CYCLOPHOSPHAMIDE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2-(bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazophosphorine-2-oxide
2) B 518
3) CPM
4) CTX
5) Cyclophosam
6) Cytophosphane
7) NSC 26271
8) WR 138719
9) CAS 50-18-0 (anhydrous)
10) CAS 6055-19-2

1.2.1) MOLECULAR FORMULA
1) C7H15Cl2N2O2P.H2O (Prod Info cyclophosphamide oral tablets, 2007)

Available Forms Sources

1) Cyclophosphamide is available as 25 and 50 mg tablets and capsules, and 500 mg, 1 gram, and 2 gram vials of powder for injection (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013; Prod Info cyclophosphamide oral tablets, 2007; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

1) Cyclophosphamide is an effective antineoplastic agent and is used for a variety of cancers including colorectal, cervical, Wilms' tumor, pulmonary adenocarcinoma, breast and ovarian carcinoma, various leukemias, non-Hodgkin's lymphoma, neuroblastoma, retinoblastoma, carcinoma of the bladder, Hodgkin's disease, multiple myeloma, and soft tissue sarcomas. Several non-malignant diseases also respond to the drug, including nephrotic syndrome (children), severe rheumatoid arthritis and systemic lupus erythematosus (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005; Ramos et al, 1996; Csuka et al, 1986).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Cyclophosphamide is used orally and intravenously as an antineoplastic agent for many types of malignancies (ie, lymphomas, leukemias, multiple myeloma, mycosis fungoides, pediatric CNS tumors, ovarian and breast cancer) and as an antirheumatic drug for a variety of conditions, including systemic lupus erythematosus and juvenile rheumatoid arthritis.
B) PHARMACOLOGY: Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and thus decreasing DNA synthesis. It is a prodrug that is metabolized in the liver and has active metabolites.
C) TOXICOLOGY: After overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (bone marrow, gastrointestinal tract).
D) EPIDEMIOLOGY: Acute cyclophosphamide poisoning is rare. The incidence of cyclophosphamide toxicity during therapeutic use varies depending on the dosage and the length of duration of therapy and sequential or concurrent use of other cytotoxic drugs, and some toxic effects (ie, cystitis) are far more common than pneumonitis or pulmonary fibrosis.
E) WITH THERAPEUTIC USE

1) COMMON: The most common effects observed include alopecia, which usually starts 3 weeks after therapy, effects on fertility (ie, irreversible sterility, amenorrhea), gastrointestinal effects (ie, nausea, vomiting, diarrhea, anorexia, mucositis, stomatitis), a potentially fatal acute hemorrhagic cystitis (in up to 40% of patients), and myelosuppression. Less common effects in patients include facial flushing, headache, skin rashes, SIADH, and renal tubular necrosis.
2) RARE: Rare but life-threatening side effects include cardiac effects (ie, congestive heart failure, cardiac necrosis, and hemorrhagic myocarditis), pulmonary effects (ie, interstitial pneumonitis and pulmonary fibrosis), anaphylactic reactions, hepatotoxicity, electrolyte imbalances, renal injury, secondary malignancy, and toxic epidermal necrolysis.
3) Cyclophosphamide is teratogenic (FDA pregnancy category D) and long-term use is associated with an increased risk of a variety of malignancies.

F) WITH POISONING/EXPOSURE

1) Overdose reports are limited. Severe left ventricular dysfunction, pleural and pericardial effusion, and myelosuppression have been reported. An extension of adverse effects (ie, alopecia, nausea, vomiting, diarrhea, stomatitis, hemorrhagic cystitis) should be expected.

0.2.20)

A) Cyclophosphamide is classified as FDA pregnancy category D. The drug can cause fetal harm and congenital abnormalities have been reported. Pregnant patients should be advised of the potential hazard to the fetus and women of childbearing potential should avoid becoming pregnant. Cyclophosphamide is excreted in breast milk. Due to the potential for serious adverse reactions, patients should be advised to either discontinue nursing or to discontinue the drug, and cyclophosphamide should be avoided in young women who plan to become pregnant. Cyclophosphamide interferes with oogenesis and spermatogenesis, resulting in sterility for both sexes that may be irreversible.

0.2.21)

A) Cyclophosphamide may cause secondary malignancies such as acute myeloid leukemia, bladder cancer, lymphomas, myeloproliferative or lymphoproliferative malignancies, renal cell carcinoma, renal pelvis carcinoma, sarcomas, thyroid cancer, and ureteric cancer when used alone or together with other antineoplastic agents. The secondary malignancy may develop several years after cyclophosphamide is discontinued.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For mild or moderate toxicity from overdose, supportive care should be sufficient. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Patients with severe neutropenia should be placed in protective isolation. Bladder toxicity may be ameliorated by hydration and forced diuresis, and the concurrent administration of MESNA (sodium 2-mercaptoethane sulfonate), which inactivates the toxic metabolite acrolein in the urine. Formalin 5% to 10% instilled into the bladder can also be used for less severe cystitis. Hyperbaric oxygen therapy has also been used for hemorrhagic cystitis. SIADH has been treated by fluid restriction and furosemide.

B) MANAGEMENT OF SEVERE TOXICITY

1) Severe toxicity from cyclophosphamide requires good supportive care, which might require an ICU setting. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Patients with severe neutropenia should be placed in protective isolation. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Bladder toxicity may be ameliorated by hydration and forced diuresis, and the concurrent administration of MESNA (sodium 2-mercaptoethane sulfonate), which inactivates the toxic metabolite acrolein in the urine. Formalin 5% to 10% instilled into the bladder can also be used for less severe cystitis. Hyperbaric oxygen therapy has also been used for hemorrhagic cystitis. SIADH has been treated by fluid restriction and furosemide.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital charcoal would be reasonable if it could be given within a few hours of ingestion and the patient was not vomiting. Standard decontamination (eg, washing skin with soap and water, irrigation of eyes with water) would be reasonable for other routes of exposure.
2) HOSPITAL: Activated charcoal would be reasonable if it can be administered soon after the ingestion. Although general guidelines recommend treating only if the patient presents within 60 minutes of the ingestion, the potential severity of cyclophosphamide ingestions warrants consideration of late administration. Gastric lavage should be considered in suicidal ingestions of cyclophosphamide, as there is no specific antidote, but should be reserved for life-threatening ingestions that have occurred recently (eg, within the last hour). There is no evidence to support the use of whole bowel irrigation or multiple doses of activated charcoal.

D) AIRWAY MANAGEMENT

1) Intubate if patient is unable to protect airway or if unstable dysrhythmias develops.

E) ANTIDOTE

1) None.

F) MYELOSUPPRESSION

1) Administer colony stimulating factors as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential for evidence of bone marrow suppression. If fever or infection develop during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.

G) NEUTROPENIA

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

H) FEBRILE NEUTROPENIA

1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

I) NAUSEA AND VOMITING

1) Doses of cyclophosphamide greater than 1500 mg/m(2) have a high emetic risk. Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).

J) HEMORRHAGIC CYSTITIS

1) Bladder toxicity may be ameliorated by hydration and forced diuresis, and the concurrent administration of MESNA (sodium 2-mercaptoethane sulfonate), which inactivates the toxic metabolite acrolein in the urine. MESNA can be given by IV bolus, at a dose equal to 40% to 60% of the cyclophosphamide dose (w/w), immediately after exposure and then at 3, 6, and 9 hours. Formalin 5% to 10% instilled into the bladder can also be used for less severe cystitis. Hyperbaric oxygen therapy has also been used for hemorrhagic cystitis.

K) SYNDROME OF INAPPROPRIATE VASOPRESSIN SECRETION

1) Treatment of SIADH is supportive. Restrict fluids to 1 L/day or less. Furosemide inhibits free water reabsorption more than it increases sodium, potassium and chloride excretion. Dosing should be adjusted to achieve a negative fluid balance.

L) STOMATITIS

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with severe cyclophosphamide overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

M) EXTRAVASATION INJURY

1) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer sodium thiosulfate (see dosing below). Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Another source recommended warm/heat compresses for local reaction. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.

a) SODIUM THIOSULFATE (SODIUM HYPOSULFITE) 10%: Prepare a 0.17 moles/L solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject into extravasation site.

