How should cyclophosphamide be administered, including dose, route, hydration, mesna, monitoring, and contraindications?

Cyclophosphamide Administration Guidelines

Route and Dosing by Indication

Cyclophosphamide should be administered either as oral daily therapy (1-3 mg/kg/day, maximum 200 mg/day) or intravenous pulse therapy (15 mg/kg or 500-1000 mg fixed dose) depending on the specific indication, with IV pulse therapy preferred due to lower cumulative exposure and reduced long-term toxicity. 1, 2

Autoimmune Disease Dosing

Oral Daily Regimen:

• Adults: 1-3 mg/kg/day (maximum 200 mg/day) 2
• Pediatric: 1.5-3 mg/kg/day 2
• Treatment failure defined as no disease control after 3 months at 2 mg/kg/day 1, 2

Intravenous Pulse Regimen:

• Standard dose: 15 mg/kg (maximum 1500 mg) initially every 2 weeks, then every 3 weeks for maximum 6 months 1, 2
• Alternative fixed dose: 500 mg monthly for pemphigus vulgaris and similar conditions 1
• Euro-Lupus regimen for lupus nephritis: 500 mg/m² every 2 weeks for 6 doses 3

Chemotherapy Regimens

Breast Cancer Protocols:

• AC regimen: 600 mg/m² IV day 1, cycled every 21 days for 4 cycles 1, 2
• TAC regimen: 500 mg/m² IV day 1 with doxorubicin and docetaxel, every 21 days for 6 cycles (requires filgrastim) 1, 2
• Dose-dense AC: 600 mg/m² IV every 14 days for 4 cycles with filgrastim 1, 2

Mandatory Dose Adjustments

Age and Renal Function-Based Reductions (Critical for Safety):

Age	Creatinine	IV Pulse Dose
<60 years	<300 μmol/L	15 mg/kg [3]
<60 years	300-500 μmol/L	12.5 mg/kg [3]
60-70 years	<300 μmol/L	12.5 mg/kg [3]
60-70 years	300-500 μmol/L	10 mg/kg [3]
>70 years	<300 μmol/L	10 mg/kg [3]
>70 years	300-500 μmol/L	7.5 mg/kg [3]

Bladder Protection with MESNA (Non-Negotiable)

MESNA is mandatory for all IV pulse cyclophosphamide to prevent hemorrhagic cystitis, which occurs in 6% of patients without protection. 1, 4

Standard MESNA Protocol:

• Initial IV dose: 20% of cyclophosphamide dose (e.g., 100 mg for 500 mg cyclophosphamide) given at time of cyclophosphamide 1, 4
• First oral dose: 40% of cyclophosphamide dose (e.g., 200 mg) at 2 hours post-cyclophosphamide 1, 4
• Second oral dose: 40% of cyclophosphamide dose (e.g., 200 mg) at 6 hours post-cyclophosphamide 1, 4
• Total daily MESNA: 100% of cyclophosphamide dose 1, 4

Critical MESNA Considerations:

• If patient vomits within 2 hours of oral MESNA, repeat the dose or switch to IV MESNA 1, 4
• MESNA may also benefit patients on continuous oral cyclophosphamide 1
• Do not rely on MESNA alone—aggressive hydration is equally essential 4

Hydration Requirements

Aggressive fluid management is mandatory to dilute toxic metabolites in urine: 1, 4

• Maintain 2-3 liters fluid intake over 24 hours on treatment days 4
• Administer IV fluids before and after IV cyclophosphamide 1
• Instruct patients to urinate frequently, especially immediately upon waking (overnight urine dwelling increases acrolein bladder exposure) 4

Infection Prophylaxis (Mandatory)

Pneumocystis jirovecii prophylaxis is required for all patients receiving cyclophosphamide: 1, 2

• Trimethoprim/sulfamethoxazole 800/160 mg on alternate days OR 400/80 mg daily 1, 2, 3
• Continue throughout cyclophosphamide therapy or for 6 months after rituximab 3
• Alternatives if contraindicated: dapsone or atovaquone 1

Antiemetic Therapy

Antiemetic prophylaxis should be routinely administered with IV cyclophosphamide. 1

Required Monitoring

Weekly during first month, then every 2-4 weeks: 3

• Complete blood count (dose adjustment or discontinuation required for acute or progressive leukopenia) 1
• Renal function 3
• Monthly urinalysis to detect hematuria 3

Cumulative Dose Limits

Strict cumulative dose limits must be observed due to secondary malignancy risk (bladder cancer, myelodysplasia): 2, 3

• General maximum: 36 grams total 3
• Preferred limit: <25 grams 3
• Fertility preservation limit: 10 grams 3
• Bladder cancer risk significantly increases with doses >36 grams 3

Fertility Preservation

For women of childbearing potential desiring future pregnancy: 1, 3

• Consider leuprolide during IV cyclophosphamide treatment 1, 3
• Mycophenolate mofetil is now preferred alternative for lupus nephritis (noninferior efficacy, preserves fertility) 1, 3

For men: 1, 3

• Sperm banking before treatment initiation 1, 3

Expected gonadal toxicity: 1, 2, 4

• Amenorrhea: 20-85% of menstruating women 1, 2
• Azoospermia in men 1, 2

Contraindications and Special Populations

Contraception is mandatory for women of childbearing potential on cyclophosphamide (teratogenic). 1

Oral vs. IV equivalence: 5

• Pharmacokinetic studies demonstrate equal bioavailability and cytotoxic metabolite exposure for oral vs. IV administration 5
• However, IV pulse therapy preferred in practice due to lower cumulative dose, less frequent neutropenia monitoring (monthly vs. weekly), and easier MESNA coadministration 1

Common Pitfalls to Avoid

• Never administer cyclophosphamide without MESNA protection for IV pulse therapy 1, 4
• Never skip hydration—both MESNA and fluids are required 4
• Never ignore age-based dose reductions in elderly patients (significantly increases hematologic and infectious toxicity) 3
• Never continue cyclophosphamide without Pneumocystis prophylaxis 1, 2
• Never exceed cumulative dose limits without compelling justification 2, 3
• Ensure bladder emptying before bedtime and immediately upon waking to minimize overnight acrolein exposure 4