Cyclophosphamide Side Effects
For the Consumer
Applies to cyclophosphamide: capsule, powder for solution, tablet
Along with its needed effects, cyclophosphamide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking cyclophosphamide:More common
- Cough or hoarseness
- fever or chills
- lower back or side pain
- missing menstrual periods
- painful or difficult urination
- Blood in the urine
- dizziness, confusion, or agitation
- fast heartbeat
- joint pain
- shortness of breath
- swelling of the feet or lower legs
- unusual tiredness or weakness
- Black, tarry stools
- pinpoint red spots on the skin
- unusual bleeding or bruising
- Frequent urination
- redness, swelling, or pain at the injection site
- sores in the mouth and on the lips
- sudden shortness of breath
- unusual thirst
- yellow eyes or skin
Some side effects of cyclophosphamide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Darkening of the skin and fingernails
- loss of appetite
- nausea or vomiting
- flushing or redness of the face
- increased sweating
- skin rash, hives, or itching
- stomach pain
- swollen lips
For Healthcare Professionals
Applies to cyclophosphamide: intravenous powder for injection, oral capsule, oral tablet
Hematologic side effects including myelosuppression have been reported. Myelosuppression consisting primarily of leukopenia is the most common dose-limiting side effect associated with cyclophosphamide. Anemia develops occasionally. Aplastic anemia has been reported rarely. One case of cyclophosphamide-induced methemoglobinemia has also been reported.[Ref]
After induction therapy, the nadir for leukopenia (much more common than thrombocytopenia or anemia) usually occurs at 8 to 14 days, and recovery typically occurs at 18 to 25 days. The leukopenia associated with cyclophosphamide increases a patient's risk of infection. Cyclophosphamide is considered a relatively platelet-sparing agent; however, clinically significant depression of the platelets may be seen when the dose of the drug exceeds 30 mg/kg.
Chronically administered cyclophosphamide may have a cumulative effect on the bone marrow reserve. After chronic oral therapy, the complete blood count (CBC), including platelets should be monitored at least every 4 weeks and more during dosage adjustments.
The most serious complication from cyclophosphamide-induced myelosuppression is life-threatening opportunistic infections or sepsis.
Cyclophosphamide is somewhat unusual among alkylating agents in that it has a relative sparing effect on hematopoietic stem cells and platelets.
An increased incidence of thromboembolic events has been reported in women receiving cyclophosphamide, methotrexate, and fluorouracil as treatment for breast cancer.[Ref]
Gastrointestinal side effects including moderate to severe emesis have been reported in the majority of patients. Standard (450-1000 mg/m2) and high-dose (>1000 mg/m2) cyclophosphamide have been reported to have resulted in severe nausea and vomiting in 70% to 90% of patients. Cyclophosphamide also causes anorexia, and, less frequently, abdominal discomfort, pain or diarrhea. There are rare reports of hemorrhagic colitis, oral mucosal ulceration, and jaundice occurring during therapy.[Ref]
Severity of the emesis typically depends on the dose of cyclophosphamide and the addition of other chemotherapeutic agents.
Cyclophosphamide-induced nausea and vomiting may last for 3 to 5 days following chemotherapy.
Selection of appropriate antiemetic agents is made based on the total dose of cyclophosphamide. Studies have shown that a serotonin-receptor antagonist such as ondansetron or granisetron plus dexamethasone provides optimal emetic control for patients receiving standard or high-dose cyclophosphamide (>450 mg/m2).
Cyclophosphamide-containing regimens may also produce clinically significant delayed nausea and vomiting. The regimens found to be effective in the prevention of delayed nausea and vomiting include oral metoclopramide or oral ondansetron plus dexamethasone.
Nausea and vomiting are more likely after IV administration, and are probably the result of direct stimulation of the chemoreceptor trigger zone.[Ref]
Dermatologic side effects including alopecia has been reported in at least 50% of patients treated with cyclophosphamide and is typically reversible. Less commonly, skin or nail pigmentation changes have been reported. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely.[Ref]
Hair loss generally occurs 1 to 3 weeks after a single dose and is maximal after 1 to 2 months. Hair may grow back a different texture and a different color. Hair regrowth typically occurs after cyclophosphamide is discontinued but sometimes begins during successive treatments of cyclophosphamide.