N) ENHANCED ELIMINATION

1) Cyclophosphamide and its metabolites are moderately dialyzable (20% to 50%) but there are no reports of dialysis after overdose. It should be considered if it can be performed soon after a large overdose.

O) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management. Even inadvertent exposures via oral ingestion that are asymptomatic should be sent in for charcoal administration to prevent further sequelae. All intentional overdoses should be sent in for evaluation.
2) OBSERVATION CRITERIA: Exposed patients should be evaluated and observed for 6 hours. If patients are asymptomatic for 6 hours, they may be sent home, but toxic effects may be delayed, so patients should return to a health care provider for any symptoms and should have blood work monitored as an outpatient (eg, CBC for myelosuppression).
3) ADMISSION CRITERIA: Any symptomatic patient and any high dose parenteral overdoses should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be resolution of symptoms and laboratory abnormalities.
4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
5) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

P) PITFALLS

1) Symptoms in patients may be delayed (particularly myelosuppression) so reliable follow up is imperative. Patients taking these medications may have severe co-morbidities and access to other drugs with significant toxicity; consider coingestants.

Q) PHARMACOKINETICS

1) Peak serum concentration develops approximately one hour after ingestion. Well-absorbed from the gastrointestinal tract after oral administration with a reported bioavailability of greater than 75%. Elimination half-life is 3 to 12 hours after IV administration. Volume of distribution is 0.4 to 0.6 L/kg. Cyclophosphamide is excreted in urine with less than 30% as unchanged drug, and 85% to 90% as metabolites. Less than 10% is bound to proteins in serum (metabolites greater than 60%). There is hepatic metabolism to active metabolites, acrolein, aldophosphamide, 4-hydroxycyclophosphamide, and nornitrogen mustard.

R) PREDISPOSING CONDITIONS

1) Predisposing conditions to toxicity include underlying renal or liver diseases or patients on other immunosuppressant agents. Underlying cardiac disease or previous treatment with anthracyclines may predispose to cardiac toxicity. Also, CYP2B6 and CYP3A4 inhibitors may decrease its metabolism.

S) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis includes other chemotherapeutic agents.

0.4.4)

A) Irrigate exposed eyes with water or normal saline for 10 to 15 minutes; repeat if irritation persists.

0.4.5)

A) OVERVIEW

1) Exposed skin should be washed with soap and water.

0.4.6)

A) INTRATHECAL OVERDOSE

1) No clinical reports available; information derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) BLURRED VISION

a) Cyclophosphamide has been reported to cause blurred vision. This is usually associated with high dose intravenous therapy (Griffin & Garnick, 1981).
b) Blurred vision occurred in 5 out of 29 children treated with cyclophosphamide 750 mg/m(2) IV every other day for 5 doses. No other chemotherapy or radiotherapy was given concomitantly or within 2 months prior to cyclophosphamide. Blurred vision appeared within minutes of the IV administration and lasted 1 hour to 14 days. These incidences of blurred vision appear transient and of short duration (Kende et al, 1979).

Cardiovascular

3.5.2)

A) CARDIOTOXICITY

1) WITH THERAPEUTIC USE

a) Reversible dose-dependent cardiotoxicity following cyclophosphamide regimens for bone marrow transplantation has been reported. Cardiotoxicity was reflected as reversible decreases in ECG voltage and increases in left ventricular mass (Braverman et al, 1991).

1) The risk of cardiac toxicity increased with doses greater than 2.5 g/m(2)/day for two days in adults given cyclophosphamide in 30 to 60-minute intravenous infusions (Neidhart et al, 1990).
2) Children and adolescents did not develop cardiotoxicity when given 2.1 g/m(2)/day for two days, given as a six-hour infusion (Kushner & Cheung, 1991).

b) Fatal cardiac toxicity occurred in 3 patients after receiving cytosine arabinoside, cyclophosphamide (45 to 60 mg/kg/day for 2 consecutive days), and total body irradiation when undergoing bone marrow transplantation preparation. Autopsies revealed myocardial and pericardial toxicity (endothelial injury, hemorrhagic myopericarditis). The authors suggest that the cardiotoxic effects of this combination may be averted by lowering the dose of cyclophosphamide (Trigg et al, 1987).
c) Acute cardiac toxicity has been reported with doses between 2.4 grams/m(2) and 26 grams/m(2) with cyclophosphamide, usually as a portion of an antineoplastic multi-drug regimen or in conjunction with transplantation procedures (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

B) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) A prospective study was conducted to determine if QT dispersion (the difference between the maximum and minimum QT intervals on a 12-lead ECG) could be used to predict the occurrence of acute heart failure in patients who received high-dose cyclophosphamide therapy. The study involved 19 patients with hematopoietic malignancies who received intensive chemotherapy, consisting of ranimustine, cytarabine, etoposide, and high-dose cyclophosphamide, in preparation for undergoing peripheral-blood stem-cell transplantation (PBSCT). Five of the 19 patients developed acute heart failure between days 1 and 8 after receiving the chemotherapy regimen. The median values of QT dispersion and corrected QT dispersion were significantly higher in the patients with acute heart failure as compared to the patients without acute heart failure (QT dispersion 61.6 ms vs 24.7 ms, p<0.001; corrected QT dispersion 72.5 ms vs 27.6 ms, p<0.001) and there was no overlap of the corrected QT dispersion values between the two groups, indicating that QT dispersion may be utilized as a predictor of acute heart failure in patients receiving high-dose cyclophosphamide therapy for PBSCT (Nakamae et al, 2000).

C) CONGESTIVE HEART FAILURE

1) WITH THERAPEUTIC USE

a) Severe and, in some instances, fatal, congestive heart failure has occurred following high-dose cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).
b) Cardiomyopathy in a 12-year-old boy with aplastic anemia secondary to chloramphenicol occurred when he received 50 mg/kg cyclophosphamide daily for 4 days in preparation for bone marrow grafting. Four days after the last dose of cyclophosphamide, he developed severe congestive heart failure with evidence of septal end wall thickening plus pericardial effusion on echocardiogram. He was treated with fluid restriction, digoxin and furosemide but did not begin to improve for 7 days. The pericardial effusion decreased, but there was evidence of permanent impairment of left ventricular contractility. The bone marrow transplant was rejected and the patient died as a result of candida septicemia 3 months after cyclophosphamide treatment (von Bernuth et al, 1980).
c) In a retrospective analysis of cyclophosphamide cardiotoxicity, 80 patients underwent 84 bone marrow transplants, and were scheduled to receive cyclophosphamide 50 mg/kg/day for 4 days in preparation for the bone marrow transplant. Signs and symptoms consistent with congestive heart failure developed in 14 of the 84 transplants within 10 days of receipt of the first dose of cyclophosphamide. Echocardiography confirmed the diagnosis of congestive heart failure in 6 patients. Six of the 14 patients subsequently died, and autopsies performed on 4 of the patients showed evidence consistent with cyclophosphamide cardiotoxicity. Calculations of the cyclophosphamide dose based on body surface area was performed on all patients, and the patients were subsequently divided into two groups: Group 1 with a cyclophosphamide dose of 1.55 g/m(2)/day or less (n=32) and Group 2 with a cyclophosphamide dose of greater than 1.55 g/m(2)/day (n=52). Cardiotoxicity was reported in 1 patient in Group 1 (3%) as compared with 13 patients in Group 2 (25%), and congestive heart failure caused or contributed to the death in 6 patients in Group 2 (12%) as compared with no patient in Group 1, suggesting that the cyclophosphamide dose per body surface area is directly related to the development of cyclophosphamide cardiotoxicity (Goldberg et al, 1986).

