveolitis, pulmonary hemorrhage, bronchospasm, dyspnea, hypoxia, cough, nasal congestion and discomfort, and rhinorrhea have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Visual impairment, conjunctivitis, and increased lacrimation have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Tumor lysis syndrome (TLS) and hyperuricemia have been reported in patients with rapidly growing tumors in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Hearing loss (deafness), impaired hearing, and tinnitus have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Both hyperglycemia and hypoglycemia have been reported in postmarketing surveillance of cyclophosphamide.[65780] [65781] [65782]

    Arthralgia, muscle spasms (muscle cramps), myalgia, myelopathy, and rhabdomyolysis have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Encephalopathy, seizures, dizziness, and neurotoxicity have been reported in postmarketing experience with cyclophosphamide, manifested as reversible posterior leukoencephalopathy syndrome (RPLS). Tremor has also been reported in postmarketing surveillance.[65780] [65781] [65782]

    Premature labor has been reported in postmarketing surveillance of cyclophosphamide.[65780] [65781] [65782]

    Confusion has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Pulmonary embolism, venous thrombosis, and peripheral ischemia have all been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Serious and life-threatening infection resulting from severe immunosuppression has been reported in patients receiving cyclophosphamide, including an increase in the risk and severity of pneumonia or other bacterial (e.g., Pneumocystis jirovecii), fungal, viral, protozoal, or parasitic infections (e.g., Strongyloides), reactivation of latent infections (e.g., viral hepatitis, tuberculosis, herpes zoster), sepsis, and septic shock; an influenza-like illness has also been reported in patients treated with cyclophosphamide in postmarketing experience. Increases in acute-phase reactants such as lactate dehydrogenase and C-reactive protein and multiorgan failure have also been reported.[65780] [65781] [65782]

    Acute pancreatitis has been reported in postmarketing surveillance of cyclophosphamide.[65780] [65781] [65782]

    Sinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD), has been reported in patients treated with cyclophosphamide, including some cases with fatal outcome. A cytoreductive regimen in preparation for bone marrow transplant that includes cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor, although it has also developed gradually in patients receiving long-term, low-dose cyclophosphamide for immunosuppression. Additional adverse hepatic reactions reported in postmarketing experience with cyclophosphamide include cholestasis, hepatitis (e.g., cholestatic hepatitis and cytolytic hepatitis), and hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, hyperbilirubinemia, and elevated hepatic enzymes. There are also isolated reports of jaundice occurring during therapy.[65780] [65781] [65782]

    Asthenia, malaise, and fatigue have been reported in postmarketing experience with cyclophosphamide, as well as general physical deterioration.[65780] [65781] [65782]

    Fever and chills have been reported during postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Disseminated intravascular coagulation (DIC) has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Hemolytic-uremic syndrome with thrombotic microangiopathy has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    A wide range of arrhythmias including supraventricular tachycardia (SVT) (e.g., atrial fibrillation and atrial flutter) and ventricular arrhythmia (e.g., severe QT prolongation associated with ventricular tachycardia or ventricular fibrillation) have been reported after treatment with regimens that included cyclophosphamide.[65780] [65781] [65782] However, arrhythmias usually occur in the context of perimyocarditis and congestive heart failure.[65788] In postmarketing experience, treatment with cyclophosphamide has also been associated with cardiac arrest, cardiogenic shock, myocardial infarction, bradycardia, and palpitations.[65780] [65781] [65782]

    Pleural effusion has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Fluid retention, edema, and facial swelling have all been reported in postmarketing surveillance of cyclophosphamide.[65780] [65781] [65782]

    Pulmonary edema has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Nausea and vomiting commonly occur with cyclophosphamide treatment if antiemetic prophylaxis is not employed. After a single dose of cyclophosphamide 1,500 mg/m2 or more, greater than 90% of patients will experience emesis. At doses of less than 1,500 mg/m2, the incidence of vomiting is 30% to 90%.[65780] [65781] [65782] [63197]

    There have been isolated reports of oral ulceration in patients treated with cyclophosphamide. Mucosal inflammation, parotid gland inflammation (parotitis), and stomatitis have also been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Cyclophosphamide may cause impaired wound healing by reducing initial vasodilation and subsequent neovascularization during the proliferative phase of healing. However, although high doses of cyclophosphamide adversely affect wound healing in several animal studies, studies in humans at therapeutic doses did not demonstrate these effects.[65780] [65781] [65782] [65794]