The scalp is most commonly affected by cyclophosphamide-induced hair follicle damage, but axillary, extremity, and pubic hair can also be lost after long-term therapy.
A definitive causal relationship between Stevens-Johnson syndrome and toxic epidermal necrolysis and cyclophosphamide has not been established[Ref]
Genitourinary side effects including hemorrhagic cystitis have been reported. The incidence ranges from 7% to 78% with 4% mortality from uncontrolled hemorrhage. Nonhemorrhagic cystitis, bladder fibrosis, hemorrhagic urethritis, irritative voiding, urinary frequency, dysuria, urgency, incontinence, nocturia, and renal tubular necrosis have also been reported.[Ref]
Hemorrhagic cystitis is probably due to acrolein, a product formed from the breakdown of aldophosphamide to phosphoramide mustard. This condition is rarely severe or fatal. Aggressive hydration (3 to 4 liters/day, if not otherwise contraindicated), frequent urinary voiding, and the use of mesna (a thiosulfate that binds the offending metabolic agent, acrolein, and can be mixed directly with cyclophosphamide) is helpful, especially when higher doses of cyclophosphamide are used, to reduce the risk of hemorrhagic cystitis. In most circumstances, hemorrhagic cystitis is a contraindication to further cyclophosphamide treatment.
During high-dose therapy, daily urinalysis and occasionally urine dipsticks (checking for blood) are recommended. The diagnosis of cyclophosphamide-induced hemorrhagic cystitis is based on (a) a history of gross hematuria; (b) laboratory findings of microscopic hematuria; (c) platelet counts of greater than 50,000/mm3; and (d) lack of significant bacterial growth urine culture.[Ref]
Risk factors for the development of lung injury after cyclophosphamide are not clear. Dosage, age of the patient, disease condition, or duration of treatment do not appear to be predisposing factors. A combination of drugs, radiation therapy, or oxygen therapy is known to exacerbate cyclophosphamide-induced pulmonary toxicity.[Ref]
Respiratory side effects including interstitial pulmonary fibrosis and pneumonitis have been reported in 1% of patients receiving high doses of cyclophosphamide over a prolonged period. Signs and/or symptoms of lung damage include dyspnea, cough fever, pulmonary edema, and abnormal lung sounds. Interstitial lung disease secondary to Pneumocystis carinii pneumonia following combination therapy with cyclophosphamide and prednisone has also been reported. A case of fatal pulmonary toxicity after a single dose of cyclophosphamide has been reported.
Cyclophosphamide has been associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.[Ref]
When a high-dose regimen is needed, splitting the daily dose of cyclophosphamide into two infusions may decrease the risk of cardiotoxicity. No residual cardiac abnormalities appear to be present in patients with apparent cardiac toxicity associated with high doses of cyclophosphamide.
Limited data (44 patients for bone marrow transplantation) suggest use of twice-daily regimens may decrease the risk of cyclophosphamide-induced systolic dysfunction.[Ref]
Cardiovascular side effects including acute cardiac toxicity have been reported with cyclophosphamide doses as low as 2.4 g/m2 to as high as 26 g/m2, usually in conjunction with other antineoplastic agents. A few cases have been reported of congestive heart failure after high dose cyclophosphamide therapy.[Ref]
Endocrine side effects including interference with oogenesis and spermatogenesis have been reported. Cyclophosphamide-induced amenorrhea associated with decreased estrogen and increased gonadotropin in women, and oligo- or azoospermia associated with normal testosterone and increased gonadotropin in men have also been reported. Cyclophosphamide may cause sterility in both sexes depending on the dose, duration of treatment, and pretreatment state of gonadal function. A syndrome of inappropriate antidiuretic hormone (SIADH) with hyponatremia has been associated with high IV doses (greater than 50 mg/kg).[Ref]
Cyclophosphamide-induced sterility may be irreversible in some patients.
Male sexual libido is unchanged by cyclophosphamide.
Both ovarian fibrosis in women and testicular atrophy in men have been associated with prolonged use of this drug.
