CYCLOPHOSPHAMIDE
Pronounciation
- (sye-kloh-FOS-fah-myd)
Trade Name(s)
- Lyophilized Cytoxan,
Procytox
Verify pregnancy status.
Although effective alone in susceptible malignancies, cyclophosphamide is more frequently used concurrently or sequentially with other antineoplastic agents. Doses may be expressed in mg/kg or mg/M2. During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis and thus reduce the risk of urinary toxicity. Cyclophosphamide should be administered in the morning; see Monitor.
Malignant diseases (adult and pediatric patients):
As a single agent: The initial dose may be 40 to 50 mg/kg of body weight, usually given in divided doses over 2 to 5 days. Alternate dosing schedules are 3 to 5 mg/kg twice weekly or 10 to 15 mg/kg every 7 to 10 days. Higher doses have been used with some protocols based on the condition being treated. Adequate hydration is indicated, and the use of mesna can be considered to attenuate or reduce the incidence of hemorrhagic cystitis. Combination protocols: Numerous combination therapies are in use. Has been used with bleomycin, bortezomib, carboplatin, cisplatin, dacarbazine, dexamethasone, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, methotrexate, prednisone, procarbazine, rituximab, topotecan, vinblastine, and vincristine. See literature for various regimens.
Adjuvant treatment of operable node-positive breast cancer:
Treatment protocol includes cyclophosphamide, doxorubicin, and docetaxel. Administer cyclophosphamide 500 mg/M2 and doxorubicin 50 mg/M2. One hour later, give docetaxel 75 mg/M2. Repeat every 3 weeks for 6 cycles. See docetaxel (Taxotere) and doxorubicin (Adriamycin) monographs.
See Usual Dose.
Dosages must be adjusted based on antitumor activity and/or leukopenia. Total leukocyte count is a good, objective guide for regulating dosage. Withhold therapy in patients with neutrophils less than or equal to 1,500/mm3 and platelets less than 50,000/mm3. ■ When used as a component of a multidrug regimen, it may be necessary to reduce the dose of cyclophosphamide as well as the doses of the other drugs. ■ Dosing should be cautious in the elderly. Lower-end initial doses may be indicated. Consider decrease in cardiac, hepatic, and renal function; concomitant disease; or other drug therapy; see Elderly.
Specific techniques required; see Precautions.
Contains no preservatives; aseptic technique imperative. Each 100 mg must be diluted with 5 mL of NS or SWFI; yields 20 mg/mL (a 2% solution). Shake solution gently and allow to stand until clear. A 2% solution reconstituted with NS may be injected directly or further diluted to a minimum concentration of 0.2% (2 mg/mL) for infusion. A 2% solution reconstituted with SWFI is hypotonic and should not be injected directly. It must be further diluted to a minimum concentration of 0.2% (2 mg/mL). D5W, ½NS, and D5NS are compatible diluents. Do not use heat to facilitate dilution. See Monitor.
May be filtered through available micron sizes of cellulose ester membrane filters.
Store unopened vials at or below 25° C (77° F). Cyclophosphamide that is reconstituted in SWFI must be used immediately. Do not store. If reconstituted in NS or further diluted, it must be used within 24 hours when stored at RT. Solutions reconstituted in NS or further diluted in ½NS are stable up to 6 days if refrigerated. Solutions further diluted in D5W or D5NS are stable for 36 hours if refrigerated. Do not use cyclophosphamide vials if there are signs of melting (clear or yellowish viscous liquid or droplets).
Compatibility information not available from manufacturer. Other sources suggest specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Rate may vary depending on protocol. May be given by IV push or as an intermittent or continuous infusion. Inject or infuse very slowly to reduce the likelihood of adverse reactions that may be administration rate–dependent (e.g., facial swelling, headache, nasal congestion, scalp burning). Duration of infusion should be appropriate for the volume to be infused.
An alkylating agent of the nitrogen mustard group with antitumor activity; cell cycle phase nonspecific, but most effective in S phase. Cyclophosphamide is a prodrug that is activated by hepatic microsomal enzymes. It is thought to prevent cell division by cross-linking DNA strands and preventing DNA synthesis. Elimination half-life is 3 to 12 hours. Metabolized in the liver, it or its metabolites are excreted in the urine. Secreted in breast milk.
