Cyclophosphamide, a nitrogen mustard-derivative, polyfunctional alkylating agent, is an antineoplastic agent and immunosuppressant.
Cyclophosphamide is used in combination regimens (e.g., bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) for the treatment of Hodgkin's disease.153, 164, 171
Cyclophosphamide is used in combination therapy for the treatment of non-Hodgkin's lymphoma, including high-grade lymphomas, such as Burkitt's lymphoma and lymphoblastic lymphoma, as well as intermediate- and low-grade lymphomas.153, 164 For example, cyclophosphamide is commonly used with doxorubicin, vincristine, and prednisone (known as the CHOP regimen), with or without other agents, in the treatment of various types of intermediate-grade non-Hodgkin's lymphoma.153 Cyclophosphamide also has been used as a single agent in the treatment of low-grade lymphomas.153
Cyclophosphamide is used in combination with prednisone, or as a component of combination chemotherapy (i.e., vincristine, carmustine, melphalan, cyclophosphamide, and prednisone [VBMCP]) for the treatment of multiple myeloma.153, 164 Comparative studies have shown the effectiveness of cyclophosphamide in the treatment of multiple myeloma to be equivalent to that of melphalan, and the combination of either agent with prednisone is considered a treatment of choice.153 Some authorities prefer melphalan to cyclophosphamide because of the lesser severity of adverse effects; in the presence of severe thrombocytopenia, others prefer cyclophosphamide because of its relative platelet-sparing effect.
Use of cyclophosphamide in combination with bortezomib and dexamethasone (bortezomib-cyclophosphamide-dexamethasone)10019, 10021, 10022, 10028, 10029 as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients may be considered a reasonable choice (accepted, with possible conditions) based on current evidence from 2 noncomparative phase 2 studies and an open-label, randomized phase 3 study (GMMG-MM5);10035 factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy include cytogenetic features, performance status, preexisting conditions (e.g., peripheral neuropathy), and tolerability.10035
In the first phase 2 study, the overall response rate and rate of very good partial response or better after 4 cycles of therapy were 88 and 61%, respectively, in the study group (cohort of 33 patients with newly diagnosed multiple myeloma who received cyclophosphamide in combination with bortezomib [twice weekly] and dexamethasone) compared with 91 and 44%, respectively, in a historical control group (34 patients who received lenalidomide and dexamethasone).10019, 10031 Among patients who underwent stem cell transplantation following bortezomib-cyclophosphamide-dexamethasone induction therapy, the posttransplant complete or near-complete response rate was 70%.10019 A subsequent cohort of 30 patients who received cyclophosphamide with bortezomib (once weekly) and dexamethasone achieved similar overall response rates and rates of very good partial response or better (93 and 60%, respectively).10019, 10021 Median progression-free survival for the 2 cohorts combined was 40 months, and 5-year progression-free and overall survival rates for the 2 cohorts were 42 and 70%, respectively.10022 Although the overall response rate was similar in patients with high-risk cytogenetic features and those with standard-risk cytogenetic features, median progression-free survival was shorter and 5-year progression-free and overall survival rates were lower in patients with high-risk cytogenetic features (27.6 months, 33%, and 54%, respectively) compared with those with standard-risk cytogenetic features (55.7 months, 48%, and 81%, respectively).10022
In another phase 2 study in 44 patients with newly diagnosed multiple myeloma who received 3 cycles of bortezomib-cyclophosphamide-dexamethasone followed by 3 cycles of bortezomib-thalidomide-dexamethasone, very good partial response or better was observed in 31 or 57% of 42 evaluable patients following 3 or 6 treatment cycles, respectively; near-complete response or better was observed following 3 or 6 cycles in 2 or 36% of patients, respectively.10029 At a median follow-up of 20.9 months, estimated 1-year event-free and overall survival rates were 81 and 91%, respectively.10029
In the GMMG-MM5 study in 502 patients with newly diagnosed multiple myeloma, rates of overall response (78.1 versus 72.1%, respectively) and very good partial response or better (37 versus 34.3%, respectively) did not differ significantly between patients receiving bortezomib-cyclophosphamide-dexamethasone and those receiving bortezomib-doxorubicin-dexamethasone.10028 In subgroups of patients with poor prognostic factors (i.e., t(4;14) translocation, chromosome 17p deletion [del(17p)], and/or chromosome 1q21 duplication [1q21 gain]; renal impairment), response rates attained with bortezomib-cyclophosphamide-dexamethasone appeared to be at least as high as those attained with bortezomib-doxorubicin-dexamethasone; the rate of progressive disease in patients with high-risk cytogenetic features, International Staging System (ISS) stage III disease, or renal impairment appeared to be higher in those receiving bortezomib-doxorubicin-dexamethasone compared with those receiving bortezomib-cyclophosphamide-dexamethasone.10028
In the treatment of chronic lymphocytic (lymphoblastic) leukemia, cyclophosphamide is considered one of the drugs of choice.153, 164 Cyclophosphamide is used in combination with busulfan as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia.166
Cyclophosphamide is used in the treatment of acute lymphoblastic leukemia, especially in children.153, 164
In the treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), cyclophosphamide has been used as an additional drug for induction or post induction therapy.153, 164
Although cyclophosphamide and its metabolites appear in the brain and CSF, concentrations are probably insufficient to treat meningeal leukemia.
Cyclophosphamide is used alone or in combination regimens for the treatment of advanced mycosis fungoides, a form of cutaneous T-cell lymphoma.
In the treatment of disseminated neuroblastoma, cyclophosphamide used alone has been reported to produce objective responses in up to 65% of patients; used in combinations, the response rate and duration of survival may increase. Combination chemotherapy that includes cyclophosphamide is a treatment of choice for this neoplasm.153
Cyclophosphamide is used in combination chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC]) as an alternative regimen for the treatment of ovarian germ cell tumors†.153, 164
Although cyclophosphamide has been used in combination with a platinum-containing agent for the treatment of advanced (stage III or IV) epithelial ovarian cancer,169, 170 evidence from randomized trials167, 168 indicates that combined therapy with paclitaxel and a platinum-containing agent is superior (higher response rates, prolonged overall survival) and therefore is the preferred regimen.153, 162 (See Uses: Ovarian Cancer, in Carboplatin 10:00 and in Cisplatin 10:00.)
Cyclophosphamide is used in combination therapy for the treatment of retinoblastoma.153, 164
In the treatment of breast cancer, cyclophosphamide used alone has been reported to produce objective responses in about 35% of patients. Used in combination regimens, objective responses have been reported in up to 90% of patients, and cyclophosphamide-containing combinations are believed by some experts to be the treatment of choice.