    Anorexia has commonly been reported with cyclophosphamide treatment. Dysgeusia, hypogeusia, and parosmia have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, and paresthesias have been reported in patients treated with cyclophosphamide in postmarketing experience.[65780] [65781] [65782]

    Reversible alopecia is common in patients treated with cyclophosphamide, especially in those who receive high doses.[65780] [65781] [65782] [65804] A skin rash occasionally occurs during treatment, while skin hyperpigmentation and nail changes can also occur. Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema, erythema multiforme, palmar-plantar erythrodysesthesia (hand and foot syndrome), radiation recall reaction, toxic skin eruption, scleroderma, urticaria, dermatitis, blisters, pruritus, and hyperhidrosis have all been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Both hypertension and hypotension have been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Pulmonary hypertension has been reported in postmarketing experience with cyclophosphamide.[65780] [65781] [65782]

    Chest pain (unspecified) has been reported in patients treated with cyclophosphamide in postmarketing experience; generalized pain has also been reported.[65780] [65781] [65782]

    Headache has been reported in postmarketing experience of patients treated with cyclophosphamide.[65780] [65781] [65782]

    Both flushing and hot flashes have been reported in postmarketing experience of patients treated with cyclophosphamide.[65780] [65781] [65782]

    Vasculitis has been reported in postmarketing experience of patients treated with cyclophosphamide.[65780] [65781] [65782]

    Renal failure (unspecified), renal tubular necrosis, renal impairment, toxic nephropathy, cystitis ulcerative, bladder spasm/contracture, nephrogenic diabetes insipidus, and atypical urinary bladder epithelial cells were each reported with cyclophosphamide treatment in postmarketing experience.[65780] [65781] [65782]

    Revision Date: 06/20/2024, 11:18:17 AM

    References

    24578 - Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996;124:477-84.63197 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017;35:3240-61.65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.65787 - Berardi R, Caramanti M, Savini A, et al. State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review. Critical Reviews in Oncology/Hematology. 2013;88:75-86.65788 - Guglin M, Aljayeh M, Saiyad S, et al. Introducing a new entity: chemotherapy-induced arrhythmia. Europace. 2009;11:1579-1586.65794 - Payne WG, Naidu DK, Wheeler CK, et al. Wound healing in patients with cancer. Eplasty. 2008;8:68-90.65796 - Popescu NA, Sheehan MG, Kouides PA, et al. Allergic reactions to cyclophosphaide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients. J Allergy Clin Immunol. 1996;97:26-33.65804 - Emadi A, Jones RJ, and Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6:638-647.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • bladder obstruction
    • urinary tract obstruction
    • alcoholism
    • anemia
    • bone marrow suppression
    • breast-feeding
    • cardiac disease
    • cardiotoxicity
    • children
    • chronic lung disease (CLD)
    • contraception requirements
    • dialysis
    • driving or operating machinery
    • ethanol ingestion
    • geriatric
    • hemorrhagic cystitis
    • hepatic disease
    • impaired wound healing
    • infection
    • infertility
    • leukopenia
    • male-mediated teratogenicity
    • neutropenia
    • new primary malignancy
    • pneumonitis
    • pregnancy
    • pregnancy testing
    • radiation therapy
    • renal impairment
    • reproductive risk
    • sinusoidal obstruction syndrome (SOS)
    • surgery
    • thrombocytopenia
    • tumor lysis syndrome (TLS)
    • urinary tract infection (UTI)
    • veno-occlusive disease (VOD)
    • viral infection

    Treatment with cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to cyclophosphamide or any component of the product. Hypersensitivity (e.g., anaphylactic reactions) has been reported with cyclophosphamide use; some cases were fatal. Cross-sensitivity with other alkylating agents is possible.[65782][69997][70001][70002]

    Treatment with cyclophosphamide is contraindicated in patients with urinary outflow obstruction (e.g., bladder obstruction or urinary tract obstruction). Before starting treatment, any urinary tract obstructions must be either excluded or corrected. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Use cyclophosphamide with caution, if at all, in patients with an active urinary tract infection (UTI). Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Discontinue cyclophosphamide if severe hemorrhagic cystitis occurs; medical and/or surgical supportive treatment may be required for prolonged cases. Urotoxicity including bladder ulceration, necrosis, fibrosis, contracture, and secondary cancer may require an interruption of cyclophosphamide treatment or cystectomy; fatal cases of urotoxicity have occurred. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity; mesna has been used to prevent severe bladder toxicity.[65780] [65781] [65782]

