cyclophosphamide (Rx)

>10%

Alopecia (40-60%)

Nausea and vomiting

GI toxicity

Leukopenia

Amenorrhea

Sterility

1-10%

Facial flushing

Headache

Rash

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Nasal congestion

Frequency Not Defined

Cardiomyopathy, CHF (high dose)

Stevens-Johnson syndrome

Toxic epidermal necrolysis (rare)

Hemorrhagic cystitis

Azoospermia

Oligozoospermia

Interstitial pneumonia

Infectious disease

Secondary malignancies: Urinary bladder, myeloproliferative, lymphoproliferative

Frequency Not Defined

Neutropenia

Fever

Nausea

Vomiting

Anorexia

Abdominal discomfort or pain

Diarrhea

Hemorrhagic colitis

Oral mucosal ulceration

Jaundice

Alopecia

Skin rash

Pigmentation of skin and changes in nails

Postmarketing Reports

Cardiac: Cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation

Congenital, familial and genetic: Intrauterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis)

Ear and labyrinth: Deafness, hearing impaired, tinnitus

Endocrine: Water intoxication

Eye: Visual impairment, conjunctivitis, lacrimation

Gastrointestinal: Gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation

General disorders and administrative site conditions: Multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache

Hematologic: Myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy)

Hepatic: Veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased

Immune: Immunosuppression, anaphylactic shock, hypersensitivity reaction

Infections: Myelosuppression and immunosuppression may increase risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock

Investigations: Blood lactate dehydrogenase increased, C-reactive protein increased

Metabolism and nutrition: Hyponatremia, fluid retention, blood glucose increased, blood glucose decreased

Musculoskeletal and connective tissue: Rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia

Neoplasms: Acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer

Nervous system: Encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia

Pregnancy: Premature labor

Psychiatric: Confusional state

Renal and urinary: Renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells

Reproductive system: Infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia

Respiratory: Pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea

Skin and subcutaneous tissue: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmoplantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis

Tumor lysis syndrome: May induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors

Vascular: Pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush

Contraindications

Severe myelosuppression

Hypersensitivity

Urinary outflow obstruction

Cautions

Use with caution in patients with hepatic or renal impairment, leukopenia, thrombocytopenia, recent radiation therapy or chemotherapy

Pelvic irradiation potentiates hemorrhagic cystitis

Potential for radiation recall when used in conjunction with radiation therapy

Risk of potentially fatal and irreversible interstitial pulmonary fibrosis if given over prolonged periods

May cause infertility in male patients who received high doses as children

Monitor for secondary malignancies

Heart Failure risk

• Acute heart failure, often occurring within 1 to 10 days of treatment, has been reported
• Subclinical decreases in LVEF in up to 50% of cases have also been seen
• The onset of HF usually resolves over 3 to 4 weeks; However, fatalities caused by HF have been reported
• Large individual doses (greater than 120–170 mg/kg or 1.55 mg/m 2 per day), old age, mediastinal radiation, and anthracycline use have been identified as risk factors

Pregnancy

Based on mechanism of action and published reports of effects in pregnant patients or animals, drug can cause fetal harm when administered to pregnant woman; exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn; drug is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys; advise pregnant women and females of reproductive potential of the potential risk to the fetus

Verify the pregnancy status of females of reproductive potential prior to the initiation of therapy

Contraception

• Therapy can cause fetal harm; advise females of reproductive potential to use effective contraception during treatment for up to 1 year after completion of therapy
• Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after completion of therapy

Infertility

• Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide
• Affected patients generally resume regular menses within a few months after cessation of therapy; risk of premature menopause with cyclophosphamide increases with age
• Oligomenorrhea has also been reported in association with cyclophosphamide treatment
• Men treated with cyclophosphamide may develop oligospermia or azoospermia, which are normally associated with increased gonadotropin but normal testosterone

Lactation

Drug is present in breast milk; neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide; because of potential for serious adverse reactions in a breastfed child from therapy, advise lactating women not to breastfeed during treatment and for 1 week after last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Metabolites interfere with malignant cell growth by cross-linking tumor cell DNA; drug does not have specificity for any phase of the cell cycle; also has potent immunosuppressive activity

Absorption

Bioavailability: 75%

Onset: 2-3 hr

Peak plasma time: Cyclophosphamide, 1 hr; metabolites, 2-3 hr

Distribution

Protein bound: Cyclophosphamide, low; metabolites, >60%

Vd: 0.48-0.71 L/kg

Metabolism

Metabolized by liver

Metabolites: 4-hydroperoxycyclophosphamide, 4-aldophosphamide

Elimination

Half-life: 3-12 hr

Excretion: Urine

Give dose early in day

Patients should drink plenty of fluids with PO doses

Patients should empty bladder frequently to prevent hemorrhagic cystitis

Sometimes, mesna is used concomitantly as prophylaxis against hemorrhagic cystitis

Monitor blood counts during therapy (WBC count may decrease to 2000-3000/μL without serious risk of infection)

May be administered IM, intraperitoneally, intrapleurally, by IV piggy-back, or by continuous IV infusion

IV Incompatibilities

Y-site: Amphotericin B cholesteryl sulfate

IV Compatibilities

Additive: Cisplatin/etoposide, fluorouracil, hydroxyzine, methotrexate, methotrexate/fluorouracil, mitoxantrone, ondansetron

Syringe: Bleomycin, cisplatin, doxapram, doxorubicin, droperidol, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

Y-site (partial list): Allopurinol, amifostine, bleomycin, most cephalosporins, cisplatin, diphenhydramine, doxorubicin, doxorubicin liposomal, filgrastim, fluorouracil, furosemide, gemcitabine, linezolid, lorazepam, mitomycin, morphine, paclitaxel, prochlorperazine, propofol, sodium bicarbonate, trimethoprim/sulfamethoxazole, vancomycin, vinblastine, vincristine

IV Preparation

Maximum concentration of cyclophosphamide is limited to 20 mg/mL because of solubility

IV push: Reconstitute with NS (do not use SWI, because it is hypotonic)

Infusion: Reconstitute with SWI to concentration of 20 mg/mL

May dilute further with D5W, NS, lactated Ringer solution, or other compatible fluids

IV Administration

Infusions may be administered over 1-2 hours

Doses >500 mg up to ~1 g may be administered over 20-30 minutes

To minimize bladder toxicity, increase normal fluid intake during and for 1-2 days after cyclophosphamide therapy; most adult patients will require fluid intake of at least 2 L/day; high-dose regimens should be accompanied by vigorous hydration with or without mesna therapy

Storage

Store intact vials at room temperature