Men and women with cyclophosphamide-induced sterility typically resume sperm production and menses, depending on their ages at the time of chemotherapy. Many affected men have subsequently fathered normal children.
SIADH associated with cyclophosphamide is not due to increased secretion of antidiuretic hormone (ADH), but is due to a direct effect of cyclophosphamide on the renal tubules, leading to excess water retention. Isotonic hydration is usually helpful for this typically short-lived problem.[Ref]
Hypersensitivity side effects including rare cases of cutaneous vasculitis, delayed-type reactions, anaphylaxis, and death have been reported.[Ref]
Secondary neoplasias have developed during cyclophosphamide monotherapy or when this drug was given with other antineoplastic drugs. Patients with hemorrhagic cystitis during therapy or patients with underlying primary myeloproliferative or lymphoproliferative malignancies or disorders appear to be at greatest risk.
In some cases, new neoplasms have been observed several years after exposure to cyclophosphamide.
A controlled longitudinal cohort study of 119 patients with severe rheumatoid arthritis revealed the relative risk of malignancy in patients treated with cyclophosphamide was 1.5. Risk was directly proportional to dose.[Ref]
Oncologic side effects including secondary neoplasms have been reported. The most commonly observed secondary malignancies are leukemia and tumors involving the urinary bladder.[Ref]
Nervous system side effects (ototoxicity and peripheral neuropathy) have been reported after cyclophosphamide was used with other antineoplastic agents (including cisplatin and carboplatin, drugs often associated with ototoxicity). Other side effects include asthenia, dizziness, depression, or headache.[Ref]
Musculoskeletal side effects including musculoskeletal pains and rheumatic syndromes have been reported in patients who have received regimens that have included cyclophosphamide. Myalgias and arthralgias have been reported 1 to 3 months after completion of adjuvant chemotherapy for breast cancer.[Ref]
1. Shehadeh N, Dansey R, Seen S, Abella E "Cyclophosphamide-induced methemoglobinemia." Bone Marrow Transplant 32 (2003): 1109-10
2. "Product Information. Cytoxan (cyclophosphamide)." Bristol-Myers Squibb, Princeton, NJ.
3. Kovarsky J "Clinical pharmacology and toxicology of cyclophosphamide: emphasis on use in rheumatic diseases." Semin Arthritis Rheum 12 (1983): 359-72
4. Closon MT, Verbeke L, Kains JP, Tijtgat J, Schallier D "Combination chemotherapy with carboplatin, cyclophosphamide and fluorouracil in advanced breast cancer." Anticancer Res 15 (1995): 591-5
5. Amato D, Niblett JS "Neutropenia from cyclophosphamide in breast milk." Med J Aust 03/12/77 (1977): 383-4
6. Baran DT, Griner PF, Klemperer MR "Recovery from aplastic anemia after treatment with cyclophosphamide." N Engl J Med 295 (1976): 1522-4
7. Grochow LB, Colvin M "Clinical pharmacokinetics of cyclophosphamide." Clin Pharmacokinet 4 (1979): 380-94
8. Fraiser LH, Kanekal S, Kehrer JP "Cyclophosphamide toxicity: characterising and avoiding the problem." Drugs 42 (1991): 781-95
9. Moore MJ "Clinical pharmacokinetics of cyclophosphamide." Clin Pharmacokinet 20 (1991): 194-208
10. Mouridsen HT, Witten J, Frederiksen PL, Hulsbaek I "Studies on the correlation between rate of biotransformation and haematological toxicity of cyclophosphamide ." Acta Pharmacol Toxicol (Copenh) 43 (1978): 328-30
11. Morgan M, Dodds A, Atkinson K, et al "The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation." Br J Haematol 77 (1991): 529-34
