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. |
| Molecular Weight | 261.09 |
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 | Teratogenic; risk of structural anomalies, miscarriage, and fetal death. Avoid unless life-threatening condition. |
| 2nd trimester | Risk of growth restriction, myelosuppression, and preterm birth. Use only if benefit outweighs risk. |
| 3rd trimester | Risk of neonatal myelosuppression, pancytopenia, and immunosuppression. Avoid near term. |
Clinical note
Allopurinol may increase the risk of leukopenia Can cause hemorrhagic cystitis and myelosuppression.
| Placental transfer | Crosses placenta extensively; fetal concentrations 25-100% of maternal levels. |
| Breastfeeding | Excreted into breast milk; potential for immunosuppression, neutropenia, and growth delay in nursing infants. Breastfeeding not recommended during therapy and for at least 36 hours after last dose. |
■ 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 |
Severe bone marrow suppressionActive infectionsHypersensitivity to cyclophosphamide or any component
| 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). |
Loading safety data…
| Lactation Rating |
| L5 - Contraindicated |
| 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. |
| 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. |
| Food/Dietary |
| Grapefruit and grapefruit juice inhibit CYP3A4 and should be avoided. Alcohol may increase hepatotoxicity; limit or avoid. No specific food restrictions beyond maintaining adequate hydration. |
| Clinical Pearls | Cyclophosphamide is a prodrug activated by hepatic CYP450; monitor for hemorrhagic cystitis (maintain high fluid intake and consider mesna). Dose reduction needed in renal impairment (CrCl < 10 mL/min). Avoid concomitant use with CYP2B6 inducers or inhibitors. Warn of potential fetal harm; effective contraception required. |
| Patient Advice | Drink plenty of fluids (at least 2-3 liters per day) to prevent bladder irritation. · Report any blood in urine, painful urination, or signs of infection immediately. · Avoid grapefruit and grapefruit juice during treatment. · Use effective contraception; do not become pregnant or father a child during therapy. · May cause hair loss, nausea, and increased risk of infections; discuss supportive measures. · Monitor for signs of bleeding or unusual bruising. |