Although effective alone in susceptible malignancies, cyclophosphamide is more frequently used concurrently or sequentially with other antineoplastic agents. Cyclophosphamide has been used in the treatment of the following malignancies: malignant lymphomas (e.g., Hodgkin disease, lymphocytic lymphoma, mixed-cell–type lymphomas, histiocytic lymphoma, Burkitt’s lymphoma), multiple myeloma, leukemias (e.g., chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, acute lymphoblastic [stem cell] leukemia in children), mycosis fungoides, neuroblastoma, adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. ■ Adjuvant treatment of operable node-positive breast cancer in combination with doxorubicin and docetaxel. ■ Used orally to treat many other indications, including biopsy-proven nephrotic syndrome, in pediatric patients when disease fails to respond to primary therapy or when primary therapy causes intolerable side effects.
Safety and effectiveness for the treatment of nephrotic syndrome in adults or of other renal disease have not been established.
Ewing’s sarcoma, granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis), lupus nephritis, non-Hodgkin lymphoma, severe rheumatologic conditions. ■ Transplant conditioning and many others; see literature.
Hypersensitivity to cyclophosphamide, any of its metabolites, or to other components of the product. ■ Urinary outflow obstruction.
Follow guidelines for handling cytotoxic agents. See Appendix A. ■ Administered by or under the direction of the physician specialist. ■ Myelosuppression (leukopenia, neutropenia, thrombocytopenia, and anemia), bone marrow failure, and severe immunosuppression may lead to serious and sometimes fatal infections. Sepsis and septic shock can occur. Latent infections (e.g., tuberculosis, viral hepatitis) can be reactivated. ■ Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported. Urotoxicity can be fatal. ■ Exclude or correct any urinary tract obstructions before starting treatment; see Contraindications. ■ Use with caution, if at all, in patients with active urinary tract infections. ■ Myocarditis, myopericarditis, pericardial effusions including cardiac tamponade, and congestive heart failure have been reported and may be fatal. Supraventricular and ventricular arrhythmias (including severe QT prolongation) have been reported. Risk of cardiotoxicity may be increased with high doses, in the elderly, in patients with pre-existing cardiac disease, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic drugs (e.g., bleomycin, doxorubicin). ■ Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and other forms of pulmonary toxicity leading to respiratory failure have been reported during and after treatment with cyclophosphamide. Late-onset pneumonitis (greater than 6 months after the start of therapy) appears to be associated with increased mortality. Pneumonitis may develop years after treatment. ■ Development of secondary malignancies has been reported in patients treated with cyclophosphamide used alone or in association with other antineoplastic agents. May develop several years after treatment has been discontinued. ■ Risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. ■ Veno-occlusive liver disease (VOD) has been reported. Fatalities have occurred. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term, low-dose, immunosuppressive doses of cyclophosphamide; in patients with pre-existing hepatic impairment; in patients who have received abdominal radiation; and in patients with low performance status. ■ Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome that resembles syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported. ■ Use caution in patients with impaired renal function. ■ Use with caution in patients with impaired hepatic function. Reduced conversion to active metabolite may cause decreased efficacy. ■ May interfere with normal wound healing. ■ Do not administer any live virus vaccine to patients receiving antineoplastic drugs. ■ Anaphylaxis resulting in death has been reported.
Monitor CBC and platelets and SCr frequently; see Dose Adjustments. ■ Check urinary sediment regularly for presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. ■ 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. ■ Monitor patients with severe renal impairment (CrCl 10 to 24 mL/min) for signs and symptoms of toxicity. ■ Observe continuously for infection. Prophylactic antibiotics may be indicated pending results of C/S in a febrile neutropenic patient. Antimycotics and/or antivirals may also be indicated. ■ Monitor patients with risk factors for cardiotoxicity. ■ Monitor patients for signs and symptoms of pulmonary toxicity. ■ Use antiemetics for patient comfort. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm3). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood).
Effective birth control recommended. Female patients should use highly effective contraception during and for up to 1 year after completion of treatment. Male patients with a female partner who is or may become pregnant should use a condom during and for at least 4 months after treatment. ■ Male and female reproductive function and fertility may be impaired. ■ Interferes with oogenesis and spermatogenesis. May cause sterility in both sexes. ■ Increase fluid intake and void frequently. ■ Promptly report any signs or symptoms of infection, any urinary symptoms, new or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain, dizziness, loss of consciousness, or other side effects. ■ See Appendix D.
Category D: may produce fetal harm. ■ Discontinue breast-feeding. ■ Safety profile in pediatric patients similar to that of adults. ■ See Patient Education.
Consider age-related organ impairment. Dose selection should be cautious; see Dose Adjustments. Toxicity may be increased. Monitoring of renal function is suggested.