D) MYOCARDITIS

1) WITH THERAPEUTIC USE

a) Hemopericardium secondary to hemorrhagic myocarditis and myocardial necrosis has been reported with cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).
b) Fatalities due to diffuse hemorrhagic myocardial necrosis and acute myopericarditis secondary to cyclophosphamide therapy have been reported (Pfizer New Zealand Ltd, 2010).
c) Two cases (one fatal) of severe cyclophosphamide-associated myocarditis have occurred. A 35-year-old man with metastatic testicular cancer received a total of 18.8 grams (g) of cyclophosphamide as part of a high-dose priming regimen for stem cell harvest. In addition to acute renal failure and pulmonary complications, left ventricular wall thickening, decreased ejection fraction (27%) and pericardial effusion were detected 2 weeks after initiation of the priming regimen. The patient died shortly thereafter; necropsy revealed widespread, diffuse hemorrhage of the myocardium (Birchall et al, 2000).

E) PERICARDIAL EFFUSION

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a series of 400 consecutive thalassemic patients receiving bone marrow transplants, 8 (2%) developed cardiac tamponade within a month of the procedure. Preparation for transplantation included cyclophosphamide 200 mg/kg, along with busulfan and cyclosporin. It was suggested that the chemotherapy regimen, alone or in combination with bacteremia or trauma increased the susceptibility to this complication (Angelucci et al, 1992).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 42-year-old man with embryonal rhabdomyosarcoma developed pericardial and moderate bilateral pleural effusion along with severe left-ventricular dysfunction approximately 8 days after receiving an inadvertent total dose of 16.2 g (77 mg/kg over 3 days) of cyclophosphamide. Following supportive care, the patient gradually improved and a repeat echocardiography on day 32 showed a normal left ventricular ejection fraction of 50% and complete resolution of the pericardial and pleural effusions (Bujanda et al, 2006).

Respiratory

3.6.2)

A) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) High dose cyclophosphamide therapy over a prolonged period of time has been associated with the development of interstitial pulmonary fibrosis (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).
b) Shortness of breath may occur and may be a sign of pneumonitis or interstitial pulmonary fibrosis (Segura et al, 2001).
c) CASE REPORT: A 52-year-old woman with breast cancer developed pulmonary fibrosis after 4 cycles of chemotherapy that included cyclophosphamide. After receiving only one cycle of chemotherapy (total cyclophosphamide dose 1.02 g), she developed dyspnea accompanied by cervico-thoracic erythema. Because of the suspicion of carcinomatous lymphangitis, chest X-ray and thoracic and high-resolution CT scans were performed, which revealed a diffuse and bilateral interstitial pattern, most prominently at the bases and middle fields. After receiving the fourth cycle (total cyclophosphamide dose 4.08 g), an open-lung biopsy revealed moderate pulmonary fibrosis with vascular sclerosis and signs of pulmonary hypertension (Segura et al, 2001).
d) Pulmonary fibrosis developed in 79% (15/25) of patients treated with cyclophosphamide 16 to 200 mg/kg (with autologous bone marrow support) and radiotherapy in patients with small cell lung cancer. The authors conclude that very high dose cyclophosphamide appears to sensitize the lung to radiotherapy and promotes the production of fibrosis (Trask et al, 1985).

B) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) Interstitial pneumonitis has been reported with post-marketing surveillance data of cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

C) RESPIRATORY FAILURE

1) WITH THERAPEUTIC USE

a) Four cases of acute respiratory failure, following the development of Pneumocystis carinii pneumonia, have been reported following receipt of combination therapy with daily oral cyclophosphamide and prednisone (Sen et al, 1991).

D) PLEURAL EFFUSION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 42-year-old man with embryonal rhabdomyosarcoma developed respiratory distress, moderate bilateral pleural effusion and severe left-ventricular dysfunction approximately 8 days after receiving an inadvertent total dose of 16.2 g (77 mg/kg over 3 days) of cyclophosphamide. Following supportive care, pulmonary signs and symptoms improved (Bujanda et al, 2006).

E) INJURY OF RESPIRATORY SYSTEM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 35-year-old man, with T-cell lymphoma and pulmonary lymphomatoid granulomatosis, developed acute dyspnea, that lasted for several hours, and died 3 days after beginning chemotherapy consisting of one cycle of cyclophosphamide, epirubicin, and vincristine. An autopsy with histologic examination of the lungs revealed exudative diffuse alveolar damage in the presence of pre-existing bilateral lymphomatoid granulomatosis. It is believed that cyclophosphamide administration may be the causative agent of the diffuse alveolar damage. An infectious etiology was not determined and the other chemotherapeutic agents used are less likely to be associated with pulmonary toxicity (Woolley et al, 1997).

Neurologic

3.7.2)

A) FATIGUE

1) WITH THERAPEUTIC USE

a) Fatigue and weakness have been reported during post-marketing surveillance of cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache has been reported with cyclophosphamide therapy (Pfizer New Zealand Ltd, 2010).

Gastrointestinal

3.8.2)

A) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea may occur (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

2) WITH POISONING/EXPOSURE

a) Diarrhea has been reported following cyclophosphamide overdose (Uner et al, 2005).

B) HEMORRHAGIC COLITIS

1) WITH THERAPEUTIC USE

a) Hemorrhagic colitis has occurred during therapy and will generally subside following discontinuation of cyclophosphamide therapy (Prod Info cyclophosphamide oral tablets, 2007; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

C) ULCER OF MOUTH

1) WITH THERAPEUTIC USE

a) Oral mucosal ulceration has been reported with cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

D) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting may occur following cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting have been reported following cyclophosphamide overdose (Uner et al, 2005).

E) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal discomfort or pain may occur with cyclophosphamide therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

2) WITH POISONING/EXPOSURE

a) Abdominal pain has been reported following cyclophosphamide overdose (Uner et al, 2005).

Hepatic

3.9.2)

A) LIVER FUNCTION TESTS ABNORMAL

1) WITH THERAPEUTIC USE

a) Hepatic function is rarely altered in patients receiving cyclophosphamide. Most cases involve patients with systemic rheumatic disease (systemic lupus erythematosus (SLE) or polymyositis) receiving dosages of 1 to 2 mg/kg/day resulting in jaundice and elevation of liver function tests. Discontinuation of the drug results in normalization of liver function tests within 4 to 5 weeks (Cleland & Pokorny, 1993; Shaunak et al, 1988; Goldberg & Lidsky, 1985; Sotaniemi et al, 1983; Bacon & Rosenberg, 1982).

B) ACUTE HEPATITIS

1) WITH THERAPEUTIC USE

a) Acute hepatitis was attributed to continuous low-dose cyclophosphamide for the treatment of Sjorgren's syndrome in a 67-year-old man. He had received 100 milligrams (mg)/day for 6 months, then 50 mg/day for 12 months, then 50 mg every other day for 6 months, for an approximate total cumulative dose of 40.5 grams over 2 years. The patient then presented with jaundice and elevated liver function tests. Liver biopsy revealed hepatocyte ballooning, cell loss, cholestasis and inflammatory cell infiltration of the portal tracts, which was consistent with drug-induced acute hepatitis. With cyclophosphamide discontinuation, hepatitis resolved completely within 6 weeks (Mok et al, 2000).

Genitourinary

3.10.2)

A) HEMORRHAGIC CYSTITIS

1) WITH THERAPEUTIC USE

a) Hemorrhagic cystitis is reported to be the dose-limiting side effect of high-dose cyclophosphamide and can be fatal (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005). It has occurred in up to 40% patients (particularly children) on long-term therapy (Pfizer New Zealand Ltd, 2010). Hematuria or dysuria may be signs of hemorrhagic cystitis (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005), and usually resolve within a few days after discontinuation of therapy; however, symptoms have been reported to persist up to 6 months after therapy cessation (Pfizer New Zealand Ltd, 2010).
b) UROEPITHELIAL TOXICITY: A 72-year-old woman developed hematuria and dysuria after receiving a cumulative oral cyclophosphamide dose of 1.4 grams over 2 weeks as treatment for relapse of the granulomatosis. Renal ultrasonography revealed mild hydroureteronephrosis. In addition, marked irregularity of the mucosa of the upper ureter, renal pelvis, and calyces were noted in retrograde ureteropyelography (Aviles et al, 1999).
c) Cyclophosphamide-induced pyelitis, ureteritis, and cystitis occurred in a 29-year-old woman with stage IIIB Hodgkin's disease receiving cyclophosphamide (4800 mg/m(2)) in preparation for bone marrow transplantation. Three months after transplantation, the patient developed left flank pain and severe hematuria resulting in death. Postmortem examination revealed acute hemorrhagic cystitis, acute pyelitis, with blood clots in both ureters and renal pelves and ureteritis. The authors conclude that cyclophosphamide-induced urothelial damage is not limited to the bladder (Efros et al, 1990).