    Monitor patients with severe renal impairment (CrCl 10 to 24 mL/min) for signs and symptoms of toxicity during treatment with cyclophosphamide. Decreased renal excretion of cyclophosphamide may result in increased plasma levels of cyclophosphamide and its metabolites. Although cyclophosphamide and its metabolites are dialyzable, there are likely quantitative differences depending on the dialysis system being used. For patients with renal failure who require dialysis, consider using a consistent interval between cyclophosphamide administration and dialysis.[65780] [65781] [65782]

    Bone marrow suppression (e.g., anemia, leukopenia, neutropenia, thrombocytopenia) has been reported with cyclophosphamide therapy. Bone marrow failure and severe immunosuppression have also occurred, leading to serious and sometimes fatal infection; latent infections (e.g. viral infection) can be reactivated. Patients pretreated with or who are receiving concomitant chemotherapy and/or radiation may be at increased risk for myelosuppression. Monitor complete blood counts during treatment. Do not administer cyclophosphamide if the neutrophil count is 1,500 cells/mm3 or less and the platelet count is less than 50,000 cells/mm3. Consider primary and secondary prophylaxis with a granulocyte colony-stimulating factor in patients who have an increased risk of neutropenic complications. Prophylactic antimicrobial, antifungal, and/or antiviral therapy may be indicated in some patients. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients who develop a serious infection.[65780] [65781] [65782]

    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.[65780] [65781] [65782]

    Use cyclophosphamide with caution in patients with a history of hepatic disease, as they may be predisposed to the development of veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS); patients with low performance status and those who have received previous abdominal radiation may also be at increased risk. Veno-occlusive disease has been reported in patients treated with cyclophosphamide, including some cases with fatal outcome. A cytoreductive regimen in preparation for bone marrow transplant that includes cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. Veno-occlusive disease has also developed gradually in patients receiving long-term, low-dose cyclophosphamide for immunosuppression.[65780] [65781] [65782]

    Notify the anesthesiologist if a patient has been treated with cyclophosphamide within 10 days of surgery requiring general anesthesia. Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity; prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). Cyclophosphamide may also cause impaired wound healing.[65780] [65781] [65782]

    Use cyclophosphamide with caution in patients with pre-existing cardiac disease and other risk factors for cardiotoxicity, as myocarditis, myopericarditis, pericardial effusion, cardiac tamponade, and congestive heart failure have been reported with cyclophosphamide use; some cases were fatal. Cardiac arrhythmias including supraventricular arrhythmias (e.g., atrial fibrillation, atrial flutter) and ventricular arrhythmias (e.g., QT prolongation associated with ventricular tachyarrhythmia) have also occurred following cyclophosphamide-containing therapy. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in geriatric patients, in patients who have received prior radiation to the cardiac region, and in those with previous or concomitant treatment with other cardiotoxic agents.[65780] [65781] [65782]

    Use cyclophosphamide with caution in patients with a history of chronic lung disease (CLD) as pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity.[65780] [65781] [65782]

    New primary malignancy has occurred following treatment with cyclophosphamide, including acute leukemias, myelodysplasia, lymphoma, thyroid cancer, sarcoma, and urinary tract cancer. Taking measures to prevent hemorrhagic cystitis may reduce the risk of bladder cancer.[65780] [65781] [65782]

    Patients who were pretreated with and/or receiving concomitant radiation therapy with cyclophosphamide are at an increased risk of several treatment-related adverse reactions, including severe myelosuppression, cardiotoxicity (previous radiation treatment to the cardiac region), and veno-occlusive disease / sinusoidal obstructive syndrome (previous radiation therapy of the abdomen).[65780] [65781] [65782]

    Cyclophosphamide solution for injection contains ethanol to dissolve the active ingredients; take this into account for patients in whom ethanol ingestion should be avoided or minimized, including patients with alcoholism or hepatic impairment. The amount of alcohol may vary between products; consult individual product labeling for alcohol content. Patients should give consideration to the effect of the alcohol content in cyclophosphamide on driving or operating machinery immediately after the infusion.[65780][65781] [65782]