12. Omdal R, Husby G, Koldingsnes W "Intravenous and oral cyclophosphamide pulse therapy in rheumatic diseases: side effects and complications." Clin Exp Rheumatol 11 (1993): 283-8
13. Stewart DJ, Morgan LR, Verma S, Maroun JA, Thibault M "Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study." Invest New Drugs 13 (1995): 99-107
14. Spitzer TR, Cirenza E, McAfee S, Foelber R, Zarzin J, Cahill R, Mazumder A "Phase I-II trial of high-dose cyclophosphamide, carboplatin and autologous bone marrow or peripheral blood stem cell rescue." Bone Marrow Transplant 15 (1995): 537-42
15. Kosirog-Glowacki JL, Bressler LR "Cyclophosphamide-induced facial discomfort." Ann Pharmacother 28 (1994): 197-9
16. Bissett D, Khan A, McLaughlin I, Davis JA, Symonds RP "Haemorrhagic cystitis requiring cystectomy after cyclophosphamide and radiotherapy." Eur J Cancer 29A (1993): 1222-3
17. Wrabetz E, Peter G, Hohorst HJ "Does acrolein contribute to the cytotoxicity of cyclophosphamide?" J Cancer Res Clin Oncol 98 (1980): 119-26
18. Erer B, Angelucci E, Baronciani D, Tomasucci M, Giardini C, Gaziev J "Hemorrhagic cystitis after allogeneic bone marrow transplantation for thalassemia." Bone Marrow Transplant 12 (1993): 93-5
19. Samra Y, Hertz M, Lindner A "Urinary bladder tumors following cyclophosphamide therapy: a report of two cases with a review of the literature." Med Pediatr Oncol 13 (1985): 86-91
20. Talarwilliams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky L, Kerr CS, Hoffman GS, Fauci AS, Sneller MC "Cyclophosphamide-induced cystitis and bladder cancer in patients with wegener granulomatosis." Ann Intern Med 124 (1996): 477
21. Levine L, Richie JP "Urological complications of cyclophosphamide." J Urol 141 (1989): 1063-9
22. Stillwell TJ. Benson RC "Cyclophosphamide-induced hemorrhagic cystitis." Cancer 61 (1988): 451-7
23. Tsukamoto N, Matsukuma K, Matsuyama T, et al "Cyclophosphamide-induced interstitial pneumonitis in a patient with ovarian carcinoma." Gynecol Oncol 17 (1984): 41-51
24. Karim FW, Ayash RE, Allam C, Salen PA "Pulmonary fibrosis after prolonged treatment with low-dose cyclophosphamide." Oncology 40 (1986): 174-6
25. Burke DA, Stoddart JC, Ward MK, Simpson CG "Fatal pulmonary fibrosis occurring during treatment with cyclophosphamide." Br Med J 285 (1982): 696
26. Spector JI, Zimbler H, Ross JS "Septicemia from infected caval "umbrella"." JAMA 243 (1980): 1133
27. Lipton JH "Therapy of cyclophosphamide-induced nasal congestion." Bone Marrow Transplant 16 (1995): 634
28. Gupta S, Mahipal A "Fatal pulmonary toxicity after a single dose of cyclophosphamide." Pharmacotherapy 27 (2007): 616-8
29. Patel JM "Metabolism and pulmonary toxicity of cyclophosphamide." Pharmacol Ther 47 (1990): 137-46
30. Segura A, Yuste A, Cercos A, et al. "Pulmonary fibrosis induced by cyclophosphamide." Ann Pharmacother 35(7-8) (2001): 894-7
31. Sen RP, Walsh TE, Fisher W, Brock N "Pulmonary complications of combination therapy with cyclophosphamide and prednisone." Chest 99 (1991): 143-6
32. Ayash LJ, Wright JE, Tretyakov O, et al. "Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response." J Clin Oncol 10 (1992): 995-1000
33. Dow E, Schulman H, Agura E "Cyclophosphamide cardiac injury mimicking acute myocardial infarction." Bone Marrow Transplant 12 (1993): 169-72
34. Rubin P, Petros W, Vredenburgh J, Hussein A, Elkordy M, Ross M, Peters W "Cyclophosphamide-induced cardiomyopathy following high-dose chemotherapy (Meeting abstract)." Proc Annu Meet Am Soc Clin Oncol 14 (1995): a9681995
35. Gardner SF, Lazarus HM, Bednarczyk EM, Creger RJ, Miraldi FD, Leisure G, Green JA "High-dose cyclophosphamide-induced myocardial damage during BMT: assessment by positron emission tomography." Bone Marrow Transplant 12 (1993): 139-44