2) WITH POISONING/EXPOSURE

a) Hemorrhagic cystitis may occur in an overdose situation (Palma et al, 1986)

B) MALIGNANT TUMOR OF URINARY BLADDER

1) WITH THERAPEUTIC USE

a) Secondary bladder cancer is related to total cumulative dose of cyclophosphamide (Pedersen-Bjergaard et al, 1988; Levine & Richie, 1989).

C) ACUTE TUBULAR NECROSIS

1) WITH THERAPEUTIC USE

a) Renal tubular necrosis and hemorrhagic ureteritis have occurred with cyclophosphamide therapy, and appear to resolve following discontinuation of therapy (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

Hematologic

3.13.2)

A) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Aplastic anemia is a rare occurrence with therapeutic regimens (Cosimi et al, 1982).

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Leukopenia is a prominent effect and occurs with a nadir of 7 to 14 days. Recovery is generally observed in 3 to 4 weeks (Pfizer New Zealand Ltd, 2010; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

C) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Thrombocytopenia may occur but the incidence is less frequent than leukopenia. Nadirs occur 10 to 15 days following exposure (Pfizer New Zealand Ltd, 2010; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

D) MYELOSUPPRESSION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 42-year-old man with embryonal rhabdomyosarcoma developed severe myelosuppression and cardiac toxicity following an inadvertent total dose of 16.2 g (77 mg/kg over 3 days) of cyclophosphamide. Leukocytes were 0.023 x 10(9)/L, absolute neutrophil count (ANC) 0.0018 x 10(9)/L, hemoglobin 9.8 g/dL and platelets 5.3 x 10(9)/L 8 days after exposure. Following supportive care the patient recovered (Bujanda et al, 2006).
b) CASE REPORT: A 23-year-old woman with diffuse large-cell lymphoma received cumulative doses of cyclophosphamide 6000 mg, doxorubicin 420 mg, and vincristine 12 mg over 6 consecutive days (instead of 6 cycles), and developed nausea, vomiting, abdominal pain, diarrhea, paralytic ileus, pancytopenia, fever, neuropathies (due to vincristine therapy), blurred vision, and neurogenic bladder. Following supportive care, including antibiotic therapy, granulocyte colony stimulating factor, and platelet transfusion, she recovered and was discharged after 25 days (Uner et al, 2005).

Dermatologic

3.14.2)

A) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia is a common occurrence with cyclophosphamide therapy, and generally occurs approximately 3 weeks after beginning therapy (Pfizer New Zealand Ltd, 2010; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

B) NAIL FINDING

1) WITH THERAPEUTIC USE

a) Nail changes (ie, transverse ridging, retarded growth, fingernail pigmentation) have occurred with cyclophosphamide therapy (Pfizer New Zealand Ltd, 2010; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

C) DISCOLORATION OF SKIN

1) WITH THERAPEUTIC USE

a) Skin hyperpigmentation has been reported (Pfizer New Zealand Ltd, 2010; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

D) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) Stevens-Johnson syndrome and toxic epidermal necrolysis have been rarely reported during post-marketing surveillance of cyclophosphamide therapy; however, a causal relationship has not been definitively established (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

E) IMPAIRED WOUND HEALING

1) WITH THERAPEUTIC USE

a) Treatment with cyclophosphamide may result in impaired wound healing (Prod Info cyclophosphamide oral tablets, 2007; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

F) FLUSHING

1) WITH THERAPEUTIC USE

a) Facial flushing has been reported with cyclophosphamide therapy (Pfizer New Zealand Ltd, 2010).

Endocrine

3.16.2)

A) ABNORMAL ANTI-DIURETIC HORMONE

1) WITH THERAPEUTIC USE

a) A syndrome resembling syndrome of inappropriate antidiuretic hormone (SIADH) may be noted (Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).
b) Water intoxication occurred in an 8-year-old boy following cyclophosphamide therapy (50 mg/kg/day for 4 doses) in preparation for a bone marrow transplant. A 30-second tonic-clonic seizure occurred 18 hours after the initial dose of cyclophosphamide; serum sodium had dropped from 135 mEq/L in the morning to 120 mEq/L obtained after the seizure in the afternoon. Fluid restriction (1000 mL/m(2)/24 hours) resulted in a normalization of the serum sodium level within 24 hours without further incident (Haas et al, 1986).
c) Water intoxication was described in a 54-year-old woman receiving cyclophosphamide 20 mg/kg intravenously monthly for the treatment of SLE as well as in five other patients with multiple sclerosis receiving moderate doses between 15 to 20 mg/kg IV (Bressler & Huston, 1985).

2) WITH POISONING/EXPOSURE

a) SIADH was reported following cyclophosphamide overdose (Uner et al, 2005).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Anaphylaxis was reported in a 36-year-old woman receiving her second course of cyclophosphamide. The patient was successfully treated with epinephrine and diphenhydramine. The patient was not rechallenged (Jones & Purdy, 1989).
b) Anaphylactic reactions, including fatal anaphylaxis, have been reported. Possible cross-sensitivity with other alkylating agents has been reported (Prod Info cyclophosphamide oral tablets, 2007; Prod Info CYTOXAN(R) IV, IM, intraperitoneal, intrapleural injection, oral tablets, 2005).

Reproductive

3.20.1)

3.20.2)

A) EMBRYOTOXICITY

1) Miscarriage has been reported after first-trimester exposure (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

B) CONGENITAL ANOMALY

1) Fetal malformations (eg, malformations of the skeleton, palate, limbs, and eyes) have been reported after first-trimester exposure to cyclophosphamide (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) Congenital abnormalities were reported for 2 infants and a 6-month-old fetus who were exposed to cyclophosphamide. The abnormalities included ectrodactylia in 2 of the 3 cases (Kirshon et al, 1988; Murray et al, 1984).
3) Multiple anomalies occurred in a neonate born to a 25-year-old woman treated with cyclophosphamide during the first trimester of pregnancy. The patient received cyclophosphamide 200 mg IV on 2 occasions for exacerbation of systemic lupus erythematosus. At 39 weeks, the patient delivered a 3150 gram female who had dysmorphic facies, abnormally shaped ears, absent thumbs, a submucous cleft of the soft palate, and dystrophic nails. Additionally, multiple eye malformations, borderline microcephaly, hypotonia, and possible developmental delay were observed (Kirshon et al, 1988).

C) UROGENITAL ABNORMALITIES

1) Administration of doxorubicin 325 mg (total) and cyclophosphamide 2.1 grams (total) with cobalt during the first trimester of pregnancy resulted in the birth of a small neonate with an imperforate anus and rectovaginal fistula, which were corrected by surgery (Murray et al, 1984).