    Prepubescent children treated with cyclophosphamide typically develop secondary sexual characteristics normally; prepubescent girls may have regular menses. However, ovarian fibrosis with complete loss of germ cells has been reported in prepubescent girls who received prolonged cyclophosphamide therapy in late pre-pubescence. Girls treated with cyclophosphamide who retain ovarian function are at an increased risk of premature menopause. Oligospermia or azoospermia, increased gonadotropin secretion, and testicular atrophy have occurred in prepubescent boys who received cyclophosphamide therapy; azoospermia may be reversible in some cases. Treatment beyond 90 days increases the probability of sterility in males.[65782] [69997] [70001] [70002]

    Pregnancy should be avoided by females of reproductive potential during cyclophosphamide treatment and for at least 1 year after the last dose. Exposure to cyclophosphamide during pregnancy can cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Women who are pregnant or who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. Malformations of the skeleton, palate, limbs, and eyes as well as miscarriage have been reported after human fetal exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects in the newborn (e.g., leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis) have also been reported after exposure to cyclophosphamide during pregnancy. When administered to pregnant animals (mice, rats, rabbits, and monkeys) during organogenesis at doses at or below the dose used in humans based on body surface area, multiple malformations occurred including neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.[65780] [65781] [65782]

    Counsel patients about the reproductive risk and contraception requirements during cyclophosphamide treatment. Cyclophosphamide can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 year after treatment with cyclophosphamide. Females of reproductive potential should undergo pregnancy testing prior to initiation of cyclophosphamide. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for at least 4 months after treatment with cyclophosphamide. Women who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. The development of infertility or sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment; it may be irreversible in some patients. Amenorrhea (transient or permanent), associated with decreased estrogen and increased gonadotropin secretion, develops in a proportion of women treated with cyclophosphamide; patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment. Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.[65780] [65781] [65782]

    Due to the potential for serious adverse reactions in nursing infants from cyclophosphamide, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Cyclophosphamide is present in human milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast-fed by women treated with cyclophosphamide.[65780] [65781] [65782]

    Revision Date: 06/20/2024, 11:18:17 AM

    References

    65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.69997 - Cyclophosphamide injection package insert. East Windsor, NJ: Eugia US LLC; 2023 Nov.70001 - Cyclophosphamide tablet package insert. Deerfield, IL: Baxter Healthcare Corporation; 2020 Aug.70002 - Cyclophosphamide capsules package insert. Berkeley Heights, NJ: Hikma Pharmaceuticals USA Inc.; 2023 July.

    Mechanism of Action

    Cyclophosphamide is a synthetic alkylating agent that is chemically related to the nitrogen mustards. It is an inactive prodrug that requires activation to release the active metabolite, phosphoramide mustard. Hydroxylation of cyclophosphamide by the cytochrome P450 system generates 4-hydroxycyclophosphamide, which coexists in equilibrium with its tautomer, aldophosphamide. These metabolites are able to freely diffuse into cells, where aldophosphamide is decomposed into 2 compounds, phosphoramide mustard and acrolein. Phosphoramide mustard produces interstrand and intrastand DNA crosslinks, responsible for the cytotoxic properties of cyclophosphamide. Acrolein is the cause of hemorrhagic cystitis.[65780][65781][65782][65804]

     

    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.[25001] 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.[25331]

    Revision Date: 06/20/2024, 11:18:17 AM

    References

    25001 - Cupps TR, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 1982;128:2453-7.25331 - Schiavoni G, Mattei F, Pucchio TD, et al. Cyclophosphamide induces type I interferon and augments the number of CD44hi T lymphocytes in mice: implications and strategies of chemoimmunotherapy of cancer. Blood 2000;95:2024-30.65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.65804 - Emadi A, Jones RJ, and Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6:638-647.

    Pharmacokinetics

    Cyclophosphamide is administered orally and intravenously. The parent drug, cyclophosphamide, is approximately 20% protein-bound, with no dose-dependent changes in protein binding; some metabolites are protein-bound to an extent greater than 60%. The volume of distribution approximates total body water (30 to 50 liters). Following IV administration, the elimination half-life of cyclophosphamide ranges from 3 to 12 hours, with total body clearance ranging from 4 liters/hour to 5.6 liters/hour. Pharmacokinetics are linear over the dose range used clinically; however, at high doses, less of the parent compound is cleared by 4-hydroxylation, resulting in nonlinear elimination. When administered at a dose of 4 g/m2 over 90 minutes, cyclophosphamide exhibited saturable elimination in parallel with first-order renal elimination. Cyclophosphamide appears to induce its own metabolism, which results in an increase in the total clearance, increased formation of the 4-hydroxyl metabolites, and shortened half-life values following repeated administration at 12- to 24-hour intervals. Cyclophosphamide is primarily excreted as metabolites, with 10% to 20% excreted as unchanged drug in the urine and 4% in the bile following IV administration.[65780][65781][65782]

