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

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