Combination chemotherapy used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 158 Adjuvant combination chemotherapy has produced overall reductions in the annual rates of recurrence and death of 28 and 16%, respectively, with overall 5-year disease-free survival rates of 58.8 versus 49.6% for patients receiving combination chemotherapy versus those who did not.138 Adjuvant combination chemotherapy that includes cyclophosphamide, methotrexate, and fluorouracil has been used extensively and is considered a regimen of choice.137, 138, 139, 140, 141, 142, 143, 144, 145, 149, 150, 153, 156, 157, 158 Although adjuvant hormonal therapy with tamoxifen (with or without combination chemotherapy) generally is used for node-positive, estrogen-receptor-positive postmenopausal women,137, 153 adjuvant combination chemotherapy (with or without tamoxifen) also can be used in such patients,137, 138, 139, 140, 141, 142, 144 but differences in toxicity profiles may influence the choice of regimen.137 For node-positive premenopausal women, adjuvant combination chemotherapy (with or without tamoxifen) generally is used.137, 153 Adjuvant therapy with combination chemotherapy and/or tamoxifen has been used in women with node-negative disease.137, 143, 147, 151, 152, 153
Controversy currently exists regarding which patients with node-negative and estrogen-receptor-negative breast cancer are most likely to benefit from such adjuvant therapy following surgery (see Uses: Breast Cancer, in Fluorouracil 10:00), 137, 138, 143, 147, 148, 149, 150, 151, 152 but such patients with poor prognosis are reasonable candidates for adjuvant chemotherapy with an effective regimen (e.g., 6-12 months of cyclophosphamide, methotrexate, and fluorouracil initiated within 6 weeks of surgery); other node-negative patients also may be suitable candidates, but toxicities, costs, and other quality-of-life considerations should be weighed in assessing potential benefit.137, 138, 147, 148, 153, 154, 155 All patients with node-negative breast cancer are at some risk of recurrence,137, 138 and effective adjuvant combination chemotherapy can increase both disease-free and overall survival, albeit less markedly than in patients with node-positive disease.137, 138
In patients with node-positive early breast cancer (i.e., stage II), an effective regimen of adjuvant combination chemotherapy (e.g., cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; cyclophosphamide and doxorubicin with or without tamoxifen) is used to reduce the rate of recurrence and improve survival in both premenopausal and postmenopausal patients once treatment to control local disease (surgery, with or without radiation therapy) has been undertaken.137, 138, 139, 140, 141, 142, 143, 144, 145, 158 These combinations have been tested and established as providing therapeutic benefit, and are superior to single-agent therapy with conventional agents;137, 138, 139, 140, 141, 142, 143, 144, 158 numerous other combination regimens providing apparently similar outcomes also have been used but are less common or have been studied less extensively.137, 138, 156, 158 Although long-term (e.g., 6 months or longer) chemotherapy with adjuvant regimens is clinically superior to short-term (e.g., preoperative and perioperative) adjuvant regimens,137, 138, 158 clinical superiority between 6- versus 12-month regimens has not been demonstrated.137, 138 There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with more than 3 positive axillary lymph nodes,142, 156 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;142, 156 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.142, 145 The dose intensity of adjuvant combination chemotherapy also appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.137, 141, 158
In stage III (locally advanced) breast cancer, combination chemotherapy (with or without hormonal therapy) is used sequentially following surgery and radiation therapy for operable disease and following biopsy and radiation therapy for inoperable disease; commonly employed effective regimens include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, methotrexate, fluorouracil, and prednisone.137 These and other regimens also have been used in the treatment or more advanced (stage IV) and recurrent disease.137
Cyclophosphamide is used in combination chemotherapy regimens (e.g., cyclophosphamide, doxorubicin, and vincristine [CAV]; cyclophosphamide, doxorubicin, and etoposide [ CAE]) for the treatment of extensive-stage small cell lung cancer†.153, 163 Survival outcomes are similar in patients with extensive-stage small cell lung cancer receiving CAV or cisplatin/etoposide.163 Combination chemotherapy regimens have produced response rates of 70-85% and complete response rates of 20-30% in patients with extensive-stage disease; however, comparative efficacy is continually being evaluated.163 Because the current prognosis for small cell lung cancer is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.163
Cyclophosphamide has been used in combination regimens (usually with dactinomycin and vincristine) and as an adjunct to surgery and radiation therapy in the treatment of rhabdomyosarcoma†.153 In children in groups I and II, 2-year relapse-free survival rates of 80-90% have been reported. Intensive regimens of dactinomycin, cyclophosphamide, and vincristine (with or without doxorubicin) followed by radiation therapy have produced an objective response in 80% of patients having residual tumor following surgery (group III) or with metastatic tumor (group IV). Cyclophosphamide used in combination regimens as an adjunct to surgery and radiation therapy is considered one of the treatments of choice for Ewing's sarcoma†.153
Cyclophosphamide is used in selected cases of biopsy-proven minimal change nephrotic syndrome in children; the drug should not be used as initial therapy in such patients. Cyclophosphamide has induced remission in patients whose disease has not responded to appropriate corticosteroid therapy or in whom such therapy produces intolerable adverse effects (e.g., growth failure).
Cyclophosphamide is used in combination with vincristine and dacarbazine for the treatment of pheochromocytoma†.153 Cyclophosphamide also is used in the treatment of brain tumors†, choriocarcinoma†, and Wilms' tumor†.153
As an immunosuppressant, cyclophosphamide has been used to control rejection following kidney, heart, liver, and bone marrow transplants†. Some experts consider cyclophosphamide as effective as azathioprine for the maintenance of renal allografts and superior to azathioprine for the maintenance of hepatic allografts. Cyclophosphamide has also been used with some success in the treatment of severe, active and progressive rheumatoid disorders†. In the treatment of glomerulonephritis,† especially in children, cyclophosphamide alone or in conjunction with corticosteroids has been useful. Other disorders of altered immune reactivity in which cyclophosphamide has been used with some success include Wegener's granulomatosis†, idiopathic pulmonary hemosiderosis†, myasthenia gravis†, multiple sclerosis†, polymyositis†, pyoderma gangrenosum†, bullous pemphigoid†, pemphigus vulgaris†, autoallergic ocular disease†, uveitis†, orbital pseudotumor†, scleromalacia perforans†, thyroid exophthalmopathy†, corneal transplant rejection†, systemic lupus erythematosus†, lupus nephritis†, autoimmune hemolytic anemia†, idiopathic thrombocytic purpura†, macroglobulinemia†, cryoglobulinemia†, and antibody-induced pure red cell aplasia†. The drug has also been used for the treatment of bleeding syndromes in patients with acquired antibodies to clotting factors†. Because of the potential for serious adverse effects, cyclophosphamide must be used as an immunosuppressant† with caution, and some experts advocate reserving use of cyclophosphamide for patients who become refractory to corticosteroids or other less toxic agents, or limiting it to short-term use whenever feasible.
Reconstitution and Administration
Cyclophosphamide is administered orally164 or by IV injection or infusion.164 Less frequently, the drug has been administered IM and by intracavitary (e.g., intrapleural, intraperitoneal) injection and direct perfusion, but some experts believe the drug should not be administered via routes which bypass activation in the liver.
