Cidofovir

Cidofovir is an intravenous nucleotide analogue of cytosine with broad activity against herpesviruses, adenovirus and some poxviruses. It is used for cytomegalovirus retinitis in patients who cannot take ganciclovir or foscarnet, and in specialist practice for adenovirus infection in transplantation and for resistant herpes simplex. Dose-dependent nephrotoxicity requires probenecid and hydration and is the main limit. Boxed warnings cover kidney impairment, neutropenia, and carcinogenic and teratogenic potential.

Class. Acyclic nucleotide analogue antiviral.

Mechanism. Phosphorylated by cellular enzymes to the diphosphate, which inhibits viral DNA polymerase and is incorporated into viral DNA, slowing chain elongation. It needs no viral kinase.

Pharmacokinetics. Intravenous only. Half life 2 to 3 hours with a long intracellular half life (days), enabling weekly or fortnightly dosing. Excreted unchanged in urine by filtration and tubular secretion, which probenecid blocks.

Cytomegalovirus retinitis (adults, normal kidney function). - Induction: 5 mg/kg intravenously once weekly for 2 weeks. - Maintenance: 5 mg/kg once every 2 weeks. - Maximum: 5 mg/kg in each dose.

Probenecid. 2 g orally 3 hours before the infusion, then 1 g at 2 hours and 1 g at 8 hours after the end of the infusion (4 g total).

Hydration. 1 L of 0.9% sodium chloride over 1 to 2 hours immediately before each infusion, and a further 1 L over 1 to 3 hours after (if tolerated).

Adenovirus infection in transplantation (specialist). 1 mg/kg three times weekly, or 5 mg/kg once weekly with probenecid.

Dose reduction. If creatinine rises by 0.3 to 0.4 mg/dL (27 to 35 micromol/L) over baseline, reduce to 3 mg/kg.

Main alternatives. Ganciclovir or foscarnet.

Contraindications. Creatinine over 133 micromol/L (1.5 mg/dL), CrCl 55 mL/min or less, urine protein 2+ or more (100 mg/dL or more), neutropenia under 0.5 x 10^9/L, hypersensitivity to probenecid or sulphonamides, and use of other nephrotoxic drugs within 7 days.

Serious adverse effects. Proximal tubular injury and acute kidney failure, neutropenia, ocular hypotony and uveitis, metabolic acidosis, and Fanconi syndrome.

Common adverse effects. Nausea, vomiting, fever, headache and probenecid-related rash.

Interactions. Nephrotoxins (aminoglycosides, amphotericin B, foscarnet, NSAIDs, tenofovir disoproxil fumarate) are contraindicated within 7 days; probenecid reduces zidovudine clearance (hold zidovudine or halve its dose on the day).

Common prescribing errors. Omitting probenecid or saline, giving it despite proteinuria or raised creatinine, and not checking urine protein before each dose.

Special groups. - Pregnancy: contraindicated; teratogenic in animals; effective contraception during and for 1 month after (women) and 3 months after (men). - Breastfeeding: avoid. - Children: limited data; specialist use. - Older adults: reduced clearance; avoid if CrCl is low. - Kidney impairment: contraindicated at CrCl 55 mL/min or less. - Liver impairment: no adjustment.

Formulations. Intravenous solution 75 mg/mL (375 mg in 5 mL).

Administration. Dilute in 100 mL of 0.9% sodium chloride and infuse over 1 hour, with probenecid and saline hydration given around each infusion. Handle as a cytotoxic drug.

Baseline. Creatinine, urine protein, full blood count, intraocular pressure, pregnancy test.

Monitoring. Creatinine and urine protein before every dose; full blood count before every dose; intraocular pressure and visual symptoms at each visit.

Stopping thresholds. Stop for creatinine rise of 0.5 mg/dL (44 micromol/L) or more over baseline, urine protein 3+, or neutropenia under 0.5 x 10^9/L.

Referral and escalation. Specialist and ophthalmology review for all patients.