What is the proper use and administration of Cyclophosphamide (chemotherapy medication)?

Cyclophosphamide: Proper Use and Administration

Cyclophosphamide is administered either as oral daily therapy (1-3 mg/kg/day, maximum 200 mg/day) or intravenous pulse therapy (15 mg/kg every 2-4 weeks, maximum 1500 mg), with mandatory mesna protection for IV dosing, adequate hydration, and Pneumocystis jirovecii prophylaxis for all patients. 1, 2

Dosing Regimens by Indication

Chemotherapy for Breast Cancer

For early breast cancer requiring adjuvant chemotherapy, anthracycline-taxane regimens containing cyclophosphamide are optimal when tolerated. 3

Recommended combination regimens include:

• AC regimen: Cyclophosphamide 600 mg/m² IV on day 1, every 21 days for 4 cycles 1
• TC regimen: Cyclophosphamide 600 mg/m² IV with docetaxel on day 1, every 21 days for 4 cycles (offers improved disease-free and overall survival compared to AC alone) 3, 1
• TAC regimen: Cyclophosphamide 500 mg/m² IV with doxorubicin and docetaxel on day 1, every 21 days for 6 cycles (requires filgrastim support) 1
• Dose-dense AC: Cyclophosphamide 600 mg/m² IV every 14 days for 4 cycles with filgrastim support 3, 1

When anthracycline-taxane therapy is contraindicated, the classic CMF regimen is the preferred alternative: cyclophosphamide 100 mg/m² orally days 1-14, methotrexate 40 mg/m² IV days 1 and 8, fluorouracil 600 mg/m² IV days 1 and 8, repeated every 28 days for six cycles. 3, 4

Autoimmune Disease Dosing

For autoimmune conditions including ANCA-associated vasculitis and CNS vasculitis, choose between oral daily or IV pulse therapy based on disease severity and patient factors. 1, 2

Oral daily therapy:

• Adults: 1-3 mg/kg/day (maximum 200 mg/day) 1, 2
• Pediatric patients: 1.5-3 mg/kg/day 1
• Age-adjusted dosing: Reduce to 1.5 mg/kg/day for patients 60-70 years; 1.0 mg/kg/day for patients >70 years 1

Intravenous pulse therapy:

• Standard dose: 15 mg/kg (maximum 1500 mg) initially every 2 weeks, then every 3 weeks 1, 2
• Age-adjusted reductions: 20% reduction for patients 60-70 years; 30-50% reduction for patients >70 years 1
• Duration: Typically 3-6 months for remission induction 1, 2

Minimal Change Nephrotic Syndrome in Pediatric Patients

For biopsy-proven minimal change nephrotic syndrome in children who failed corticosteroids, use 2 mg/kg orally once daily for 8-12 weeks (maximum cumulative dose 168 mg/kg). 5

Critical caveat: Treatment beyond 90 days significantly increases the probability of sterility in males. 5

Mandatory Protective Measures

Mesna Administration

All patients receiving IV pulse cyclophosphamide must receive mesna (2-mercaptoethanesulfonate sodium) to prevent hemorrhagic cystitis, which occurs in 6% of patients without protection. 1, 2

Mesna binds to acrolein (the toxic metabolite responsible for bladder toxicity) and should be considered even for patients on continuous oral cyclophosphamide. 2

Hydration Requirements

During or immediately after cyclophosphamide administration, force diuresis with adequate fluid intake or infusion to reduce urinary tract toxicity. 5

• Oral cyclophosphamide should be taken in the morning to allow daytime voiding 5
• Patients must increase fluid intake and void frequently 5
• Report immediately if urine turns pink or red 5

Infection Prophylaxis

Pneumocystis jirovecii prophylaxis is mandatory for all patients on cyclophosphamide: trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily. 1, 2

Alternative prophylaxis should be used if trimethoprim/sulfamethoxazole is contraindicated. 2

Glucocorticoid Co-Administration for Vasculitis

For CNS vasculitis and ANCA-associated vasculitis, glucocorticoids are mandatory with cyclophosphamide: 1

• Initial: IV methylprednisolone 1000 mg/day for 3-5 days 1
• Continuation: Prednisone 1 mg/kg/day (maximum 60-80 mg/day) for first month 1
• Taper: Reduce to 15 mg/day by 12 weeks, then to 5 mg/day by 6 months 1

Administration Guidelines

Oral Administration

Cyclophosphamide capsules must be swallowed whole—never opened, chewed, or crushed. 5

Caregivers must wear gloves when handling containers and capsules; if contact with broken capsules occurs, wash hands immediately and thoroughly. 5

Monitoring Requirements

Complete blood counts are essential during treatment to adjust dosing: 5

• Do not administer if neutrophils ≤1,500/mm³ or platelets <50,000/mm³ 5
• Monitor liver function tests, particularly in patients with pre-existing liver disease 2
• Instruct patients to monitor temperature frequently and report fever immediately 5

Critical Toxicities and Management

Myelosuppression

Cyclophosphamide causes dose-limiting myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia) and severe immunosuppression leading to potentially fatal infections including sepsis. 5

• G-CSF may be administered to reduce neutropenia complications 5
• Antimicrobial prophylaxis may be indicated at physician discretion 5
• Treatment should be interrupted or dose reduced in patients with serious infections 5

Gonadal Toxicity

Amenorrhea occurs in 20-85% of menstruating women; azoospermia occurs in men, with risk increasing with age and cumulative dose. 1, 2

Fertility preservation should be discussed before initiating therapy, especially in younger patients. 2

The Euro-Lupus cyclophosphamide regimen (total dose 3 grams) carries lower infertility risk than oral or NIH regimens. 2

Urinary Tract Toxicity

Hemorrhagic cystitis occurs in 6% of patients without mesna protection. 1, 2

Patients must report urinary symptoms immediately, particularly pink or red urine. 5

Severe Hyponatremia

Severe hyponatremia is an uncommon but potentially fatal complication of low-dose cyclophosphamide, occasionally followed by secondary diabetes insipidus. 6

Monitor serum sodium closely, particularly after first cycle; symptoms include headaches, disorientation, weakness, and seizures. 6

Cardiotoxicity and Pulmonary Toxicity

Patients must report immediately: new or worsening shortness of breath, cough, ankle/leg swelling, palpitations, weight gain >5 pounds in 24 hours, dizziness, or loss of consciousness. 5

Non-infectious pneumonitis can develop; report any new or worsening respiratory symptoms promptly. 5

Contraception and Pregnancy

Females of reproductive potential must use effective contraception during treatment and for up to 1 year after completion. 5

Males with female partners of reproductive potential must use effective contraception during treatment and for 4 months after completion. 5

Lactating women must not breastfeed during treatment and for 1 week after the last dose. 5

Dose Modifications

Reduce doses for moderate to severe renal impairment. 1

For high-risk breast cancer patients unable to receive taxanes, use optimal-dose anthracycline three-drug regimens: cumulative doxorubicin ≥240 mg/m² or epirubicin ≥600 mg/m² but not >720 mg/m² with cyclophosphamide. 3

Maintenance Therapy

After achieving remission with cyclophosphamide for vasculitis, switch to azathioprine 2 mg/kg/day for 18-24 months as maintenance therapy. 1

This approach limits total cumulative cyclophosphamide exposure, reducing malignancy risk (bladder cancer, myelodysplasia). 1