     

    Affected cytochrome P450 isoenzymes: CYP2A6, CYP2B6, CYP3A4/5, CYP2C9, CYP2C18, CYP2C19

    Cyclophosphamide is a prodrug that is primarily (75%) biotransformed in the liver to active alkylating metabolites by a mixed-function microsomal oxidase system including CYP2A6, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C18, and CYP2C19; CYP2B6 exhibits the highest 4-hydroxylase activity.[65780][65781][65782] The contribution of CYP3A4 to the activation of cyclophosphamide is variable, from a low level of 5% to 10% up to 35% of total enzyme activity. CYP3A5 and CYP2C9 might be important in extrahepatic activation of cyclophosphamide.[26572] 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.[27058] Cyclophosphamide, the parent compound, is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide; these active metabolites then undergo oxidation by aldehyde dehydrogenase to form inactive 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can also undergo beta-elimination to form other active metabolites, phosphoramide mustard, and acrolein; this spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of a dose of cyclophosphamide is directly detoxified by side-chain oxidation, leading to the formation of inactive metabolite 2-dechloroethylcyclophosphamide.[65780][65781][65782] 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.[27058]

    Route-Specific Pharmacokinetics

    Oral Route

    Peak concentrations of cyclophosphamide occurred 1 hour after oral administration (Tmax). The AUC ratio for cyclophosphamide after oral and IV administration (AUCPO to AUCIV) ranged from 0.87 to 0.96.[65780][65781][65782]

    Special Populations

    Hepatic Impairment

    The mean total body clearance of cyclophosphamide was 45 liters/kg (+/- 8.6 liters/kg) in patients with severe hepatic impairment, which is a 40% decrease compared to the control group. The elimination half-life was 12.5 hours (+/- 1 hour) in patients with severe hepatic impairment, representing a 64% increase from the control group. Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy.[65780][65781][65782]

    Renal Impairment

    Systemic exposure to cyclophosphamide increases as renal function decreases. Following a one-hour IV infusion, the mean dose-corrected AUC increased by 30% in patients with moderate renal impairment (CrCl 25 to 50 mL/min) and by 64% in patients with severe renal impairment (CrCl 10 to 24 mL/min) compared to the control group; cyclophosphamide exposure increased by 23% in patients receiving hemodialysis (CrCl less than 10 mL/min). A reduction in half-life, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable. In four patients on long-term hemodialysis, the dialysis clearance of cyclophosphamide averaged 104 mL/min (calculated by arterial venous difference and actual drug recovery in dialysate); this is in the range of the metabolic clearance of 95 mL/min for cyclophosphamide. A mean of 37% of the administered dose was removed during hemodialysis. The elimination half-life of cyclophosphamide was 3.3 hours during hemodialysis, which is a 49% reduction from that reported for uremic patients (6.5 hours).[65780][65781][65782]

    Revision Date: 06/20/2024, 11:18:17 AM

    References

    26572 - Roy P, Yu LJ, Crespi CL, et al. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999;27:655-666.27058 - Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechlorethylation of cyclophosphamide and ifosphamide. Biochem Pharmacol 2000;59:961-972.65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.

    Pregnancy/Breast-feeding

    pregnancy

    Pregnancy should be avoided by females of reproductive potential during cyclophosphamide treatment and for at least 1 year after the last dose. Exposure to cyclophosphamide during pregnancy can cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Women who are pregnant or who become pregnant while receiving cyclophosphamide should be apprised of the potential hazard to the fetus. Malformations of the skeleton, palate, limbs, and eyes as well as miscarriage have been reported after human fetal exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects in the newborn (e.g., leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis) have also been reported after exposure to cyclophosphamide during pregnancy. When administered to pregnant animals (mice, rats, rabbits, and monkeys) during organogenesis at doses at or below the dose used in humans based on body surface area, multiple malformations occurred including neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.[65780] [65781] [65782]

    breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from cyclophosphamide, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Cyclophosphamide is present in human milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast-fed by women treated with cyclophosphamide.[65780] [65781] [65782]

    Revision Date: 06/20/2024, 11:18:17 AM

    References

    65780 - Cyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2023 Jan.65781 - Cyclophosphamide capsules package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp; 2019 Sept.65782 - Cyclophosphamide powder for solution package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023 Aug.69997 - Cyclophosphamide injection package insert. East Windsor, NJ: Eugia US LLC; 2023 Nov.70001 - Cyclophosphamide tablet package insert. Deerfield, IL: Baxter Healthcare Corporation; 2020 Aug.70002 - Cyclophosphamide capsules package insert. Berkeley Heights, NJ: Hikma Pharmaceuticals USA Inc.; 2023 July.