The choice of diluent for reconstituting cyclophosphamide powder for injection containing cyclophosphamide monohydrate depends on the route of administration to be used.164 If the solution is to be used for direct injection, cyclophosphamide powder for injection (containing cyclophosphamide monohydrate) is reconstituted by adding 0.9% sterile sodium chloride solution.164 If the solution is to be used for IV infusion, cyclophosphamide powder for injection (containing cyclophosphamide monohydrate) is reconstituted by adding sterile water for injection.164 Cyclophosphamide powder for injection (containing cyclophosphamide monohydrate) reconstituted in water is hypotonic and should not be injected directly.164 Cyclophosphamide powder for injection (containing cyclophosphamide monohydrate) is reconstituted by adding 25 mL of diluent to the vial labeled as containing 500 mg, 50 mL to the vial labeled as containing 1 g, or 100 mL to the vial labeled as containing 2 g.164 After adding the diluent to the vial, the vial should be shaken vigorously to dissolve the drug.164 If the powder fails to dissolve immediately and completely, the vial should be allowed to stand for a few minutes.164
Reconstituted solutions of cyclophosphamide to be used for IV infusion may be diluted in one of the following compatible solutions: 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and Ringer's injection, lactated Ringer's injection, 0.45% sodium chloride injection, or (1/6) M sodium lactate injection.164
Cyclophosphamide solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.164
Extemporaneous liquid preparations of the drug for oral administration may be prepared by dissolving cyclophosphamide powder for injection in aromatic elixir.164 The manufacturer states that such solutions should be stored under refrigeration in glass containers and used within 14 days.164
Because of the risk of certain toxicities (e.g., cardiotoxicity) and overdosage with high doses of cyclophosphamide,159, 160, 161 particular care should be taken to ensure that correct dosages and administration schedules have been prescribed and appropriate monitoring instituted when higher than usual dosages (e.g., those employed under protocol conditions) are encountered.159
Clinicians should consult published protocols for the dosage of cyclophosphamide and other chemotherapeutic agents in combination regimens and the method and sequence of administration.
The manufacturers state that, in patients with no hematologic deficiencies receiving cyclophosphamide monotherapy, induction therapy in adults and children is usually initiated with an IV cyclophosphamide loading dose of 40-50 mg/kg administered in divided doses over 2-5 days.164 Other regimens for IV administration include 10-15 mg/kg every 7-10 days or 3-5 mg/kg twice weekly.164
If cyclophosphamide is administered orally, the usual dose for induction or maintenance therapy is 1-5 mg/kg daily, depending on the tolerance of the patient.164
Various other regimens for IV or oral cyclophosphamide have been reported.164 Dosage of cyclophosphamide must be adjusted according to tumor response and/or leukopenia.164 The total leukocyte count is used as a guide for regulating cyclophosphamide dosage.164 Transient decreases in the total leukocyte count to 2000/mm3 (following short courses of therapy) or more persistent reduction to 3000/mm3 (with continuing therapy) may be tolerated without serious risk of infection if there is no marked granulocytopenia.164
When cyclophosphamide is included in combination regimens with other cytotoxic agents, dosage reduction for cyclophosphamide as well as for the other agents may be necessary.164
Various cyclophosphamide-containing combination chemotherapy regimens have been used in the treatment of breast cancer, and published protocols should be consulted for dosages and the method and sequence of administration.139, 140, 141, 142, 143, 144, 145, 147, 151, 152, 154, 156, 158 The dose intensity of adjuvant combination chemotherapy appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.137, 141, 158
One commonly employed regimen for the treatment of early breast cancer includes a cyclophosphamide dosage of 100 mg/m2 orally139, 140, 158 on days 1 through 14 of each cycle combined with methotrexate 40 mg/m2 IV on days 1 and 8 of each cycle and fluorouracil 600 mg/m2 IV on days 1 and 8 of each cycle.139, 140, 158 In patients older than 60 years of age, the initial methotrexate dosage was reduced to 30 mg/m2 IV and the initial fluorouracil dosage was reduced to 400 mg/m2 IV.140 Dosage also was reduced if myelosuppression developed.139, 140 Cycles generally were repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6-12 cycles (i.e., 6-12 months of therapy).139, 140, 158 Clinical superiority between 6- versus 12-month regimens has not been demonstrated.137, 138
There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with early breast cancer and more than 3 positive axillary lymph nodes,142 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;142 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.142, 145 In the sequential regimen, 4 doses of doxorubicin hydrochloride 75 mg/m2 IV were administered initially at 3-week intervals followed by 8 cycles of cyclophosphamide 600 mg/m2 IV, methotrexate 40 mg/m2 IV, and fluorouracil 600 mg/m2 IV at 3-week intervals for a total of approximately 9 months of therapy.142, 156 If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than reducing dosage.142, 156
In the treatment of minimal change nephrotic syndrome in children, an oral dosage of 2.5-3 mg/kg daily for 60-90 days has been recommended.164 In males, treatment for longer than 60 days increases the incidence of oligospermia and azoospermia; treatment for longer than 90 days increases the risk of sterility.164 Corticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy.164
Cyclophosphamide has been used in several regimens in combination with bortezomib and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients.10019, 10021, 10028, 10029
When cyclophosphamide has been used in combination with bortezomib and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, cyclophosphamide 300 mg/m2 has been administered orally on days 1, 8, 15, and 22 along with bortezomib 1.3 mg/m2 by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 of each 28-day cycle for 4 cycles.10019
Cyclophosphamide 300 mg/m2 also has been administered orally on days 1, 8, 15, and 22 along with bortezomib 1.5 mg/m2 by IV injection once weekly (days 1, 8, 15, and 22) during each 28-day cycle for 4 cycles.10021 In this regimen, dexamethasone 40 mg has been administered orally on days 1-4, 9-12, and 17-20 during cycles 1 and 2 and then once weekly during cycles 3 and 4.10021
Cyclophosphamide 300 mg/m2 also has been administered IV on days 1 and 8 along with bortezomib 1.3 mg/m2 by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 1-3) followed by bortezomib 1 mg/m2 by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 4-6).10029
Cyclophosphamide 900 mg/m2 also has been administered IV on day 1 along with bortezomib 1.3 mg/m2 by subcutaneous or IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.10028
Dosage in Renal and Hepatic Impairment
The effects of renal or hepatic impairment on the elimination of cyclophosphamide have not been elucidated.164 The manufacturers recommend caution and careful monitoring for toxicity in patients with renal and/or hepatic impairment, but makes no specific recommendations for adjustment of cyclophosphamide dosage.164 Measurable changes in pharmacokinetic parameters for cyclophosphamide may be observed in patients with renal impairment, but there is no consistent evidence demonstrating the need for dosage adjustment.164
One of the major and dose-limiting adverse effects of cyclophosphamide is hematologic toxicity, which is usually reversible after discontinuance of the drug. Hematopoietic adverse effects include leukopenia, thrombocytopenia, hypothrombinemia, and anemia. Leukopenia is considered to be an expected effect of cyclophosphamide therapy and may be severe. Leukopenia nadirs generally occur at 8-15 days following a single dose of cyclophosphamide and recovery usually occurs within 17-28 days. Fever in the absence of documented infection has been reported in some patients with neutropenia.164 Thrombocytopenia reportedly is less common, with nadirs occurring 10-15 days after administration of the drug. Anemia, particularly after large doses or prolonged therapy, and rarely, hypoprothrombinemia have been reported. Rarely, cyclophosphamide has been reported to produce positive direct antiglobulin (Coombs') test results and hemolytic anemia.