D) LACK OF EFFECT

1) Cyclophosphamide use during the second and third trimesters may present a lower risk of congenital malformations (King et al, 1991; Blatt et al, 1980)
2) CASE SERIES: Of 11 relapsing-remitting multiple sclerosis patients between the ages of 22 and 36 years and treated with cyclophosphamide before conception, 10 successfully gave birth to children free of birth defects, while 1 performed a voluntary abortion. All 10 children have correctly achieved developmental milestones and there have been no reports of malignancies. The patients received an average cumulative cyclophosphamide dose of 19,109 mg (8400 to 51,700 mg) over an average of 19 doses (6 to 33 doses), and the time from last cyclophosphamide dose to conception was an average of 3.7 years (0.33 to 5.9 years). They were also treated with leuprorelin every 3 months to induce a temporary menopause and to prevent ovarian failure. Five patients delivered preterm (before gestational week 37), and one of the preterm infants was small for gestational age (below the 10th percentile). The mothers who delivered preterm received a mean cumulative cyclophosphamide dose of 13,960 mg over an average of 17 doses, and their mean time from last cyclophosphamide dose to conception was 34.5 months. The mother of the small infant received a total of 19,350 mg of cyclophosphamide over 24 doses, and her time from last cyclophosphamide dose to conception was 72.1 months (Patti et al, 2014).
3) CASE REPORT: A 33-year-old patient treated with 5 courses of the FEC regimen (5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks) during the first 28 weeks of pregnancy subsequently delivered a healthy infant at week 35 of gestation. She was not pregnant when diagnosed with locally advanced malignant neoplasm of the left breast. After complaining of dilatation and bloating of the abdomen, an ultrasound showed a pregnancy of 28 weeks gestation. The 2070 gram infant, delivered by cesarean section and without complications, was developing normally at 1 year of age (Andreadis et al, 2004).
4) CASE REPORT: A 40-year-old primigravida found to have ovarian cancer at 17 weeks of gestation delivered a normal infant after receiving cisplatin/carboplatin and cyclophosphamide at 20 weeks of gestation. At 36 weeks, a 3600 gram infant was delivered with APGAR scores of 9/9. Cisplatin-DNA adducts were found in amniotic cells and in placental tissue, but not in the infant's blood at 3 and 12 months of age. Growth, neurologic findings, hematologic parameters, and renal function were normal in the infant at 12 months of age (Henderson et al, 1993).

E) ANIMAL STUDIES

1) MICE, RATS, RABBITS, AND MONKEYS

a) Animal studies showed pregnant mice, rats, rabbits, and monkeys administered cyclophosphamide during organogenesis at doses at or below the dose in humans based on body surface area had offspring with various malformations, including neural tube defects, cleft lip and palate, limb and digit defects, reduced skeletal ossification, and other skeletal anomalies (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified cyclophosphamide as FDA pregnancy category D (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) Advise the patient of the potential harm to a fetus that may occur if cyclophosphamide is used during pregnancy or if the patient becomes pregnant while taking the drug (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013). Cyclophosphamide should be avoided in young women who plan to become pregnant (Patti et al, 2014).

B) FETAL GROWTH RETARDATION AND TOXIC EFFECTS

1) Fetal growth retardation and toxic effects (eg, leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis) have been reported in the newborn after exposure to cyclophosphamide (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

C) MATERNAL ADVERSE EFFECTS

1) During a retrospective study of women with systemic lupus erythematosus, the incidence of amenorrhea (transient or sustained) was significantly higher in women administered IV cyclophosphamide compared with women in the non-IV cyclophosphamide group (28.2% vs 2.3%). The infertility rate amongst women receiving IV cyclophosphamide was higher compared with those not receiving IV cyclophosphamide (51.5% vs 41.8%). Of the 90 pregnancies reported in the IV cyclophosphamide group, 29 resulted in fetal loss and 61 resulted in live births. In the non-IV cyclophosphamide group, of 293 pregnancies, 85 resulted in fetal loss and 208 resulted in live births. There was no difference in the rate of fetal loss, live births, or intrauterine growth retardation between the IV cyclophosphamide and non-IV cyclophosphamide groups; however, there was a significant increase in preterm births amongst the IV cyclophosphamide group compared with the non-IV cyclophosphamide group (Alarfaj & Khalil, 2014).

3.20.4)

A) BREAST MILK

1) Cyclophosphamide is excreted in breast milk (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013). Possible adverse effects of cyclophosphamide on the breastfed infant suggested by the American Academy of Pediatrics include immune suppression, carcinogenesis, and unknown effects on growth (Anon, 2001). Infants who were breastfed by mothers treated with cyclophosphamide have experienced neutropenia, thrombocytopenia, low hemoglobin, and diarrhea. Due to the potential for serious adverse reactions in nursing infants exposed to cyclophosphamide, it is recommended to either discontinue nursing or to discontinue the drug, after considering the importance of the drug to the mother (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) CASE REPORT: Cyclophosphamide 6 mg/kg (total dose 300 mg) IV daily for 3 days to a lactating patient resulted in severely depressed leukocyte and platelet counts in her 23-day-old infant. The breast milk concentration of the drug was considered to be sufficient to be toxic to the infant's bone marrow. Quantitative data were not available (Durodola, 1979).
3) CASE REPORT: A case of neutropenia in a breastfed infant was reported after the mother was treated with cyclophosphamide, vincristine, and prednisone (Amato & Niblett, 1977).
4) CASE REPORT: Cyclophosphamide is distributed in human milk. One case report describes a patient who received a single IV dose of cyclophosphamide (500 mg) eight months postpartum. Unmetabolized cyclophosphamide was detected in breast milk samples collected at 1, 3, 5, and 6 hours after the injection. Quantitative data were not given. The authors recommended that women not breastfeed while being treated with cyclophosphamide (Wiernik & Duncan, 1971).

3.20.5)

A) AMENORRHEA

1) Cyclophosphamide may cause amenorrhea from decreased estrogen and increased gonadotropin secretion, although patients generally resume regular menses within a few months after treatment is discontinued. Patients who are treated during prepubescence will frequently develop secondary sexual characteristics normally and have regular menses (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

B) GONADAL SUPPRESSION

1) Gonadal suppression has been reported with cyclophosphamide, which interferes with oogenesis and spermatogenesis and causes sterility in both sexes. The degree of sterility seems to depend on dose, duration, and state of gonadal function at the time of therapy. The sterility may be irreversible for some patients (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) Men exposed to cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin secretion but normal testosterone secretion Testicular atrophy has also been reported. Patients who are treated during prepubescence will frequently develop secondary sexual characteristics normally, but may have oligospermia, azoospermia, and increased gonadotropin secretion. The azoospermia is reversible, although it make take several years after therapy is discontinued (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

C) OVARIAN FIBROSIS

1) Young females have experienced ovarian fibrosis with a complete loss of germ cells after prolonged cyclophosphamide therapy during late prepubescence (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS50-18-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Cyclophosphamide
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

3.21.3)

A) SECONDARY MALIGNANCIES

1) Cyclophosphamide may cause secondary malignancies when used alone or together with other antineoplastic agents and/or oncology modalities. These include urinary bladder, myeloproliferative, or lymphoproliferative malignancies in patients who primarily were treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant diseases where an immune process was felt to be involved. Case reports of secondary malignancies have also been reported in patients who received cyclophosphamide-containing regimens for various solid tumors. The secondary malignancy may develop several years after cyclophosphamide is discontinued (Prod Info cyclophosphamide intravenous injection, oral tablets, 2012).
2) ACUTE MYELOID LEUKEMIA

a) Acute myeloid leukemia occurred in a small number of patients within 2 years after treatment initiation with 2 to 4 times the standard dose of cyclophosphamide plus doxorubicin for breast cancer (Prod Info cyclophosphamide intravenous injection, oral tablets, 2012).
b) A cyclophosphamide dose of 46.35 g over a one year period was associated with an 11.1% cumulative risk for leukemia after a 10-year follow-up period. The cumulative risk for control patients was 0.1%. According to linear extrapolation from high to low dose, the excess lifetime risk of leukemia at age 80 for exposure during a 40-year period was approximately 1.04 per million oncology nurses. The excess lifetime leukemia risk in the worst case dermal exposure scenario was 154 per million oncology nurses (Fransman et al, 2014).

3) BLADDER CARCINOMA

a) Cyclophosphamide has caused urinary bladder malignancies in patients who previously had hemorrhagic cystitis (Prod Info cyclophosphamide intravenous injection, oral tablets, 2012); the risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
b) Secondary bladder cancer is related to total cumulative dose of cyclophosphamide (Pedersen-Bjergaard et al, 1988; Levine & Richie, 1989).

4) LYMPHOMA

a) Secondary lymphomas have been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

5) MYELODYSPLASIA

a) Secondary myelodysplasia has been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

6) RENAL CELL CARCINOMA

a) Secondary renal cell carcinoma has been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

7) RENAL PELVIS CARCINOMA

a) Renal pelvis carcinoma was reported in a patient with cerebral vasculitis who received long-term cyclophosphamide therapy (Prod Info cyclophosphamide intravenous injection, oral tablets, 2012).