    Interactions

    Level 2 (Major)

    • Anifrolumab
    • Belimumab
    • Etanercept
    • Natalizumab
    • Succinylcholine

    Level 3 (Moderate)

    • Abacavir; Lamivudine, 3TC; Zidovudine, ZDV
    • Abatacept
    • Adalimumab
    • Aliskiren; Hydrochlorothiazide, HCTZ
    • Allopurinol
    • Amiloride; Hydrochlorothiazide, HCTZ
    • Amiodarone
    • Amlodipine; Benazepril
    • Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ
    • Amphotericin B
    • Amphotericin B lipid complex (ABLC)
    • Amphotericin B liposomal (LAmB)
    • Angiotensin-converting enzyme inhibitors
    • Anthracyclines
    • Articaine; Epinephrine
    • Atazanavir
    • Atazanavir; Cobicistat
    • Atenolol; Chlorthalidone
    • Azathioprine
    • Azilsartan; Chlorthalidone
    • Benazepril
    • Benazepril; Hydrochlorothiazide, HCTZ
    • Bismuth Subcitrate Potassium; Metronidazole; Tetracycline
    • Bismuth Subsalicylate; Metronidazole; Tetracycline
    • Bisoprolol; Hydrochlorothiazide, HCTZ
    • Bupivacaine
    • Bupivacaine Liposomal
    • Bupivacaine; Epinephrine
    • Bupivacaine; Lidocaine
    • Bupivacaine; Meloxicam
    • Busulfan
    • Candesartan; Hydrochlorothiazide, HCTZ
    • Captopril
    • Captopril; Hydrochlorothiazide, HCTZ
    • Carbamazepine
    • Chloroprocaine
    • Chlorothiazide
    • Chlorthalidone
    • Cholera Vaccine
    • Cyclosporine
    • Cytarabine, ARA-C
    • Darunavir
    • Darunavir; Cobicistat
    • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
    • Daunorubicin
    • Daunorubicin Liposomal; Cytarabine Liposomal
    • Dengue Tetravalent Vaccine, Live
    • Doxorubicin
    • Doxorubicin Liposomal
    • Enalapril, Enalaprilat
    • Enalapril; Hydrochlorothiazide, HCTZ
    • Epirubicin
    • Eprosartan; Hydrochlorothiazide, HCTZ
    • Fam-Trastuzumab deruxtecan
    • Fosamprenavir
    • Fosinopril
    • Fosinopril; Hydrochlorothiazide, HCTZ
    • Hydrochlorothiazide, HCTZ
    • Hydrochlorothiazide, HCTZ; Moexipril
    • Idarubicin
    • Indinavir
    • Indomethacin
    • Irbesartan; Hydrochlorothiazide, HCTZ
    • Lamivudine, 3TC; Zidovudine, ZDV
    • Lidocaine
    • Lidocaine; Epinephrine
    • Lidocaine; Prilocaine
    • Lisinopril
    • Lisinopril; Hydrochlorothiazide, HCTZ
    • Lopinavir; Ritonavir
    • Losartan; Hydrochlorothiazide, HCTZ
    • Mepivacaine
    • Metolazone
    • Metoprolol; Hydrochlorothiazide, HCTZ
    • Metronidazole
    • Moexipril
    • Nelfinavir
    • Nirmatrelvir; Ritonavir
    • Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ
    • Olmesartan; Hydrochlorothiazide, HCTZ
    • Paclitaxel
    • Penicillin G Benzathine; Penicillin G Procaine
    • Penicillin G Procaine
    • Pentostatin
    • Perindopril
    • Perindopril; Amlodipine
    • Pertuzumab; Trastuzumab; Hyaluronidase
    • Prilocaine
    • Prilocaine; Epinephrine
    • Protease inhibitors
    • Quinapril
    • Quinapril; Hydrochlorothiazide, HCTZ
    • Ramipril
    • Ritonavir
    • Ropivacaine
    • Saquinavir
    • SARS-CoV-2 (COVID-19) vaccines
    • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
    • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
    • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
    • Spironolactone; Hydrochlorothiazide, HCTZ
    • Tamoxifen
    • Telmisartan; Hydrochlorothiazide, HCTZ
    • Tetracaine
    • Thiazide diuretics
    • Thiotepa
    • Tipranavir
    • Trandolapril
    • Trandolapril; Verapamil
    • Trastuzumab
    • Trastuzumab; Hyaluronidase
    • Triamterene; Hydrochlorothiazide, HCTZ
    • Tuberculin Purified Protein Derivative, PPD
    • Valsartan; Hydrochlorothiazide, HCTZ
    • Vasopressin, ADH
    • Warfarin
    • Zidovudine, ZDV

