What is the proper administration protocol for Cidofovir (cytosine nucleoside analog) in a patient with potential impaired renal function?

Cidofovir Administration Protocol

Cidofovir must be administered as a 5 mg/kg intravenous infusion over 60 minutes, accompanied by mandatory probenecid and aggressive saline hydration, with strict contraindication in patients with creatinine >1.5 mg/dL or creatinine clearance ≤55 mL/min due to severe nephrotoxicity risk. 1

Pre-Administration Requirements

Absolute Contraindications

• Serum creatinine >1.5 mg/dL 1
• Calculated creatinine clearance ≤55 mL/min 1
• Urine protein ≥100 mg/dL (≥2+ proteinuria) 1
• Concomitant nephrotoxic agents (aminoglycosides, amphotericin B, foscarnet, IV pentamidine, vancomycin, NSAIDs) must be discontinued at least 7 days prior 1

Mandatory Pre-Dose Assessment (Within 48 Hours)

• Serum creatinine measurement 1
• Urine protein by urinalysis 1
• White blood cell count with differential 1
• Intraocular pressure and visual acuity 1

Standard Dosing Protocol

Induction Therapy

• 5 mg/kg IV once weekly for 2 weeks 2
• Infuse over 60 minutes at constant rate 2, 1
• Consider second dose 1 week later if no response to first dose 2

Maintenance Therapy

• 5 mg/kg IV once every 2 weeks 1
• Same infusion parameters as induction 1

Mandatory Nephroprotective Measures

Probenecid Administration (Required)

• 2 grams orally 3 hours before cidofovir 2, 1
• 1 gram orally at 2 hours after infusion completion 2, 1
• 1 gram orally at 8 hours after infusion completion 2, 1
• Total dose: 4 grams per cidofovir administration 2, 1
• Administer with food to reduce nausea 1
• Consider prophylactic antiemetic and antihistamine/acetaminophen for hypersensitivity reactions 2, 1

Saline Hydration (Required)

• Minimum 1 liter 0.9% normal saline IV over 1-2 hours immediately before cidofovir 2, 1
• Second liter (if tolerated) at start of or immediately after cidofovir infusion, over 1-3 hours 2, 1
• This aggressive hydration is essential to prevent irreversible renal failure 2, 1

Preparation and Infusion Technique

• Extract appropriate volume from vial and add to 100 mL 0.9% normal saline 1
• Use standard infusion pump for controlled rate 1
• Administer within 24 hours of preparation; may refrigerate (2-8°C) for maximum 24 hours 1
• Single-dose vials only—discard partially used vials 1

Dose Modifications for Renal Dysfunction

During Therapy Adjustments

• Reduce from 5 mg/kg to 3 mg/kg if serum creatinine increases 0.3-0.4 mg/dL above baseline 1
• Discontinue immediately if serum creatinine increases ≥0.5 mg/dL above baseline 1
• Discontinue immediately if urine protein develops ≥3+ proteinuria 1
• Dose adjustment needed for second dose if renal dysfunction develops 2

Dialysis Patients

• Not significantly cleared by continuous ambulatory peritoneal dialysis 3
• High-flux hemodialysis removes 52% of dose—aggressive dose reduction required 3
• In continuous venovenous hemofiltration, 30.99% removed after 24 hours with prolonged half-life (53.32 hours), suggesting toxic accumulation risk with repeated dosing 4

Critical Monitoring During Treatment

Before Each Dose (Within 48 Hours)

• Serum creatinine and urine protein 1
• Complete blood count with differential 1

Periodic Monitoring

• Intraocular pressure, visual acuity, and ocular symptoms 1
• Serum bicarbonate (risk of metabolic acidosis and Fanconi syndrome) 1
• Electrolytes (phosphate, uric acid, bicarbonate) 2

Special Populations and Considerations

Pediatric Patients

• Insufficient data for appropriate dosing in children 2
• Dosages must be determined in consultation with CDC and DoD specialists 2
• Cidofovir has not been studied in pediatric CMV disease 2

Drug Interactions

• Temporarily discontinue zidovudine or reduce by 50% on cidofovir administration days due to probenecid interaction 1
• Probenecid interacts with numerous medications including acetaminophen, acyclovir, ACE inhibitors, benzodiazepines, NSAIDs, and theophylline 1

Reduced Probenecid Regimen

• Alternative regimen of 2 grams probenecid 1 hour before cidofovir only (total 2 grams) showed similar pharmacokinetics and renal protection in small study, but safety not adequately established 5

Critical Safety Warnings

Life-Threatening Nephrotoxicity

• Dose-dependent nephrotoxicity is the major dose-limiting toxicity 1
• Acute renal failure requiring dialysis can occur with as few as 1-2 doses 1
• Irreversible renal failure and death have been reported 2, 1
• Proteinuria may be early indicator—continued administration can lead to Fanconi syndrome with glycosuria, phosphaturia, polyuria, and nephrogenic diabetes insipidus 2, 1
• Renal function may not return to baseline after discontinuation 2

Other Serious Toxicities

• Neutropenia (monitor CBC before each dose) 2, 1
• Decreased intraocular pressure/ocular hypotony and anterior uveitis/iritis (monitor ophthalmologically) 2, 1
• Metabolic acidosis associated with proximal tubule injury 2, 1
• Carcinogenicity (mammary adenocarcinomas in rats at 0.04 times human exposure) 2
• Teratogenicity and hypospermia in animal studies 2

Handling Precautions

• Mutagenic properties require Class II laminar flow biological safety cabinet for preparation 1
• Personnel must wear surgical gloves and closed-front gown with knit cuffs 1
• If skin contact occurs, wash and flush thoroughly with water 1
• Dispose via high-temperature incineration 1

Contraceptive Requirements

• Women of childbearing potential: effective contraception during and for 1 month after treatment 1
• Men: barrier contraception during and for 3 months after treatment 1