Anorexia, nausea, and vomiting occur commonly with cyclophosphamide, especially at high doses; some clinicians reported that these effects respond to treatment with antiemetics. Occasionally, diarrhea, hemorrhagic colitis, mucosal irritation, and oral ulceration have been reported. Rarely, aphthous stomatitis, enterocolitis, and hepatotoxicity as evidenced by jaundice and hepatic dysfunction have occurred.
Sterile hemorrhagic cystitis has been reported to occur in up to 20% of patients (especially children) on long-term cyclophosphamide therapy. This effect, which rarely can be severe and even fatal, is attributed to chemical irritation by active metabolites of cyclophosphamide that accumulate in concentrated urine. Hematuria usually resolves spontaneously within a few days after discontinuance of cyclophosphamide therapy but may persist for several months. Fibrosis of the bladder (sometimes extensive), with or without cystitis, also has occurred, but less frequently. Atypical epithelial cells may be found in the urinary sediment. These adverse effects appear to be related to the dosage and duration of cyclophosphamide therapy. Nephrotoxicity, including hemorrhagic ureteritis and renal tubular necrosis, has been reported; such lesions reportedly resolve in most instances following discontinuance of cyclophosphamide therapy.
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide therapy appears to be lower than that associated with ifosfamide therapy, mesna (sodium 2-mercaptoethanesulfonate) has been used prophylactically as a uroprotective agent in some patients receiving cyclophosphamide.106, 108, 111, 114, 116, 119, 120, 121, 122, 124, 127, 130 (See Drug Interactions: Mesna.) Evidence from animal107, 113, 117, 121, 123, 125 and clinical studies106, 108, 111, 114, 116, 119, 120, 121, 122, 124, 127, 130 suggests that prophylactic mesna therapy, when used concomitantly with cyclophosphamide, can substantially decrease the incidence and severity of, or prevent, cyclophosphamide-induced urothelial toxicity (e.g., hemorrhagic cystitis).106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 130, 131, 132 Mesna also has uroprotective activity in preventing or ameliorating recurrent or worsening bladder toxicity during subsequent cyclophosphamide therapy in patients with a history of such toxicity induced by the drug or other oxazaphosphorine derivatives (e.g., ifosfamide).105, 106 Clinical studies indicate that mesna generally is more effective than,120, 121, 122, 124, 127 but at least as effective as, standard prophylactic measures (e.g., forced diuresis, hydration) in preventing bladder toxicity (e.g., hematuria, hemorrhagic cystitis) commonly associated with cyclophosphamide therapy, although prophylactic mesna therapy is not effective in all patients.105
Alopecia occurs frequently in patients who receive cyclophosphamide, and patients should be forewarned of this possibility. In usual doses, about 33% of patients who receive the drug experience alopecia, generally beginning about 3 weeks after initiation of therapy; the condition is usually reversible, but new hair may be a different color or texture. Transverse ridging, retarded growth, and/or pigmentation of fingernails may occur, as well as skin pigmentation. Nonspecific dermatitis has also been reported.
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients receiving cyclophosphamide; a causal relationship to the drug has not been established.164
Patients who receive high doses of cyclophosphamide over prolonged periods may develop interstitial pulmonary fibrosis, which can be fatal. In some cases, discontinuance of the drug and administration of corticosteroids has failed to reverse this syndrome. Interstitial pneumonitis also has been reported in patients receiving cyclophosphamide.164
As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in some patients receiving cyclophosphamide, especially those with non-Hodgkin's lymphomas or leukemias. Hyperuricemia may be minimized by adequate hydration, alkalinization of the urine, and/or administration of allopurinol. If allopurinol is administered, the patient should be watched carefully for cyclophosphamide toxicity. (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Hyperkalemia has been reported in patients receiving cyclophosphamide. Hyperkalemia probably is related to rapid lysis of tumor cells which occurs especially in connection with lymphomas or leukemias.
A syndrome of inappropriate antidiuretic hormone secretion has occurred during cyclophosphamide therapy. Hyponatremia resulting from impaired excretion of water associated with progressive weight gain without edema occurs. The tendency toward water retention in these patients is aggravated by the common practice of encouraging fluid intake to prevent formation of uric acid calculi and the occurrence of chemical cystitis.
Cardiotoxicity, which is uncommon at usual dosages, has been reported in patients receiving high doses of cyclophosphamide (120 [i.e., 60 mg/kg daily] to 270 mg/kg over a period of a few days), generally as part of an intensive, multiple-drug antineoplastic regimen or in conjunction with transplantation procedures. Potentially fatal cardiotoxicity also has occurred when cyclophosphamide (given concomitantly with mesna and followed with autologous bone marrow transplant) was administered inadvertently in a dosage of 4 g/m2 daily for 4 doses rather than in a total dosage of 4 g/m2 administered over 4 days in equally divided doses of 1 g/m2 daily as part of a phase I protocol.159, 160 Deaths have occurred from diffuse hemorrhagic myocardial necrosis and from a syndrome of acute myopericarditis when cyclophosphamide was used in high doses alone or in combination regimens; severe, sometimes fatal congestive heart failure has occurred rarely within a few days after the first dose of cyclophosphamide in such cases. Hemopericardium secondary to hemorrhagic myocarditis and myocardial necrosis, and pericarditis without evidence of hemopericardium, also have been reported. Acute myocardial infarction occurred in a patient with no history of cardiac conditions who received conventional doses of cyclophosphamide in conjunction with vincristine.172
The precise mechanism of cyclophosphamide-induced cardiotoxicity is not known, but it has been postulated that the drug and/or its metabolites may affect the endothelium directly with secondary extravasation of blood containing high concentrations of cyclophosphamide.161 The antidiuretic effect of cyclophosphamide observed with high doses also may contribute to cardiopulmonary manifestations.161 Although clear risk factors have not been established, patients who have received or are receiving concomitantly radiation therapy and/or other potentially cardiotoxic drugs (e.g., anthracyclines) appear to be at increased risk.161 Some indicators of cyclophosphamide-induced cardiotoxicity include sudden weight gain, ECG abnormalities, dyspnea, and/or other signs of congestive heart failure,159, 160, 161 and patients receiving higher than usual dosages of the drug should be monitored for such effects.161 In addition to death, possible consequences of the cardiotoxicity include debilitating heart failure, arrhythmias, and potentially irreversible cardiomyopathy and/or pericarditis.159, 160, 161
Malaise and asthenia have been reported in patients receiving cyclophosphamide.164 Other reported adverse effects of cyclophosphamide include headache, dizziness, and myxedema. Faintness, facial flushing, diaphoresis, and oropharyngeal sensation have occurred following IV administration. Rarely, decreased serum cholinesterase concentrations, especially following IV administration of cyclophosphamide, have been reported. The drug may interfere with normal wound healing.
Anaphylactic reaction, including fatality, has been reported with cyclophosphamide therapy.164 Possible cross-sensitivity with other alkylating agents also has been reported.164 Positive reactions to skin test antigens (e.g., tuberculin purified protein derivative, mumps, trichophyton, candida) are reported to be frequently suppressed in patients receiving cyclophosphamide.
Precautions and Contraindications
Cyclophosphamide is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.
