Side Effects of Cytoxan (cyclophosphamide)

Cytoxan (cyclophosphamide) is a cancer (chemotherapy) medication used alone to treat several types of cancers, but often in combination with other drugs to treat breast cancer, leukemia, ovarian cancer, and nephrotic syndrome (a disease of the kidneys) in children. 

Unapproved uses of Cytoxan include the treatment of granulomatosis with polyangiitis, severe rheumatoid arthritis, lupus erythematosus, advanced mycosis fungoides, and several of forms of vasculitis. 

In order to work, cyclophosphamide first is converted by the liver into two chemicals, acrolein and phosphoramide. Acrolein and phosphoramide are the active compounds, and they slow the growth of cancer cells by interfering with the actions of deoxyribonucleic acid (DNA) within the cancerous cells. Unfortunately, normal cells also are affected, and this results in serious side effects. In addition to slowing the growth of cancerous cells, Cytoxan also suppresses the immune system and is referred to as immunosuppressive.

Common side effects of Cytoxan include

• hair loss,
• nausea,
• vomiting,
• diarrhea,
• mouth sores,
• weight loss,
• stomach pain,
• rash,
• mouth sores,
• skin pigmentation,
• nail changes,
• sterility, and
• yellowing skin and eyes (jaundice).

Serious side effects of Cytoxan include

• kidney failure, heart and lung problems,
• suppression of the immune system which may result in serious and sometimes fatal infections,
• severe allergic reactions,
• inflammation of the urinary bladder with bleeding (hemorrhagic cystitis) that can lead to abdominal pain from the bladder,
• problems urinating due to blood clots, and
• anemia due to loss of blood.

Cytoxan suppresses production of blood cells from the bone marrow, including white blood cells (leukopenia) which reduces the ability of the body to fight infection, red blood cells (anemia) which reduces the ability of blood to carry oxygen, and platelets (thrombocytopenia), which impairs the ability of blood to clot.

Drug interactions of Cytoxan include allopurinol, which enhances the ability of Cytoxan to reduce production of blood cells from the bone marrow. Cytoxan increases the occurrence of heart failure that is caused by doxorubicin, increases the action of blood thinners such as warfarin, and decreases the effectiveness of quinolone antibiotics ciprofloxacin.

Use of Cytoxan during pregnancy may cause birth defects. Cytoxan should not be administered during pregnancy. Cytoxan is excreted in breast milk and could cause serious problems in breastfeeding infants.

Side effects of cyclophosphamide include:

• Hair loss
• Nausea
• Vomiting
• Diarrhea
• Mouth sores
• Weight loss
• Stomach pain
• Rash
• Mouth sores (stomatitis)
• Skin pigmentation
• Nail changes
• Sterility
• Jaundice

Cyclophosphamide causes kidney failure, and it also may affect the heart and lungs. Cyclophosphamide suppresses production of blood cells from the bone marrow, including white blood cells (leukopenia), red blood cells (anemia) and platelets (thrombocytopenia).

Leukopenia reduces the ability of the body to fight infection, thrombocytopenia impairs the ability of blood to clot, and anemia reduces the ability of blood to carry oxygen.

Cyclophosphamide suppresses the immune system which may result in serious and sometimes fatal infections. Severe allergic reactions also may occur.

Cyclophosphamide may cause inflammation of the urinary bladder with bleeding (hemorrhagic cystitis). This can result in lower abdominal pain from the bladder, problems urinating due to blood clots, and anemia due to loss of blood.

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Hypersensitivity
• Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections
• Urinary Tract and Renal Toxicity
• Cardiotoxicity
• Pulmonary Toxicity
• Secondary Malignancies
• Veno-occlusive Liver Disease
• Embryo-Fetal Toxicity
• Reproductive System Toxicity
• Impaired Wound Healing
• Hyponatremia

Common Adverse Reactions

Hematopoietic System

• Neutropenia occurs in patients treated with cyclophosphamide.
• 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.

Gastrointestinal System

• Nausea and vomiting 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.

Skin And Its Structures

• Alopecia occurs in patients treated with cyclophosphamide.
• Skin rash occurs occasionally in patients receiving the drug.
• Pigmentation of the skin and changes in nails can occur.

Postmarketing Experience

The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made.

• Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.
• Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis).
• Ear and Labyrinth: deafness, hearing impaired, tinnitus.
• Endocrine: water intoxication.
• Eye: visual impairment, conjunctivitis, lacrimation.
• Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation.
• General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache.
• Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).
• Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased.
• Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.
• Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock.
• Investigations: blood lactate dehydrogenase increased, C-reactive protein increased.
• Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.
• Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.
• Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.
• Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.
• Pregnancy: premature labor.
• Psychiatric: confusional state.
• Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.
• Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia.
• Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.
• Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis.
• Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.
• Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s.

An increase of the concentration of cytotoxic metabolites may occur with:

• Protease inhibitors: Concomitant use of protease inhibitors 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 use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen.

Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.

• Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:
  • ACE inhibitors: ACE inhibitors can cause leukopenia.
  • Natalizumab
  • Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
  • Thiazide diuretics
  • Zidovudine
• Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:
  • Anthracyclines
  • Cytarabine
  • Pentostatin
  • Radiation therapy of the cardiac region
  • Trastuzumab
• Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:
  • Amiodarone
  • G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.
• Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:
  • Amphotericin B
  • Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin
• Increase in other toxicities:
  • Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
  • Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
  • Protease inhibitors: Increased incidence of mucositis
• Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

Etanercept

• In patients with Wegener's granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors.

Metronidazole

• Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen

• Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Coumarins

• Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.

Cyclosporine

• Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.

Depolarizing muscle relaxants

• Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity.
• Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).
• If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.