36. DeFronzo RA, Braine H, Colvin M, Davis PJ "Water intoxication in man after cyclophosphamide therapy: time course and relation to drug activation." Ann Intern Med 78 (1973): 861-9
37. Bogdanovic R, Banicevic M, Cvoric A "Testicular function following cyclophosphamide treatment for childhood nephrotic syndrome: long-term follow-up study." Pediatr Nephrol 4 (1990): 451-4
38. Boumpas DT, Austin HA, 3d Vaughan EM, Yarboro CH, Klippel JH, Balow JE, Austin HA "Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy." Ann Intern Med 119 (1993): 366-9
39. Anderson D, Bishop JB, Garner RC, Ostrosky-Wegman P, Selby PB "Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks." Mutat Res 330 (1995): 115-81
40. Bogdanovic R, Banicevic M, Cvoric A "Pituitary-gonadal function in women following cyclophosphamide treatment for childhood nephrotic syndrome: long-term follow-up study." Pediatr Nephrol 4 (1990): 455-8
41. Webberley MJ, Murray JA "Life-threatening acute hyponatraemia induced by low dose cyclophosphamide and indomethacin." Postgrad Med J 65 (1989): 950-2
42. Garas G, Crawford GP, Cain M "Anaphylactic reaction to intravenous cyclophosphamide." Aust N Z J Med 25 (1995): 59
43. Green RM, Schapel GJ, Sage RE "Cutaneous vasculitis due to cyclophosphamide therapy for chronic lymphocytic leukemia." Aust N Z J Med 19 (1989): 55-7
44. Anku V "Apparent cyclophosphamide hypersensitivity: urticaria associated with cyclophosphamide." Cancer Treat Rep 66 (1982): 2106-7
45. Popescu MA, Sheehan MG, Kouides PA, Loughner JE, Condemi JJ, Looney RJ, Leddy JP "Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients." J Allergy Clin Immunol 97 (1996): 26-33
46. Kritharides L, Lawrie K, Varigos GA "Cyclophosphamide hypersensitivity and cross-reactivity with chlorambucil." Cancer Treat Rep 71 (1987): 1323-4
47. Brenner DW, Schellhammer PF "Upper tract urothelial malignancy after cyclophosphamide therapy: a case report and literature review." J Urol 137 (1987): 1226-7
48. Kawamura J, Sakurai M, Tsukamoto K, Tochigi H "Leiomyosarcoma of the bladder eighteen years after cyclophosphamide therapy for retinoblastoma." Urol Int 51 (1993): 49-53
49. Escalante A, Kaufman RL, Beardmore TD "Acute myelocytic leukemia after the use of cyclophosphamide in the treatment of polyarteritis nodosa." J Rheumatol 16 (1989): 1147-9
50. Ortiz A, Gonzalez-Parra E, Alvarez-Costa G, Egido J "Bladder cancer after cyclophosphamide therapy for lupus nephritis." Nephron 60 (1992): 378-9
51. Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, Stolzer BL, Agarwal AK, Medsger TA Jr, Kwoh CK "Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study." Arthritis Rheum 38 (1995): 1120-7
52. Stein JP, Skinner EC, Boyd SD, Skinner DG "Squamous cell carcinoma of the bladder associated with cyclophosphamide therapy for Wegener's granulomatosis: a report of 2 cases." J Urol 149 (1993): 588-9
53. Pedersenbjergaard J, Jonsson V, Pedersen M, Houjensen K "Leiomyosarcoma of the urinary bladder after cyclophosphamide." J Clin Oncol 13 (1995): 532-3
54. Zemlickis D, Lishner M, Erlich R, Koren G "Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide." Teratogenesis Carcinog Mutagen 13 (1993): 139-43
55. Wall RL, Clausesn KP "Carcinoma of the urinary bladder in patients receiving cyclophosphamide." N Engl J Med 293 (1975): 2713
56. Arranz JA "Cycolophosphamide-induced myopia." Ann Intern Med 116 (1992): 92-3
57. Loprinzi CL, Duffy J, Ingle JN "Postchemotherapy rheumatism." J Clin Oncol 11 (1993): 768-70
Some side effects of cyclophosphamide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
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