Patients who receive myelosuppressive drugs experience an increased frequency of infections, as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. The patient's hematologic status must be carefully monitored, at least weekly for the first few months of therapy or until the maintenance dosage is determined, and then at intervals of 2-3 weeks. Leukopenia is dose-related and can be used as a guide to adjusting dosage of cyclophosphamide. A reduction in leukocyte count to less than 2000/mm3 occurs commonly with initial loading doses of the drug, and less frequently in patients maintained on smaller doses. Transient decreases in leukocyte count to 2000/mm3(during short courses of treatment) or more persistent reductions to 3000/mm3 (with continuing therapy) reportedly are tolerated without serious risk of infection if marked granulocytopenia is not present.
To prevent the occurrence of hemorrhagic cystitis in patients receiving cyclophosphamide, many experts recommend adequate hydration and frequent voiding. Patients should be instructed to increase their fluid intake for 24 hours before, during, and for at least 24 hours after receiving cyclophosphamide and to void frequently for 24 hours after receiving the drug. Urine also should be examined regularly for the presence of red cells, which may precede hemorrhagic cystitis. Since hemorrhagic cystitis can be severe and even fatal, the drug should be discontinued and not resumed if possible in patients who develop this complication. In severe cases, replacement of blood may be needed. Protracted cases have been treated with 1-10% formaldehyde irrigations, electrocautery to the telangiectatic areas of the bladder, diversion of urine flow, and cryosurgery.
Because of the immunosuppressive activity of cyclophosphamide, interruption or reduction of dosage should be considered for patients who develop bacterial, fungal, protozoan, helminthic, or viral infections, especially those patients who are receiving or perhaps in those who have recently received corticosteroid therapy. Infections in some of these patients have been fatal; varicella-zoster infections appear to be particularly dangerous. Cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, and adjustment of both replacement corticosteroids and cyclophosphamide may be necessary in adrenalectomized patients.
Cyclophosphamide should be administered with caution to patients with severe leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, previous therapy with radiation or other cytotoxic agents, impaired hepatic function, or impaired renal function.164 The drug is contraindicated in patients with severely depressed bone marrow function and in those who have demonstrated hypersensitivity to cyclophosphamide.164
Patients should be informed that exposure to large doses of cyclophosphamide causes gonadal toxicity (see Cautions: Pregnancy, Fertility, and Lactation); counseling on fertility options, prior to such therapy whenever possible for young patients, and long-term follow-up for evaluation of gonadal function is advised.173
According to the manufacturers, the safety profile of cyclophosphamide in children is similar to that observed in adult patients.164 Children receiving large doses of cyclophosphamide are at high risk for long-term gonadal damage and infertility.173 (See Cautions: Pregnancy, Fertility, and Lactation.)
Safety and efficacy of cyclophosphamide in geriatric patients have not been studied specifically to date.164 Clinical studies of cyclophosphamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast cancer did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.164 In 2 clinical trials in which cyclophosphamide and cisplatin were compared with paclitaxel and cisplatin for the treatment of advanced ovarian cancer, 154 (28%) of 552 patients receiving cyclophosphamide and cisplatin were 65 years or older.164 Subset analyses according to age (younger than 65 years versus 65 years or older) from these trials, published reports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin's lymphoma, and postmarketing experience suggest that geriatric patients may be more susceptible to cyclophosphamide-induced toxicity.164 In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.164
Some patients who have received cyclophosphamide alone, as part of a combination regimen, or as adjunctive therapy have developed secondary malignancies, most frequently urinary bladder, myeloproliferative, and lymphoproliferative malignancies.164 Although a causal relationship has not been definitely established, the possibility of development of a secondary malignancy should be considered in weighing the possible benefit from the drug against the potential risk. Secondary malignancies have occurred most frequently in patients who have been treated with cyclophosphamide for primary myeloproliferative and lymphoproliferative malignancies and primary nonmalignant diseases in which immune processes are believed to be involved. Secondary urinary bladder malignancies generally have occurred in patients who previously developed hemorrhagic cystitis. In some cases, the secondary malignancy was not detected until several years after discontinuance of cyclophosphamide therapy. In one study in patients with breast cancer who received 2-4 times the standard dose of cyclophosphamide in conjunction with doxorubicin, cases of secondary acute myeloid leukemia were reported within 2 years of treatment initiation.164 Long-term follow-up of women who received cyclophosphamide-containing adjuvant chemotherapy regimens for the treatment of early breast cancer indicates that the incidence of other solid tumors and secondary leukemia in these women is not substantially greater than that in the general population.137, 157
Pregnancy, Fertility, and Lactation
Cyclophosphamide can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus. Abnormalities, including ectrodactylia, have occurred in infants born to women treated with the drug during pregnancy. Normal infants also have been born to women who received cyclophosphamide, including during the first trimester. Cyclophosphamide should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When the drug is administered during pregnancy or if the patient becomes pregnant while receiving cyclophosphamide, the patient should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Gonadal suppression, which appears to be related to dose and duration of therapy, has been reported in patients who received cyclophosphamide.164 The drug interferes with oogenesis and spermatogenesis.164 Amenorrhea, azoospermia, oligospermia, and ovarian fibrosis have been reported in patients who receive cyclophosphamide.164 Sterility may occur in both men and women and may be permanent.164 Although the full effect of cyclophosphamide on prepubertal gonads has not been established, ovarian failure and testicular atrophy have occurred. Male patients who receive high-dose cyclophosphamide for childhood cancer, including treatment prior to the onset of puberty, are at high risk for long-term, irreversible gonadal damage, such as infertility and subclinical Leydig cell insufficiency.173
Cyclophosphamide is distributed into milk. Because of the potential for serious adverse reactions to cyclophosphamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Mesna (sodium 2-mercaptoethanesulphonate) is a synthetic sulfhydryl compound that can chemically interact with urotoxic metabolites (and/or their precursors) of cyclophosphamide (e.g., acrolein, 4-hydroxycyclophosphamide) and other oxazaphosphorine derivatives (e.g., ifosfamide) to decrease the incidence and severity of, or prevent, bladder toxicity (e.g., hemorrhagic cystitis) induced by these drugs.106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 133, 134, 135, 136 (See Mesna 91:04.12.)
Mesna is rapidly oxidized in systemic circulation to dimesna (mesna disulfide), which is substantially less chemically reactive than mesna; following glomerular filtration, dimesna is reduced to mesna by the glutathione system in the renal tubular epithelium and is excreted by the kidneys.105, 106, 108, 109, 119, 121, 123, 126, 128, 129, 130, 131, 134, 135, 136 In urine, mesna reacts chemically (e.g., binding with 4-hydroxycyclophosphamide to form 4-sulfoethylthiocyclophosphamide and/or binding with double-bonds of acrolein) with the urotoxic metabolites (and/or their precursors) of cyclophosphamide thought to be principally responsible for drug-induced hematuria and hemorrhagic cystitis and thus detoxifies these metabolites.108, 110, 115, 116, 118, 120, 121, 123, 124, 126, 128, 130, 132, 133, 134, 135, 136 In addition, mesna enhances urinary excretion of cysteine, which also can react chemically with acrolein, and this effect may contribute to the uroprotective activity of mesna.111, 135, 136 While limited evidence in animals suggests that mesna also may enhance systemic deactivation of cyclophosphamide to some extent, pharmacokinetic characteristics of mesna may differ in mice compared with humans,119 and the poor lipophilicity of mesna and dimesna (resulting in poor distribution into tumor cells in humans), evidence from in vitro and in vivo tumor models, and clinical evidence in humans indicate that mesna does not substantially deactivate active cyclophosphamide metabolites in tumor cells or interfere with the systemic antineoplastic activity of the drug.105, 110, 117, 120, 121, 122, 123, 124, 126, 129, 132, 136
Because potentiation of cardiotoxic effects may result, caution should be exercised in the concomitant administration of cyclophosphamide and other cardiotoxic drugs such as doxorubicin.