    Level 4 (Minor)

    • Filgrastim, G-CSF
    • Pegfilgrastim
    • Sargramostim, GM-CSF
    • Tbo-Filgrastim
    Abacavir; lamiVUDine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Abatacept: (Moderate) Concomitant use of immunosuppressives such as cyclophosphamide may increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection. [31761] Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients taking concomitant immunosuppressants have not been evaluated. Patients receiving cyclophosphamide along with adalimumab may be at a greater risk of developing an infection. [27939] Aliskiren; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Allopurinol: (Moderate) Monitor for evidence of myelosuppression if cyclophosphamide is coadministered with allopurinol. Coadministration of allopurinol with cytotoxic agents, such as cyclophosphamide, may increase the risk of myelosuppression in patients with neoplastic disease (with the exception of leukemia). Routinely obtain complete blood cell counts. [32197] aMILoride; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Amiodarone: (Moderate) Use caution if cyclophosphamide is used concomitantly with amiodarone as there may be an increased risk of pulmonary toxicity. [28224] [28896] [65780] [65781] [65782] amLODIPine; Benazepril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] amLODIPine; Valsartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Amphotericin B lipid complex (ABLC): (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity. [65780] [65781] [65782] Amphotericin B liposomal (LAmB): (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity. [65780] [65781] [65782] Amphotericin B: (Moderate) Monitor renal function if cyclophosphamide is used concomitantly with amphotericin B as there may be an increased risk of nephrotoxicity. [65780] [65781] [65782] Angiotensin-converting enzyme inhibitors: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as cyclophosphamide. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal. [66846] Anthracyclines: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] 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. [28996] Atazanavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Atazanavir; Cobicistat: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Atenolol; Chlorthalidone: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] azaTHIOprine: (Moderate) Monitor hepatic function if coadministration of cyclophosphamide with azathioprine is necessary as there is an increased risk of hepatotoxicity (liver necrosis). [65780] [65781] [65782] Azilsartan; Chlorthalidone: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [43658] Benazepril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Benazepril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Bismuth Subcitrate Potassium; metroNIDAZOLE; Tetracycline: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity. [65780] [65781] [65782] Bismuth Subsalicylate; metroNIDAZOLE; Tetracycline: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity. [65780] [65781] [65782] Bisoprolol; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [52331] 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. [52331] BUPivacaine; EPINEPHrine: (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. [52331] 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. [52331] (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. [43383] BUPivacaine; Meloxicam: (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. [52331] Busulfan: (Moderate) Monitor hepatic function if coadministration of cyclophosphamide with busulfan is necessary as there is an increased risk of hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD). An increased incidence of mucositis has also been reported with concomitant use. [65780] [65781] [65782] Candesartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Captopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Captopril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] carBAMazepine: (Moderate) Monitor for cyclophosphamide-related adverse reactions if coadministration with carbamazepine is necessary. Chronic carbamazepine administration may increase the rate of metabolism and leukopenic activity of cyclophosphamide. Cyclophosphamide is an inactive prodrug that is converted to its active metabolite in part by CYP3A. Carbamazepine is a strong CYP3A4 inducer. [28024] [41237] 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. [29062] Chlorothiazide: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Chlorthalidone: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] cycloSPORINE: (Moderate) Closely monitor cyclosporine concentrations if coadministration with cyclophosphamide is necessary. Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. [65780] [65781] [65782] Cytarabine, ARA-C: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with cytarabine is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] Darunavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Darunavir; Cobicistat: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] DAUNOrubicin Liposomal; Cytarabine Liposomal: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] DAUNOrubicin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine. [60092] [64100] [65107] DOXOrubicin Liposomal: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] DOXOrubicin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] Enalapril, Enalaprilat: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Enalapril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] epiRUBicin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] Eprosartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [28060] [32637] [65780] [65781] [65782] Fam-Trastuzumab deruxtecan: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab deruxtecan is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] 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. [65780] [65781] [65782] Fosamprenavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Fosinopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Fosinopril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] hydroCHLOROthiazide, HCTZ; Moexipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] IDArubicin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy. [61628] [65780] [65781] [65782] Indinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Indomethacin: (Moderate) Use caution if coadministration