8) SARCOMA

a) Secondary sarcomas have been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

9) THYROID CANCER

a) Secondary thyroid cancer has been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

10) URETERIC CANCER

a) Secondary ureteric cancer has been reported in patients treated with cyclophosphamide-containing regimens (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

3.21.4)

A) BREAST CANCER

1) Benign and malignant mammary gland tumors were detected in mice and rats who received cyclophosphamide in drinking water or by IV, subQ or intraperitoneal injection (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

B) LIVER CANCER

1) Benign and malignant liver tumors were detected in mice and rats who received cyclophosphamide in drinking water or by IV, subQ or intraperitoneal injection (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

C) LUNG CANCER

1) Benign and malignant lung tumors were detected in mice and rats who received cyclophosphamide in drinking water or by IV, subQ or intraperitoneal injection (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

D) SKIN CANCER

1) Benign and malignant injection site tumors were detected in mice and rats who received cyclophosphamide by IV, subQ or intraperitoneal injection (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serial CBC with differential and platelet count until there is evidence of bone marrow recovery. Neutrophil and platelet nadirs typically occur 7 to 15 days following therapeutic doses and recovery is generally in 3 to 4 weeks. Monitor for signs of bleeding.
B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
C) Monitor vital signs and mental status.
D) Monitor BUN, serum electrolytes, serum creatinine, and liver enzymes.
E) Monitor urinalysis (for hemorrhagic cystitis) and urine output.
F) Obtain a chest radiograph and ECG in patients with cardiopulmonary complaints.
G) Cyclophosphamide concentrations can be performed but are not likely to be available in a timely manner and cannot be used to guide therapy.

4.1.2)

A) HEMATOLOGIC

1) Monitor serial CBC with differential and platelet count until there is evidence of bone marrow recovery.
2) Anemia, leukopenia, and thrombocytopenia have been reported in patients receiving cyclophosphamide. The WBC/neutrophil nadir typically occurs 7 to 14 days following receipt of a single dose, and recovery occurs within 3 to 4 weeks. Thrombocytopenia occurs less frequently, with nadirs appearing 10 to 15 days following cyclophosphamide administration (Pfizer New Zealand Ltd, 2010)

B) BLOOD/SERUM CHEMISTRY

1) Monitor BUN, serum electrolytes, serum creatinine, and liver enzymes.
2) Cyclophosphamide concentrations can be performed but are not likely to be available in a timely manner and cannot be used to guide therapy.

4.1.3)

A) URINALYSIS

1) Monitor urinalysis for hemorrhagic cystitis.
2) Monitor urine output and specific gravity to detect possible SIADH.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status.
b) Obtain a chest radiograph and ECG in patients with cardiopulmonary complaints.
c) Monitor for signs of infection or bleeding.

2) OTHER

a) Unmetabolized cyclophosphamide was found in 12 of 31 24-hour urine samples collected from hospital personnel preparing dosage formulations, in spite of using gloves and laminar flow hoods. Total excretion ranged from 3.5 to 38 micrograms per 24 hours (Ensslin et al, 1994).

Radiographic Studies

1) Chest x-ray may be of value if pulmonary toxicity is suspected.

Methods

1) Cyclophosphamide can be quantitated in urine samples by gas chromatography with electron capture detection (Ensslin et al, 1994).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any symptomatic patient and any high dose parenteral overdoses should be admitted to the hospital, and depending on the severity of their symptoms, either to the floor or ICU. Criteria for discharge should be resolution of symptoms and laboratory abnormalities.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no data to support home management. Even inadvertent exposures via oral ingestion that are asymptomatic should be sent in for charcoal administration to prevent further sequelae. All intentional overdoses should be sent in for evaluation.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.

6.3.1.4) PATIENT TRANSFER/ORAL

A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Exposed patients should be evaluated and observed for 6 hours. If patients are asymptomatic for 6 hours, they may be sent home, but toxic effects may be delayed, so patients should return to a health care provider for any symptoms and should have blood work monitored as an outpatient (eg, CBC for myelosuppression).

Monitoring

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) MONITORING OF PATIENT

1) Monitor serial CBC with differential and platelet count until there is evidence of bone marrow recovery. Neutrophil and platelet nadirs typically occur 7 to 15 days following therapeutic doses and recovery is generally in 3 to 4 weeks. Monitor for signs of bleeding.
2) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
3) Monitor vital signs and mental status.
4) Monitor BUN, serum electrolytes, serum creatinine, and liver enzymes.
5) Monitor urinalysis (for hemorrhagic cystitis) and urine output.
6) Obtain a chest radiograph and ECG in patients with cardiopulmonary complaints.
7) Cyclophosphamide concentrations can be performed but are not likely to be available in a timely manner and cannot be used to guide therapy.

B) MYELOSUPPRESSION

1) Neutropenia, anemia, and thrombocytopenia have been reported in patients receiving cyclophosphamide. The WBC/neutrophil nadir typically occurs 7 to 14 days following receipt of a single dose, and recovery occurs within 3 to 4 weeks. Thrombocytopenia occurs less frequently, with nadirs appearing 10 to 15 days following cyclophosphamide administration (Pfizer New Zealand Ltd, 2010).
2) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). They should be administered to any patient who receives a cyclophosphamide overdose.
3) Patients with severe neutropenia should be in protective isolation. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Transfer to a bone marrow transplant center should be considered.

C) NEUTROPENIA

1) COLONY STIMULATING FACTORS

a) DOSING

1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
3) The preferred route of administration is subcutaneous (Smith et al, 2006).

2) HIGH-DOSE THERAPY

a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours, or as a continuous 24 hour subQ infusion. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010):

1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.

c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010).
d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).

3) SPECIAL CONSIDERATIONS

a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).

4) ANTIBIOTIC PROPHYLAXIS

a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).

D) FEBRILE NEUTROPENIA

1) SUMMARY

a) Due to the risk of potentially severe neutropenia following overdose with cyclophosphamide, all patients should be monitored for the development of febrile neutropenia.

2) CLINICAL GUIDELINES FOR ANTIMICROBIAL THERAPY IN NEUTROPENIC PATIENTS WITH CANCER

a) SUMMARY: The following are guidelines presented by the Infectious Disease Society of America (IDSA) to manage patients with cancer that may develop chemotherapy-induced fever and neutropenia (Freifeld et al, 2011).
b) DEFINITION: Patients who present with fever and neutropenia should be treated immediately with empiric antibiotic therapy; antibiotic therapy should broadly treat both gram-positive and gram-negative pathogens (Freifeld et al, 2011).
c) CRITERIA: Fever (greater than or equal to 38.3 degrees C) AND neutropenia (an absolute neutrophil count (ANC) of less than or equal to 500 cells/mm(3)). Profound neutropenia has been described as an ANC of less than or equal to 100 cells/mm(3) (Freifeld et al, 2011).
d) ASSESSMENT: HIGH RISK PATIENT: Anticipated neutropenia of greater than 7 days, clinically unstable and significant comorbidities (ie, new onset of hypotension, pneumonia, abdominal pain, neurologic changes). LOW RISK PATIENT: Neutropenia anticipated to last less than 7 days, clinically stable with no comorbidities (Freifeld et al, 2011).
e) LABORATORY ANALYSIS: CBC with differential leukocyte count and platelet count, hepatic and renal function, electrolytes, 2 sets of blood cultures with a least a set from a central and/or peripheral indwelling catheter site, if present. Urinalysis and urine culture (if urinalysis positive, urinary symptoms or indwelling urinary catheter). Chest x-ray, if patient has respiratory symptoms (Freifeld et al, 2011).
f) EMPIRIC ANTIBIOTIC THERAPY: HIGH RISK patients should be admitted to the hospital for IV therapy. Any of the following can be used for empiric antibiotic monotherapy: piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK patients should be placed on an oral empiric antibiotic therapy (ie, ciprofloxacin plus amoxicillin-clavulanate), if able to tolerate oral therapy and observed for 4 to 24 hours. IV therapy may be indicated, if patient poorly tolerating an oral regimen (Freifeld et al, 2011).