Drugs Affecting Hepatic Microsomal Enzymes
Barbiturates and other drugs which induce liver microsomal enzymes may result in an increased pharmacologic effect and increased toxicity of cyclophosphamide because of increased conversion of the drug to active metabolites. Although the full clinical importance of this interaction has not been assessed, it is advisable to monitor patients who receive both drugs closely for cyclophosphamide toxicity.
Although it has been proposed that corticosteroids and sex hormones may inhibit liver microsomal enzymes and that discontinuance or reduction in steroid dosage can cause an increase in the toxicity of previously well-tolerated doses of cyclophosphamide, the clinical importance of this effect has not been established. Other drugs which may inhibit microsomal enzyme activity in the liver and therefore interfere with the metabolism of cyclophosphamide include allopurinol, chloramphenicol, chloroquine, imipramine, phenothiazines, potassium iodide, and vitamin A. In one controlled study, concomitant administration of cyclophosphamide and allopurinol increased the incidence of bone marrow depression as compared to cyclophosphamide alone, but the mechanism or clinical importance of the interaction has not been established.
Cyclophosphamide reportedly reduces serum pseudocholinesterase concentrations and may prolong the neuromuscular blocking activity of succinylcholine, especially in very ill patients who are receiving large IV doses of cyclophosphamide. Although the clinical importance has not been established, it has been suggested that succinylcholine be administered with caution in patients receiving cyclophosphamide and that succinylcholine or cyclophosphamide be avoided in patients with substantially depressed pseudocholinesterase concentrations. The anesthesiologist should be informed before general anesthesia is administered if a patient has received cyclophosphamide within the previous 10 days.
Limited information is available on acute overdosage of cyclophosphamide.
Overdosage with cyclophosphamide would be expected to produce effects that are mainly extensions of common adverse reactions, particularly severe leukopenia and thrombocytopenia; cardiotoxicity also may be prominent. In patients who received 4- to 10-day courses of cyclophosphamide with total dosage of the drug per course exceeding 140 mg/kg (5.2 g/m2), cardiac damage manifested by heart failure occurred within 15 days of the initial dose. Impairment of water excretion with hyponatremia, weight gain, and inappropriately concentrated urine has been reported after cyclophosphamide doses exceeding 50 mg/kg (2 g/m2).
Overdosage, which was fatal in at least one case, also has occurred in several patients who were enrolled in high-dose protocols in which cyclophosphamide (given concomitantly with mesna and followed with autologous bone marrow transplant) was administered inadvertently in a dosage of 4 g/m2 daily for 4 doses rather than in a total dosage of 4 g/m2administered over 4 days in equally divided doses of 1 g/m2 daily; potentially irreversible or fatal cardiotoxicity was the most serious consequence of overdosage in these patients.159, 160 Potentially fatal cardiotoxicity, manifested as congestive heart failure, ECG abnormalities, cardiomyopathy, and/or pericarditis, also has been reported in other patients receiving high doses of cyclophosphamide (120 mg/kg [60 mg/kg daily] or more over several days), and the risk of such toxicity appears to be increased in patients who have received or are receiving concomitantly radiation therapy or other potentially cardiotoxic drugs (e.g., anthracyclines).161 (See Cautions: Cardiac Effects.)
If overdosage of cyclophosphamide is known or suspected, the patient should be hospitalized for general supportive therapy. There is no known specific antidote. Although cyclophosphamide theoretically is dialyzable, no studies have been performed to date to evaluate efficacy of dialysis in the treatment of acute overdosage of the drug.
Following conversion to active metabolites in the liver, cyclophosphamide functions as an alkylating agent, interfering with DNA replication and transcription of RNA, and ultimately resulting in the disruption of nucleic acid function. The drug exhibits phosphorylating properties that also enhance its cytotoxicity. Cyclophosphamide also possesses potent immunosuppressive activity.
Cyclophosphamide appears to be well absorbed following oral administration, with a reported bioavailability greater than 75%. Maximum plasma concentrations of cyclophosphamide occur at about 1 hour. Concentrations of cyclophosphamide metabolites reportedly reach maximum levels 2-3 hours after an IV dose of the drug.
Cyclophosphamide and its metabolites appear to be distributed throughout the body, including the brain and CSF, but probably not in concentrations sufficient to treat meningeal leukemia. It is assumed that cyclophosphamide crosses the placenta. The drug is distributed into milk.
Although in vitro binding of cyclophosphamide to plasma proteins has not been demonstrated, in vivo binding generally has been reported to range from 0-10% and protein binding for some alkylating metabolites has been reported to exceed 60%.
The serum half-life after IV administration of cyclophosphamide has been reported to range from 3-12 hours; however, the drug and/or its metabolites can be detected in the serum up to 72 hours after administration.
Cyclophosphamide is metabolized in the liver by the enzymatic mixed-function oxidase system of liver microsomes to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide, the acyclic tautomer. 4-Hydroxycyclophosphamide may be enzymatically metabolized to 4-ketocyclophosphamide, and aldophosphamide may be enzymatically metabolized to carboxyphosphamide, phosphoramide mustard, and acrolein. Some authorities believe that phosphoramide mustard and acrolein account for the cytotoxic properties of the drug, and that 4-ketocyclophosphamide and carboxyphosphamide do not possess substantial biologic activity. However, there is controversy regarding the toxicity of 4-ketocyclophosphamide.
Cyclophosphamide and its metabolites are excreted principally in urine, with about 36-99% of a dose being eliminated within 48 hours; of the amount excreted, about 5-30% is unchanged drug.
Cyclophosphamide is a nitrogen mustard-derivative, polyfunctional alkylating agent. The drug occurs as a monohydrate, white, crystalline powder and is soluble in water and in alcohol. Potency of cyclophosphamide is calculated on the anhydrous basis.
