Cyclophosphamide Side Effects

Not all side effects for cyclophosphamide may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to cyclophosphamide: powder for solution, tablet

In addition to its needed effects, some unwanted effects may be caused by cyclophosphamide. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking cyclophosphamide:

More common
  • Cough or hoarseness
  • fever or chills
  • lower back or side pain
  • missing menstrual periods
  • painful or difficult urination
With high doses and/or long-term treatment
  • 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
Less common
  • Black, tarry stools
  • pinpoint red spots on the skin
  • unusual bleeding or bruising
Rare
  • 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 of the side effects that can occur with cyclophosphamide may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Darkening of the skin and fingernails
  • loss of appetite
  • nausea or vomiting
Less common
  • Diarrhea
  • flushing or redness of the face
  • headache
  • 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

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

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

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

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]

Respiratory

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]

Cardiovascular

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

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

Hypersensitivity side effects including rare cases of cutaneous vasculitis, delayed-type reactions, anaphylaxis, and death have been reported.[Ref]

Oncologic

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

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

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]

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