CYCLOPHOSPHAMIDE
Clinical safety rating: avoid
Contraindicated (not allowed)
Cyclophosphamide is an alkylating agent that crosslinks DNA, leading to cell cycle nonspecific cytotoxicity. It requires hepatic metabolism by cytochrome P450 (CYP2B6, CYP3A4, CYP2C9) to form active metabolites, phosphoramide mustard and acrolein, which alkylate DNA and inhibit protein synthesis.
| Metabolism | Hepatic metabolism via CYP2B6, CYP3A4, and CYP2C9 to active metabolites (phosphoramide mustard and acrolein). Also metabolized by aldehyde dehydrogenase. Excretion: primarily renal as metabolites. |
| Excretion | Renal: approximately 30-60% of dose excreted unchanged in urine; biliary/fecal excretion is minimal (<5%). |
| Half-life | Terminal elimination half-life: 4-8 hours in adults with normal renal function; prolonged in renal impairment (up to 15 hours) and in children. |
| Protein binding | Approximately 20% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | 0.5-0.8 L/kg; distributes into total body water, with highest concentrations in liver, kidneys, and tumors. |
| Bioavailability | Oral: >75% absorbed; food may reduce absorption. |
| Onset of Action | IV: onset of immunosuppression within 1-2 weeks; oral: 2-4 weeks. |
| Duration of Action | Immunosuppressive effects persist for 4-6 weeks after a single dose; myelosuppression nadir occurs 7-14 days after dose, recovery by 21 days. |
400-600 mg/m2 IV every 2-4 weeks; or 50-100 mg/m2 orally daily for 7-14 days; or 1-2 g/m2 IV as a single dose every 3-4 weeks.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl >20 mL/min: 100% dose; CrCl 10-20 mL/min: 75% dose; CrCl <10 mL/min: 50% dose. |
| Liver impairment | Child-Pugh A: 100% dose; Child-Pugh B: 75% dose; Child-Pugh C: 50% dose or consider alternative. |
| Pediatric use | Induction: 1-2 g/m2 IV every 3-4 weeks; maintenance: 30-150 mg/m2 orally daily for 7-14 days. Adjust based on BSA. |
| Geriatric use | No specific dose adjustment; monitor renal function and hematologic toxicity closely; consider lower initial doses (e.g., 75% of standard) due to decreased renal function and increased risk of myelosuppression. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Allopurinol may increase the risk of leukopenia Can cause hemorrhagic cystitis and myelosuppression.
| Breastfeeding | Contraindicated during breastfeeding due to potential severe adverse effects (immunosuppression, neutropenia, carcinogenesis) in the infant. No M/P ratio available; however, cyclophosphamide and its metabolites are excreted into breast milk in clinically significant amounts. |
| Teratogenic Risk | Category D. First trimester exposure: high risk of major malformations (neural tube defects, cleft palate, limb defects) and fetal growth restriction. Second and third trimester exposure: risk of fetal growth restriction, premature birth, and bone marrow suppression; use only if benefit outweighs risk. |
■ FDA Black Box Warning
Hemorrhagic cystitis occurs commonly and may be severe; adequate hydration and frequent voiding are required. Myelosuppression, immunosuppression, and dose-related cardiotoxicity may occur. Secondary malignancies (bladder cancer, myelodysplasia, acute leukemia) have been reported. Fetal harm can occur when administered to pregnant women; advise females of reproductive potential to avoid pregnancy.
| Common Effects | immunosuppression |
| Serious Effects |
Hypersensitivity to cyclophosphamide or any component, severely depressed bone marrow function, active infections, urinary outflow obstruction, pregnancy.
| Precautions | Hemorrhagic cystitis (hydration, mesna prophylaxis), myelosuppression (monitor CBC), cardiotoxicity (especially high doses), pulmonary toxicity (pneumonitis, fibrosis), hepatotoxicity, nephrotoxicity, secondary malignancies, infertility, impaired wound healing, tumor lysis syndrome, severe infections including Pneumocystis jirovecii, adrenal insufficiency (if used with corticosteroids). |
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| Fetal Monitoring | Monitor complete blood count (CBC) with differential, liver function tests (LFTs), renal function, and urinalysis in the mother. Fetal monitoring: serial ultrasound for growth and anatomy, amniocentesis for karyotype if indicated, and fetal echocardiography if second trimester exposure. |
| Fertility Effects | Causes ovarian failure and azoospermia; risk depends on cumulative dose and age. Gonadotoxic; may lead to premature ovarian insufficiency and permanent infertility. Consider fertility preservation options (e.g., oocyte or sperm cryopreservation) before treatment. |