Cyclophosphamide is commercially available as cyclophosphamide tablets containing anhydrous cyclophosphamide.164 Cyclophosphamide for injection is commercially available as a sterile white powder containing cyclophosphamide monohydrate.164
When reconstituted as directed with sterile 0.9% sodium chloride solution (for direct injection), solutions of cyclophosphamide monohydrate (Cytoxan®) have an osmolarity of 374 mOsm/L.164 When reconstituted as directed with sterile water for injection (for IV infusion), solutions of cyclophosphamide monohydrate (Cytoxan®) have an osmolarity of 74 mOsm/L and are hypotonic.164
Commercially available cyclophosphamide tablets should be stored at a temperature not exceeding 25°C; the tablets will withstand brief exposure to temperatures up to 30°C, but should be protected from temperatures exceeding 30°C.164
Commercially available cyclophosphamide powder for injection containing cyclophosphamide monohydrate should be stored at a temperature not exceeding 25°C.164 During storage or transport, exposure of the vials to temperature fluctuations may result in melting of the contents; vials should be visually inspected, and any vials with signs of melting of the cyclophosphamide monohydrate into a clear or yellowish viscous liquid, in droplets or as a connected phase, should be discarded.164
Following reconstitution as directed with sterile 0.9% sodium chloride solution or sterile water for injection, solutions of cyclophosphamide powder for injection containing cyclophosphamide monohydrate are stable for 24 hours at room temperature or 6 days when refrigerated.164 Reconstituted solutions of the drug to be used for IV infusion are compatible with 5% dextrose, 5% dextrose and 0.9% sodium chloride, 5% dextrose and Ringer's, lactated Ringer's, 0.45% sodium chloride, or (1/6) M sodium lactate injection.164
Extemporaneous oral liquid preparations of cyclophosphamide, prepared by dissolving the powder for injection in aromatic elixir, are stable for 14 days in glass containers when refrigerated.164
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mg (of anhydrous cyclophosphamide)* | Cyclophosphamide Tablets | |
50 mg (of anhydrous cyclophosphamide)* | Cyclophosphamide Tablets | |||
Cytoxan® | Bristol-Myers Squibb | |||
Parenteral | For injection | 500 mg (of anhydrous cyclophosphamide)* | Cyclophosphamide for Injection | |
Cytoxan® | Bristol-Myers Squibb | |||
1 g (of anhydrous cyclophosphamide)* | Cyclophosphamide for Injection | |||
Cytoxan® | Bristol-Myers Squibb | |||
2 g (of anhydrous cyclophosphamide)* | Cyclophosphamide for Injection | |||
Cytoxan® | Bristol-Myers Squibb |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Weiner HL, Hauser SL, Hafler DA et al. The use of cyclophosphamide in the treatment of multiple sclerosis. Ann NY Acad Sci . 1984; 436:373-81. [PubMed 6099707]
101. Hauser HL, Dawson DM, Lehrich JR et al. Intensive immunosuppression in progressive multiple sclerosis: a randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med . 1983; 308:173-80. [PubMed 6294517]
102. Balow JE, Austin HA III, Tsokos GC et al. Lupus nephritis. Ann Intern Med . 1987; 106:79-94. [PubMed 3789582]
103. Austin HA III, Klippel JH, Balow JE et al. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med . 1986; 314:614-9. [PubMed 3511372]
104. Carette S, Klippel JH, Decker JL et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis: a long-term follow-up. Ann Intern Med . 1983; 99:1-8. [PubMed 6344715]
105. Luce JK, Simons JA. Efficacy of mesna in preventing further cyclophosphamide-induced hemorrhagic cystitis. Med Ped Oncol . 1988; 16:372-4.
106. Andriole GL, Sandlund JT, Miser JS et al. The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy. J Clin Oncol . 1987; 5:799-803. [PubMed 3106585]
107. Kunze E, Köhnecke B, Engelhardt W et al. Effect of the uroprotector sodium 2-mercaptoethane sulfonate (mesna) on the proliferation of the bladder urothelium in the rat after administration of cyclophosphamide. Urol Int . 1984; 39:61-7. [PubMed 6426112]
108. Brock N, Pohl J. Prevention of urotoxic side effects by regional detoxification with increased selectivity of oxazaphosphorine cytostatics. IARC Sci Publ . 1986; 78:269-79.
109. Brock N, Hilgard P, Pohl J et al. Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols. J Cancer Res Clin Oncol . 1984; 108:87-97. [PubMed 6746722]
110. Elia J. Mesna as a uroprotective agent. Can J Hosp Pharm . 1986; 39:144.
111. Finn GP, Sidau RNB, Shaw IC. Protecting the bladder from cyclophosphamide with mesna. N Engl J Med . 1986; 314:61. [PubMed 3079620]
112. Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture. Cancer Res . 1989; 49:1-7. [PubMed 2491747]
113. Cavalletti E, Tofanetti O, Zunino F. Comparison of reduced glutathione with 2-mercaptoethane sulfonate to prevent cyclophosphamide-induced urotoxicity. Cancer Lett . 1986; 32:1-6. [PubMed 3091245]
114. Shepherd JD, Pringle LE, Barnett MJ et al. 2-mercaptoethane sulfonate (mesna) vs hyperhydration (HH) for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. Proc ASCO . 1990; 9:A39.
115. Relling MV. Prevention of hemorrhagic cystitis after cyclophosphamide. Ann Intern Med . 1990; 112:634.
116. Ehrlich RM, Freedman A, Goldsobel AB et al. The use of sodium 2-mercaptoethane sulfonate to prevent cyclophosphamide cystitis. J Urol . 1984; 131:960-2. [PubMed 6423841]
117. Brock N, Pohl J, Stekar J et al. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention—III: profile of action of sodium 2-mercaptoethane sulfonate (mesna). Eur J Cancer Clin Oncol . 1982; 18:1377-87. [PubMed 6819957]
118. Calabresi P, Chabner BA. Cyclophosphamide. In: Goodman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1216-9.
119. Wagner T, Zink M, Schwieder G. Influence of mesna and cysteine on the systemic toxicity and therapeutic efficacy of activated cyclophosphamide. J Cancer Res Clin Oncol . 1987; 113:160-5. [PubMed 3104347]
120. Hows JM, Mehta A, Ward L et al. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer . 1984; 50:753-6. [PubMed 6437430][PubMedCentral]
121. Connors TA. Protection against alkylating toxicity using thiols. In: Chabner BA, Pinedo HM eds. The cancer pharmacology annual 3. New York: Elsevier; 1985:37-9.
122. Asta-Werke AG. Clinical overview of mesna. Cancer Treat Rev . 1983; 10:175-81. [PubMed 6414692]
123. Millar BC, Millar JL, Clutterbuck R et al. Studies on the toxicity of cyclophosphamide in combination with mesna in vitro and in vivo. Cancer Treat Rev . 1983; 10:63-71. [PubMed 6414698]
124. Hows J, Mehta A, Gordon-Smith EC. Mesna versus forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplant patients (preliminary data). Cancer Treat Rev . 1983; 10:53-6. [PubMed 6414696]
125. Freedman A, Ehrlich RM, Ljung BM. Prevention of cyclophosphamide cystitis with 2-mercaptoethane sodium sulfonate: a histologic study. J Urol . 1984; 132:580-2. [PubMed 6433044]
126. Garrick CL, Cronin SM, Sensenbrenner LL. Effect of mesna on cyclophosphamide. DICP . 1989; 23:798-9. [PubMed 2510409]
127. Scheef W, Klein HO, Brock N et al. Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results. Cancer Treat Rep . 1979; 63:501-5. [PubMed 106965]
128. Shaw IC. Mesna and oxazaphosphorine chemotherapy. Anticancer Drugs: Therapeutic index improvement by toxicity reduction. Paper presented at London Westminster Hospital, Imperial Cancer Research Fund, and Deutsches Krebsforschungszentrum. Abstract No. 4.2. London: 1987 Apr 6-7.