of cyclophosphamide with indomethacin is necessary as acute water intoxication has been reported with concomitant use. [65780] [65781] [65782] Irbesartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] lamiVUDine, 3TC; Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [43383] Lidocaine; EPINEPHrine: (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. [43383] Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as cyclophosphamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. [43383] (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. [29064] Lisinopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Lisinopril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Lopinavir; Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Losartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [29100] metOLazone: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Metoprolol; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] metroNIDAZOLE: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with metronidazole is necessary. Acute encephalopathy has been reported in one patient receiving cyclophosphamide and metronidazole, although causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with an increase in cyclophosphamide toxicity. [65780] [65781] [65782] Moexipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as cyclophosphamide. Ordinarily, patients with multiple sclerosis who are receiving chronic immunosuppressant therapy (including with cyclophosphamide) should not be treated with natalizumab for similar reasons. The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with cyclophosphamide is also a risk factor for PML. [30470] [65780] [65781] [65782] Nelfinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Olmesartan; amLODIPine; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Olmesartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] PACLitaxel: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with paclitaxel is necessary. Increased hematologic toxicity has been reported when cyclophosphamide was administered after paclitaxel infusion. [65780] [65781] [65782] Pegfilgrastim: (Minor) Use caution if cyclophosphamide is used concomitantly with pegfilgrastim; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GM-CSF. [65780] [65781] [65782] 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. [31217] 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. [31217] Pentostatin: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with pentostatin is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] Perindopril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Perindopril; amLODIPine: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Pertuzumab; Trastuzumab; Hyaluronidase: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] 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. [29064] 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. [29064] Protease inhibitors: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Quinapril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Quinapril; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Ramipril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Ritonavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] 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. [52330] Saquinavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Sargramostim, GM-CSF: (Minor) Use caution if cyclophosphamide is used concomitantly with sargramostim, GM-CSF; reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and GM-CSF. [65780] [65781] [65782] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Spironolactone; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Succinylcholine: (Major) Notify the anesthesiologist if a patient has been treated with cyclophosphamide within 10 days of general anesthesia. Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity; prolonged apnea may occur with concurrent use of depolarizing muscle relaxants such as succinylcholine. [65780] [65781] [65782] Tamoxifen: (Moderate) Monitor for signs and symptoms of thrombosis if coadministration of cyclophosphamide with tamoxifen is necessary; concomitant use of tamoxifen with chemotherapy may increase the risk of thromboembolic complications. [65780] [65781] [65782] 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. [65780] [65781] [65782] Telmisartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [31353] Thiazide diuretics: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [61718] Tipranavir: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. [65780] [65781] [65782] Trandolapril: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Trandolapril; Verapamil: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with angiotensin-converting enzyme inhibitors (ACE inhibitors) is necessary as there is an increased risk of hematologic toxicity (specifically leukopenia) and immunosuppression. [65780] [65781] [65782] Trastuzumab: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] Trastuzumab; Hyaluronidase: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with trastuzumab is necessary as there is an increased risk of cardiotoxicity. [65780] [65781] [65782] Triamterene; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] 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. [43298] [43299] Valsartan; hydroCHLOROthiazide, HCTZ: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with thiazide diuretics is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782] Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as cyclophosphamide. Use together may increase the pressor and antidiuretic effects of vasopressin. [58023] Warfarin: (Moderate) Monitor the PT/INR in patients receiving cyclophosphamide with warfarin therapy; both increased and decreased warfarin effect have been reported in patients receiving concomitant therapy. [65780] [65781] [65782] Zidovudine, ZDV: (Moderate) Closely monitor complete blood counts if coadministration of cyclophosphamide with zidovudine is necessary as there is an increased risk of hematologic toxicity and immunosuppression. [65780] [65781] [65782]
    Revision Date: 06/20/2024, 11:18:17 AM

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    Monitoring Parameters

    • CBC with differential
    • pregnancy testing
    • urinalysis

    US Drug Names

    • Cyclophosphamide
    • Cytoxan
    • Neosar
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