Severe myelosuppression may be expected in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy. ■ Concomitant use of protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir) may increase the concentration of cytotoxic metabolites. 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 in patients receiving a nonnucleoside reverse transcriptase inhibitor–based regimen (e.g., delavirdine [Rescriptor], nevirapine [Viramune]). ■ Increased hematotoxicity and/or immunosuppression may result from the combined effect of cyclophosphamide and ACE inhibitors (e.g., enalapril, lisinopril), allopurinol, natalizumab, paclitaxel, thiazide diuretics (e.g., hydrochlorothiazide), and zidovudine. ■ Cardiotoxicity may result from a combined effect of cyclophosphamide and anthracyclines (e.g., doxorubicin, liposomal doxorubicin, epirubicin), cytarabine, pentostatin (Nipent), radiation therapy of the cardiac region, and trastuzumab. ■ Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and amiodarone, filgrastim, and sargramostim. ■ Increased nephrotoxicity may result from the combined effect of cyclophosphamide and amphotericin B and indomethacin.■ Risk of hepatotoxicity is increased when administered with azathioprine. ■ Increased incidence of hepatic VOD and mucositis when administered with busulfan. ■ Increased incidence of mucositis when administered with protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir). ■ Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. ■ Higher incidence of noncutaneous malignant solid tumors in patients with Wegener’s granulomatosis when administered with etanercept. ■ Acute encephalopathy has been reported in patients receiving metronidazole and cyclophosphamide. ■ Concomitant use with tamoxifen may increase the risk of thromboembolic complications. ■ May increase or decrease activity of anticoagulants (e.g., warfarin); monitor INR and adjust dose as indicated. ■ May reduce serum digoxin and cyclosporine levels. ■ May prolong neuromuscular blockade and prolonged respiratory depression caused by succinylcholine. These effects are dose dependent and may occur up to several days after cyclophosphamide is discontinued. Alert the anesthesiologist. ■ May decrease effectiveness of oral quinolone antibiotics (e.g., ciprofloxacin, levofloxacin). ■ Capable of many other interactions.
The most commonly reported side effects are alopecia (regrowth may be slightly darker), diarrhea, febrile neutropenia, fever, nausea, neutropenia, and vomiting. Other side effects include abdominal pain, amenorrhea, anorexia, gonadal suppression, impaired wound healing, leukopenia (see Precautions), malaise, mucosal ulcerations, darkening of skin and fingernails, susceptibility to infection, including opportunistic infections.
Anaphylaxis, bone marrow suppression (anemia, leukopenia, thrombocytopenia) or failure, hemorrhagic cystitis or ureteritis (reversible), infection, pneumonitis, pulmonary fibrosis, rash, renal tubular necrosis (reversible), secondary neoplasia, SIADH, urinary tract and renal toxicity (e.g., bladder fibrosis, hemorrhagic cystitis, ureteritis), veno-occlusive disease.
Numerous side effects have been identified from post-marketing surveillance. These include acute respiratory distress syndrome, arthralgia, ascites, asthenia, bronchospasm, cardiotoxicity (e.g., arrhythmias, cardiac arrest, cardiac failure, cardiogenic shock, cardiomyopathy, myocardial infarction, myocarditis, pericarditis), chest pain, chills, cholestasis, colitis, convulsions, disseminated intravascular coagulation, dizziness, dyspnea, edema, encephalopathy, fatigue, fever, fluid retention, headache, hemolytic-uremic syndrome, hepatic encephalopathy, hepatitis, hepatotoxicity with hepatic failure, hyperglycemia, hypertension, hypoglycemia, hyponatremia, hypotension, increased liver function tests, infusion site reactions, interstitial pneumonitis, malaise, muscle spasms, myalgia, pancreatitis, paresthesia, peripheral neuropathy, pruritus, pulmonary edema, radiation recall dermatitis, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, Stevens-Johnson syndrome, stomatitis, toxic epidermal necrolysis, visual impairment, and many others.
No specific antidote available. Minor side effects will be treated symptomatically if necessary. Discontinue the drug in cases of severe hemorrhagic cystitis. Urotoxicity may require interruption of treatment or cystectomy. Mesna has been used to decrease the incidence of cystitis. Interrupt therapy, reduce dose, or discontinue in patients who have or who develop potentially serious infections. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) and/or blood modifiers (e.g., darbepoetin alfa [Aranesp], epoetin alfa [Epogen], filgrastim [Neupogen, Zarxio], pegfilgrastim [Neulasta], sargramostim [Leukine]) may be indicated to treat bone marrow toxicity. Leukocyte and thrombocyte nadirs are usually reached in the first or second week of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Supportive therapy as indicated will help sustain the patient in toxicity. Cyclophosphamide and its metabolites are dialyzable.