129. Brock N, Pohl J, Stekar J et al. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention—III: profile of action of sodium 2-mercaptoethane sulfonate (mesna). Eur J Cancer Clin Oncol . 1982; 18:1377-87. [PubMed 6819957]
130. Brock N, Pohl J, Stekar J. Detoxification of urotoxic oxazaphosphorines by sulfhydryl compounds. J Cancer Res Clin Oncol . 1981; 100:311-20. [PubMed 6792207]
131. Ormstad K, Orrenius S, Lastbom T et al. Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res . 1983; 43:333-8. [PubMed 6401168]
132. Brock N, Pohl J, Stekar J. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: 2. Comparative study on the uroprotective efficacy of the thiols and other sulfur compounds. Eur J Cancer Clin Oncol . 1981; 17:1155-63. [PubMed 7199463]
133. Brock N, Pohl J, Stekar J. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: I. Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer . 1981; 17:595-607. [PubMed 7308258]
134. Brock N, Pohl J. Regional detoxification, a principle for increasing the selectivity of cancer chemotherapy. In: Kuemmerle HP, Berkarda B, Karrer K et al, eds. Clinical chemotherapy. Vol. III: Antineoplastic chemotherapy. New York: Thieme-Stratton; 1984:389-412.
135. Shaw IC. Mesna and oxazaphosphorine cancer chemotherapy. Cancer Treat Rev . 1987; 14:359-64. [PubMed 3125971]
136. Shaw IC, Graham MI. Mesna—a short review. Cancer Treat Rev . 1987; 14:67-86. [PubMed 3119211]
137. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.
138. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet . 1992; 339:1-15,71-85. [PubMed 1345950]
139. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med . 1976; 294:405-10. [PubMed 1246307]
140. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med . 1995; 332:901-6. [PubMed 7877646]
141. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med . 1994; 330:1253-9. [PubMed 8080512]
142. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA . 1995; 273:542-7. [PubMed 7837388]
143. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med . 1989; 320:473-8. [PubMed 2644531]
144. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol . 1990; 8:1483-96. [PubMed 2202791]
145. Moliterni A, Bonadonna G, Valagussa P et al. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive nodes. J Clin Oncol . 1991; 9:1124-30. [PubMed 2045854]
146. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol . 1989; 7:572-82. [PubMed 2651576]
147. McGuire WL. Adjuvant therapy of node-negative breast cancer. N Engl J Med . 1989;320:525-7. Editorial. [PubMed 2915655]
148. De Vita VT Jr. Breast cancer therapy: exercising all our options. N Engl J Med . 1989; 320:527-9. [PubMed 2915656]
149. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of early-stage breast cancer. JAMA . 1991; 265:391-5. [PubMed 1984541]
150. Early Breast Cancer Trialists' Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality on early breast cancer: and overview of 61 randomized trials among 28,896 women. N Engl J Med . 1988; 319:1681-92. [PubMed 3205265]
151. The Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med . 1989; 320:491-6. [PubMed 2644533]
152. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med . 1998; 320:485-90.
153. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]
154. Rosen PP, Groshen S, Saigo PE et al. Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 16 years. J Clin Oncol . 1989; 7:1239-51. [PubMed 2549203]
155. Reviewers' comments (personal observations).
156. Buzzoni R, Bonadonna G, Valagussa P et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol . 1991; 9:2134-40. [PubMed 1960555]
157. Tallman MS, Gray R, Bennett JM et al. Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience. J Clin Oncol . 1995; 13:1557-63. [PubMed 7602344]
158. Goldhirsch A, Gelber RD, Price KN et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet . 1994; 343:377-81. [PubMed 7905550]
159. Countryman G, Walsh CT. A special report from the Board of Trustees and administration of the Dana-Farber Cancer Institute to its various constituencies. 1995 Oct 30.
160. Altman LK. Big doses of experimental drug killed patient, hurt a second. NY Times News Serv . 1995 Mar 24 (12:00 EST).
161. Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity: characterizing and avoiding the problem. Drugs . 1991; 42:781-95. [PubMed 1723374]
162. Ovarian epithelial cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Jun 16.
163. Small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2002 Jun.
164. Bristol-Myers Squibb. Cytoxan® (cyclophosphamide for injection) and Cytoxan® tablets (cyclophosphamide tablets) prescribing information. Princeton, NJ; 2003 Nov.
166. Chronic myelogenous leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2002 Sep.
167. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med . 1996; 334:1-6. [PubMed 7494563]
168. Piccart MJ, Bertelsen K, James K et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst . 2000; 92:699-708. [PubMed 10793106]
169. Swenerton K, Jeffrey J, Stuart G et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol . 1992; 10:718-26. [PubMed 1569444]
170. Alberts DS, Green S, Hannigan EV et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stage III and IV ovarian cancer. J Clin Oncol . 1992; 10:706-17. [PubMed 1569443]
171. Adult Hodgkin's lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 May 20.
172. Federman DG, Henry G. Chemotherapy-induced myocardial necrosis in a patient with chronic lymphocytic leukemia. Respir Med . 1997; 9:565-7.
173. Kenney LB, Laufer MR, Grant FD et al. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer . 2001; 91:613-21. [PubMed 11169946]
10006. Reeder CB, Stewart AK, Hentz JG et al. Efficacy of induction with CyBorD in newly diagnosed multiple myeloma. J Clin Oncol. 2008; 26: Abstract 8517 (presented at the 44th Annual ASCO meeting. Chicago, IL: 2008 May 31).
10007. Reeder C, Reece D, Fonseca Ret al. A phase II trial of myeloma induction therapy with cyclophosphamide, bortezomib and dexamethasone (Cybor-D): improved response over historical lenalidomide-dexamethasone controls. Blood. 2007; 110: Abstract No. 3601.
10008. Jagannath S, Bensinger B, Vescio Ret al. A phase II study of bortezomib (Velcade®), cyclophosphamide (Cytoxan®), thalidomide and dexamethasone as first-line therapy for multiple myeloma. Blood. 2007; 110: Abstract 188 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).
10019. Reeder CB, Reece DE, Kukreti V et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia . 2009; 23:1337-41. [PubMed 19225538]
10021. Reeder CB, Reece DE, Kukreti V et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood . 2010; 115:3416-7. [PubMed 20413666]
10022. Reeder CB, Reece DE, Kukreti V et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol . 2014; 167:563-5. [PubMed 24974945]
10028. Mai EK, Bertsch U, Dürig J et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia . 2015; 29:1721-9. [PubMed 25787915]
10029. Bensinger WI, Jagannath S, Vescio R et al. Phase 2 study of two sequential three-drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma. Br J Haematol . 2010; 148:562-8. [PubMed 19919652]
10030. Merz M, Salwender H, Haenel M et al. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica . 2015; 100:964-9. [PubMed 25840597]
10031. Lacy MQ, Gertz MA, Dispenzieri A et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc . 2007; 82:1179-84. [PubMed 17908524]
10035. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with cyclophosphamide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.