1) ADJUST THERAPY: Adjust therapy based on culture results, clinical assessment (ie, hemodynamic instability or sepsis), catheter-related infections (ie, cellulitis, chills, rigors) and radiographic findings. Suggested therapies may include: vancomycin or linezolid for cellulitis or pneumonia; the addition of an aminoglycoside and switch to carbapenem for pneumonia or gram negative bacteremia; or metronidazole for abdominal symptoms or suspected C. difficile infection (Freifeld et al, 2011).
2) DURATION OF THERAPY: Dependent on the particular organism(s), resolution of neutropenia (until ANC is equal or greater than 500 cells/mm(3)), and clinical evaluation. Ongoing symptoms may require further cultures and diagnostic evaluation, and review of antibiotic therapies. Consider the use of empiric antifungal therapy, broader antimicrobial coverage, if patient hemodynamically unstable. If the patient is stable and responding to therapy, it may be appropriate to switch to outpatient therapy (Freifeld et al, 2011).

g) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011):

1) GRAM-POSITIVE PATHOGENS: Coagulase-negative staphylococci, S. aureus (including MRSA strains), Enterococcus species (including vancomycin-resistant strains), Viridans group streptococci, Streptococcus pneumoniae and Streptococcus pyrogenes.
2) GRAM NEGATIVE PATHOGENS: Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, Acinetobacter species, and Stenotrophomonas maltophilia.

h) HEMATOPOIETIC GROWTH FACTORS (G-CSF or GM-CSF): Prophylactic use of these agents should be considered in patients with an anticipated risk of fever and neutropenia of 20% or greater. In general, colony stimulating factors are not recommended for the treatment of established fever and neutropenia (Freifeld et al, 2011).

E) VOMITING

1) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING

a) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
b) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
c) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
d) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
e) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
f) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
g) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).

F) HEMORRHAGIC CYSTITIS

1) SUMMARY: Glutathione, 2-mercaptoethane sulfonate (MESNA), N-acety-L-cysteine (NAC) and other thiol compounds are being studied for use as uroprotective agents. MESNA and NAC appear to be uroprotective in various investigations.
2) MESNA

a) During randomized controlled trials, MESNA was given to patients undergoing bone marrow transplantation, and who received high-dose cyclophosphamide therapy, by IV bolus dose equal to 40% of the cyclophosphamide dose (w/w), given immediately following exposure, then at 3, 6, and 9 hours (Hensley et al, 1999; Shepherd et al, 1991; Hows et al, 1984) plus IV fluids 1.5 L/m(2)/day (Hensley et al, 1999).

1) In another study, MESNA was given investigationally by intravenous bolus injection at 30 milligrams/kilogram/day in four equal doses. The first dose is given immediately after and at three, six, and nine hours after cyclophosphamide.

a) In this study cyclophosphamide was dosed at 50 milligrams/kilogram/day for 4 days intravenously. This represents a 60% (w/w) MESNA dose compared to cyclophosphamide (Finn & Sidau, 1986).

3) FLUID INTAKE: May be necessary and should be maintained at 3 to 4 liters per day. Use of a diuretic and alkalinization of the urine may be of benefit.
4) FORMALIN: If hemorrhagic cystitis is present and the presentation is less severe, instillation of 5% to 10% formalin may be of value to control bleeding (Garat et al, 1985).
5) CONJUGATED ESTROGEN CASE REPORT: A patient with severe cyclophosphamide-induced hemorrhagic cystitis failed to respond to formalin therapy. Hematuria decreased one day after initiation of conjugated estrogen 5 milligrams/day orally. By the fourth day, the urine color normalized. Estrogen was continued at 1.25 milligrams/day for the next 12 months with no recurrence of hematuria. Decreased vascular fragility was the proposed mechanism (Liu et al, 1990). It is not clear that the resolution of hematuria was related to estrogen administration.
6) HYPERBARIC OXYGEN CASE REPORT: A 40-year-old woman with systemic lupus erythematosus and on cyclophosphamide therapy for 4 years, developed intermittent episodes of gross hematuria over a 2-year-period. Cystoscopy indicated urinary bladder mucosa diffuse sloughing with active bleeding. Bleeding persisted despite several attempts at cauterization of the bleeding points. The patient then underwent 28-day hyperbaric oxygen therapy (100% oxygen at 2.5 atmospheres chamber pressure for 120 minutes daily), and the bleeding decreased, with complete resolution after a second 28-day course. A six-month follow-up period indicated no recurrence of the hematuria. It is not clear that the hyperbaric oxygen was responsible for resolution of her hematuria (Jou et al, 2008).

G) SYNDROME OF INAPPROPRIATE VASOPRESSIN SECRETION

1) Treatment of SIADH is supportive. If drug-induced, discontinue the causative agent and restrict fluids to 1000 milliliters per day or less.
2) For more rapid correction of fluids and electrolytes hypertonic saline with furosemide is the treatment of choice. Dosing should be adjusted to achieve a negative fluid balance. Furosemide inhibits free water reabsorption more than it increases sodium, potassium, and chloride excretion.
3) To replace fluid loss hypertonic saline alone or with potassium, chloride may be used.

H) STOMATITIS

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Patients who are receiving myelosuppressive therapy may receive prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection (Bensinger et al, 2008). Consider using palifermin in patients with severe neutropenia and mucositis (Hensley et al, 2009); usual adult dose 60 mcg/kg/day IV bolus for 6 consecutive days (Prod Info KEPIVANCE(TM) IV injection, 2005).
2) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.
3) PALIFERMIN

a) Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis. (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). In patients with severe cyclophosphamide overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

I) APLASTIC ANEMIA

1) Aplastic anemia is only rarely encountered with therapeutic regimens. When other treatments fail lymphocyte immune globulin, antithymocyte globulin (Atgam(R)-Upjohn) may be of benefit.
2) PROTOCOL: A proposed protocol is for daily intravenous infusion of 10 to 15 milligrams/kilogram/day for 14 days. This may be followed by 2 more weeks of alternate day therapy. Response may be delayed, improvement of blood counts may occur 1 to 3 months post-treatment (Cosimi et al, 1982).

J) EXTRAVASATION INJURY

1) Cyclophosphamide is classified as a neutral agent by one source (Gippsland Oncology Nurses Group, 2010). Another classified it as an irritant (The University of Kansas Hospital, 2009).
2) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer sodium thiosulfate (see dosing below). Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Another source recommended warm/heat compresses for local reaction. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy (The University of Kansas Hospital, 2009; Gippsland Oncology Nurses Group, 2010; Wengstrom et al, 2008; National Institutes of Health Clinical Center Nursing Department, 1999; Bellin et al, 2002; Cohan et al, 1996; Upton et al, 1979; Brown et al, 1979; Banerjee et al, 1987; Chait & Dinner, 1975; Dorr & Fritz, 1980; Hirsh & Conlon, 1983; Hoff et al, 1979; Ignoffo & Friedman, 1980; Larson, 1982; Loth & Eversmann, 1986; Lynch et al, 1979; Upton et al, 1979a; Yosowitz et al, 1975).
3) SODIUM THIOSULFATE (SODIUM HYPOSULFITE) 10%: Prepare a 0.17 moles/L solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject into extravasation site (Fenchel & Karthaus, 2000).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) INITIAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

B) DISPOSAL GUIDELINES

1) LABELING: Cytotoxic waste should be regarded as HAZARDOUS or TOXIC waste. It must be handled differently from other trash and should be clearly labeled "HAZARDOUS CHEMICAL WASTE - DISPOSE OF PROPERLY" (Anon, 1990).
2) CONTAINER: Cytotoxic waste may be placed in a leakproof, puncture resistant container which is then placed in disposable wire-tie or sealable 4-mil-thick polyethylene or 2-mil-thick propylethylene bags. These bags should be colored so as to be easily distinguishable from other trash bags, and labeled with a "Cytotoxic Hazard" label (Jeffrey LP, Anderson RW & Fortner CL et al, 1984; Anon, 1986).
3) SPILL PROCEDURE: Spills should be cleaned up immediately by a person trained in such procedures and wearing appropriate protective clothing (commercial spill kits are available) (Anon, 1990). The area of the spill should be marked so that while cleanup is occurring someone in the area is not accidentally contaminated. Broken glass should be carefully removed possibly by using a scoop. A broom or mop is not advised due to the risk of further contamination of the environment.
4) DISPOSAL: Cytotoxic waste may be disposed of at an EPA permitted hazardous waste incinerator, an EPA permitted hazardous waste burial site, or by a licensed hazardous waste disposal company and in accordance with all applicable state, federal, and local regulations (Anon, 1990; Jeffrey LP, Anderson RW & Fortner CL et al, 1984).

