Cyclophosphamide

Leukopenia, neutropenia, thrombocytopenia, and anemia may commonly occur; may be dose related. Bone marrow failure has been reported. Bone marrow failure and severe immunosuppression may lead to serious (and fatal) infections, including sepsis and septic shock, or may reactive latent infections. Antimicrobial prophylaxis may be considered in appropriate patients. Initiate antibiotics for neutropenic fever; antifungal and antiviral medications may also be necessary. Monitor blood counts during treatment. Avoid use if neutrophils are ≤1,500/mm3 and platelets are 3. Consider growth factors (primary or secondary prophylaxis) in patients at increased risk for complications due to neutropenia. Platelet and neutrophil nadirs are usually at weeks 1 and 2 of treatment and recovery is expected after ~20 days. Severe myelosuppression may be more prevalent in heavily pretreated patients or in patients receiving concomitant chemotherapy and/or radiation therapy.

Cardiotoxicity has been reported (some fatal), usually with high doses associated with transplant conditioning regimens, although may rarely occur with lower doses. Cardiac abnormalities do not appear to persist. Cardiotoxicities reported have included arrhythmias (supraventricular and ventricular [some with QT prolongation]), congestive heart failure, heart block, hemopericardium (secondary to hemorrhagic myocarditis and myocardial necrosis), myocarditis (including hemorrhagic), pericarditis, pericardial effusion including cardiac tamponade, and tachyarrhythmias. Cardiotoxicity is related to endothelial capillary damage; symptoms may be managed with diuretics, ACE inhibitors, beta-blockers, or inotropics (Floyd 2005). The risk for cardiotoxicity may be increased with higher doses, advanced age, prior radiation to the cardiac region, and in patients who have received prior or concurrent cardiotoxic medication. Use with caution in patients with preexisting cardiovascular disease or those at risk for cardiotoxicity. For patients with cardiac risk factors or preexisting cardiac disease, monitor during treatment. In a scientific statement from the American Heart Association, cyclophosphamide has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

May impair fertility; interferes with oogenesis and spermatogenesis. Effect on fertility is generally dependent on dose and duration of treatment and may be irreversible. The age at treatment initiation and cumulative dose were determined to be risk factors for ovarian failure in cyclophosphamide use for the treatment of systemic lupus erythematosus (SLE) (Mok 1998).

Nausea and vomiting commonly occur. Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016). Stomatitis/mucositis may also occur.

Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive liver disease (VOD), has been reported in patients receiving chemotherapy regimens containing cyclophosphamide. A major risk factor for SOS is cytoreductive conditioning transplantation regimens with cyclophosphamide used in combination with total body irradiation or busulfan (or other agents). Other risk factors include preexisting hepatic dysfunction, prior radiation to the abdominal area, and low performance status. Children 1.4 mg/dL, unexplained weight gain, ascites, hepatomegaly, or unexplained right upper quadrant pain (Arndt 2004). SOS has also been reported in patients receiving long-term lower doses for immunosuppressive indications.

Anaphylactic reactions have been reported. Cross-sensitivity with other alkylating agents may occur.

Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone) has been reported; some have been fatal.

Monitor for infections; immunosuppression and serious infections may occur. Serious infections may require dose reduction, or interruption or discontinuation of treatment.

Pulmonary toxicities, including pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and acute respiratory distress syndrome, have been reported. Monitor for signs/symptoms of pulmonary toxicity. Consider pulmonary function testing to assess the severity of pneumonitis (Morgan 2011). Cyclophosphamide-induced pneumonitis is rare and may present as early (within 1 to 6 months) or late onset (several months to years). Early onset may be reversible with discontinuation; late onset is associated with pleural thickening and may persist chronically (Malik 1996). In addition, late onset pneumonitis (>6 months after therapy initiation) may be associated with increased mortality.

Secondary malignancies (bladder cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported with both single-agent and with combination chemotherapy regimens; onset may be delayed (up to several years after treatment). Bladder cancer usually occurs in patients previously experiencing hemorrhagic cystitis; risk may be reduced by preventing hemorrhagic cystitis.

Cyclophosphamide is associated with the development of hemorrhagic cystitis, pyelitis, ureteritis, and hematuria. Hemorrhagic cystitis may rarely be severe or fatal. Bladder fibrosis may also occur, either with or without cystitis. Urotoxicity is due to excretion of cyclophosphamide metabolites in the urine and appears to be dose- and treatment duration-dependent, although may occur with short-term use. Increased hydration and frequent voiding is recommended to help prevent cystitis; some protocols utilize mesna to protect against hemorrhagic cystitis. Monitor urinalysis for hematuria or other signs of urotoxicity. Severe or prolonged hemorrhagic cystitis may require medical or surgical treatment. While hematuria generally resolves within a few days after treatment is withheld, it may persist in some cases. Discontinue cyclophosphamide with severe hemorrhagic cystitis. Exclude or correct any urinary tract obstructions prior to treatment initiation (use is contraindicated with bladder outlet obstruction). Use with caution (if at all) in patients with active urinary tract infection.

May interfere with wound healing. Disease-related concerns:

Use with caution in patients with hepatic impairment; dosage adjustment may be needed. The conversion between cyclophosphamide to the active metabolite may be reduced in patients with severe hepatic impairment, potentially reducing efficacy.

Use with caution in patients with renal impairment; dosage adjustment may be needed. Decreased renal excretion and increased serum levels (cyclophosphamide and metabolites) may occur in patients with severe renal impairment (CrCl 10 to 24 mL/minute); monitor for signs/symptoms of toxicity. Cyclophosphamide and metabolites are dialyzable; differences in amount dialyzed may occur due to dialysis system used. If dialysis is required, maintain a consistent interval between administration and dialysis. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Cyclophosphamide may potentiate the cardiotoxicity of anthracyclines.