Cyclophosphamide Side Effects

Brand Names: Cytoxan

Please note - some side effects for Cyclophosphamide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Cyclophosphamide - for the Consumer

Cyclophosphamide

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Cyclophosphamide:

Appetite loss; absence of menstrual periods; color change in skin; diarrhea; general unwell feeling; hair loss; nausea; skin rash; stomach discomfort or pain; texture change in nails; vomiting; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in urine; bloody or black tarry stools; chest pain; chills; fever; hallucinations; increased or decreased urination; infection; lower back or abdominal pain; pain, swelling, or redness at the injection site; painful urination; persistent cough; pneumonia; red, swollen, or blistered skin; seizures; severe stomach pain; shortness of breath; sore throat; sores in the mouth; swelling of the hands or feet; unusual bruising or bleeding; unusual or severe tiredness or weakness; yellowing of the skin or eyes.

Cyclophosphamide Tablets

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Cyclophosphamide Tablets:

Appetite loss; absence of menstrual periods; color change in skin; diarrhea; general unwell feeling; hair loss; nausea; skin rash; stomach discomfort or pain; texture change in nails; vomiting; weakness.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in urine; bloody or black tarry stools; chest pain; chills; fever; hallucinations; increased or decreased urination; infection; lower back or abdominal pain; painful urination; persistent cough; pneumonia; red, swollen, or blistered skin; seizures; severe stomach pain; shortness of breath; sore throat; sores in the mouth; swelling of the hands or feet; unusual bruising or bleeding; unusual or severe tiredness or weakness; yellowing of the skin or eyes.

Cyclophosphamide Side Effects - for the Professional

Cyclophosphamide

Information on adverse reactions associated with the use of Cyclophosphamide is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section.

Reproductive System

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Digestive System

Nausea and vomiting commonly occur with Cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when Cyclophosphamide treatment is stopped.

Skin and Its Structures

Alopecia occurs commonly in patients treated with Cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to Cyclophosphamide has not been established.

Hematopoietic System

Leukopenia occurs in patients treated with Cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Thrombocytopenia or anemia develop occasionally in patients treated with Cyclophosphamide. These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.

Urinary System

See WARNINGS: Urinary System for information on cystitis and urinary bladder fibrosis.

Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with Cyclophosphamide. Such lesions usually resolve following cessation of therapy.

Infections

See WARNINGS: Infections for information on reduced host resistance to infections.

Carcinogenesis

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Respiratory System

Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of Cyclophosphamide over a prolonged period.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of Cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.

Side Effects by Body System

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

Cardiovascular

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.

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.

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).

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.

Hypersensitivity

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

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.

Oncologic side effects including secondary neoplasms have been reported. The most commonly observed secondary malignancies are leukemia and tumors involving the urinary bladder.

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.

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.

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