C) SMALL SPILL CLEANUP

1) SUMMARY: Small spills (less than 5 milliliters or 5 grams) should be cleaned immediately by personnel wearing double surgical latex gloves, disposable gown, a face shield or splash goggles and a dust/mist respirator mask (Anon, 1986; Chasse & Gaudet, 1992; Peters, 1995).

a) CLEAN UP PROCEDURE: Liquids should be adsorbed with gauze pads; solids should be wiped up with wet absorbent gauze (Anon, 1986).
b) DECONTAMINATION: The spill area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
c) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).

D) LARGE SPILL CLEANUP

1) SUMMARY: Large spills (greater than 5 milliliters or 5 grams) should be covered immediately with absorbent sheets or spill control pads to reduce the spread. If a powder was spilled use a damp cloth or towel (Anon, 1986).

a) SECURE AREA: Restrict access to the spill area and take precautions to minimize the generation of aerosols (Anon, 1986).
b) PERSONNEL PROTECTION: Protective clothing should be worn as with the small spill with the addition of a respirator or breathing apparatus when there is an airborne contamination danger (Anon, 1986).
c) DECONTAMINATION: The area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
d) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).

E) PERSONNEL PROTECTION

1) PROTECTIVE CLOTHING: A double layer of disposable surgical latex gloves, protective disposable gowns (non-permeable, made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs) with cuff tucked into glove, eye protection (splash goggles), breathing apparatus, in ventilated cabinets when there is airborne contamination danger (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a; Anon, 1986).
2) DECONTAMINATION/CLOTHING: Laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. DISPOSAL: The appropriate procedure for the disposal of these materials should be determined by the institution (or as required by state or local regulation or disposal contractor) (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a).

Enhanced Elimination

1) Cyclophosphamide and its metabolites are moderately dialyzable (20% to 50%) but there are no reports of dialysis after overdose.

a) One study showed removal of cyclophosphamide by hemodialysis to be approximately 36 percent (Wang et al, 1981). This study did not look at the removal of the active metabolites, only the prodrug.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) INITIAL DOSE

1) 40 to 50 mg/kg is given IV in a divided dose over 2 to 5 days, or 1 to 5 mg/kg/day orally (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

B) MAINTENANCE THERAPY

1) 1 to 5 mg/kg/day orally (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) 10 to 15 mg/kg IV every 7 to 10 days (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
3) 3 to 5 mg/kg IV twice weekly (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013) .

C) BONE MARROW TRANSPLANT

1) In a review of allogenic bone marrow transplantation in the treatment of hematologic disease, cyclophosphamide was used in the preparative regimens prior to the marrow infusion to suppress the immune system of the recipients so the graft was not rejected. Typical doses were 50 mg/kg x 4 doses (aplastic anemia) or 60 mg/kg x 2 doses (acute leukemia or chronic myelogenous leukemia) (Yee & McGuire, 1985).

7.2.2)

A) TREATMENT OF MALIGNANT DISEASES

1) INITIAL DOSE: 40 to 50 mg/kg is given IV in a divided dose over 2 to 5 days, or 1 to 5 mg/kg/day orally (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
2) MAINTENANCE THERAPY

a) 1 to 5 mg/kg/day orally (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
b) 10 to 15 mg/kg IV every 7 to 10 days (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).
c) 3 to 5 mg/kg IV twice weekly (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

B) "MINIMAL CHANGE" NEPHROTIC SYNDROME (BIOPSY PROVEN)

1) 2 mg/kg/day orally for 8 to 12 weeks; MAXIMUM CUMULATIVE DOSE: 168 mg/kg (Prod Info CYCLOPHOSPHAMIDE intravenous injection, oral tablets, 2013).

Maximum Tolerated Exposure

1) CASE REPORT: Following a cumulative dose of 16.2 g of cyclophosphamide over 3 days, a 42-year-old man with embryonal rhabdomyosarcoma developed severe neutropenia, mucositis, fever, respiratory distress, thrombocytopenia, and cardiac toxicity. Neither renal failure nor hemorrhagic cystitis developed, and his cardiac dysfunction was reversible. Following supportive care, the patient gradually improved (Bujanda et al, 2006).

1) A prospective study was conducted to determine the maximum tolerated dose of cyclophosphamide given to pediatric patients with recurrent CNS tumors. Thirteen children (ages ranging from 1 to 17 years) received cyclophosphamide, 2 doses administered 24 hours apart; all children received hematopoietic stem-cell rescue after the second dose. Two children were treated with the starting dose of 2.5 g/m(2), 3 children received 3 g/m(2), six children received 3.5 g/m(2), and 2 children were treated with 4 g/m(2). Both children who received the highest cyclophosphamide dose died shortly after the first dose was given. Adverse effects included vomiting, transiently elevated AST concentrations, grade IV neutropenia, and fever.

a) Both children who were given 4 g/m(2) of cyclophosphamide developed persistent tachycardia and refractory hypotension within 36 hours of the first dose, ultimately resulting in cardiac arrest . An autopsy, performed on one of the children, showed no evidence of cyclophosphamide-associated cardiotoxicity, and both children had developed fluid overload despite normal renal and cardiac function, suggesting generalized capillary leak syndrome (Yule et al, 1997).

2) A cyclophosphamide dose-escalation trial was conducted in pediatric patients who received induction therapy, involving four 3-week cycles of a chemotherapeutic regimen of vincristine, actinomycin D, and cyclophosphamide, to treat rhabdomyosarcoma. Three dose levels of cyclophosphamide were tested: 3.6 g/m(2)/cycle, 4.5 g/m(2)/cycle, and 5.4 g/m(2)/cycle. Cumulative doses were 34.2 g/m(2), 37.8 g/m(2), and 41.4 g/m(2), respectively. Initially, 38 patients were treated at dose level 1 (3.6 g/m(2)/cycle), with only 1 patient experiencing dose-limiting toxicity (sudden death secondary to fever and neutropenia after receiving 3 cycles of chemotherapy). Of the 15 patients initially treated at dose level 2 (4.5 g/m(2)/cycle), 3 patients experienced dose limiting toxicity (typhlitis (n=3), pancreatitis (n=1), perianal desquamation (n=1), and bacterial septic shock and alveolar damage (n=1)). The toxicity experienced at dose level 2 determined that the maximum tolerated cyclophosphamide dose was 3.6 g/m(2)/cycle. Ninety-one patients were then treated at dose level 1. The most common toxicities included myelosuppression, with all patients experiencing grade 3 or 4 neutropenia, and approximately 75% of the patients experiencing grade 3 or 4 anemia and thrombocytopenia. Infection was the most common non-hematologic toxicity, occurring in 64% of patients (Spunt et al, 2004).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Cyclophosphamide

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 110 mg/kg (RTECS , 2002)

B) LD50- (ORAL)MOUSE:

1) 137 mg/kg (RTECS , 2002)

C) LD50- (SUBCUTANEOUS)MOUSE:

1) 200 mg/kg (RTECS , 2002)

D) LD50- (INTRAPERITONEAL)RAT:

1) 40 mg/kg (RTECS , 2002)

E) LD50- (ORAL)RAT:

1) 100 mg/kg (RTECS , 2002)

F) LD50- (SUBCUTANEOUS)RAT:

1) 144 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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CYCLOPHOSPHAMIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography