Valganciclovir

Valganciclovir is the oral L-valyl ester prodrug of ganciclovir. It is the usual oral drug for cytomegalovirus retinitis, for step-down after intravenous induction, for prophylaxis and pre-emptive therapy in transplantation, and for symptomatic congenital cytomegalovirus infection. It has the same toxicities as ganciclovir, including boxed warnings for haematological toxicity, fertility impairment, foetal toxicity and carcinogenicity.

Class. Nucleoside analogue antiviral; prodrug.

Mechanism. Hydrolysed to ganciclovir, then phosphorylated by viral UL97 kinase and cellular kinases to the triphosphate, which inhibits viral DNA polymerase and terminates the chain.

Pharmacokinetics. Oral bioavailability about 60%, increased with food, half life of ganciclovir about 4 hours, renal elimination. Cerebrospinal fluid and vitreous penetration similar to ganciclovir.

Cytomegalovirus retinitis and end-organ disease (adults, CrCl 60 mL/min or more). - Induction: 900 mg orally twice daily with food for 21 days. - Maintenance: 900 mg once daily until immune recovery (CD4 count over 100 cells/microlitre for 3 to 6 months). - Loading dose: none. Maximum: 1800 mg daily.

Prophylaxis in transplantation. 900 mg once daily with food, started within 10 days of transplantation and continued for 100 days (heart, kidney, pancreas) to 200 days (kidney, high risk).

Symptomatic congenital cytomegalovirus infection (neonates 32 weeks gestation or more). 16 mg/kg orally twice daily for 6 months.

Children (4 months to 16 years, post-transplant prophylaxis). Once daily dose in mg is 7 x body surface area x creatinine clearance (Schwartz), maximum 900 mg.

Dose adjustment for kidney function (adults). - Induction: CrCl 40 to 59 mL/min 450 mg twice daily; 25 to 39: 450 mg once daily; 10 to 24: 450 mg every 2 days. - Maintenance: CrCl 40 to 59: 450 mg once daily; 25 to 39: 450 mg every 2 days; 10 to 24: 450 mg twice weekly. - Haemodialysis: tablets not advised; use intravenous ganciclovir with dosing after dialysis.

Main alternatives. Intravenous ganciclovir for severe disease or malabsorption; foscarnet or cidofovir for resistance or marrow toxicity.

Contraindications. Hypersensitivity to ganciclovir, valganciclovir, acyclovir or valaciclovir; severe neutropenia, thrombocytopenia or anaemia.

Serious adverse effects. Neutropenia, thrombocytopenia, anaemia, kidney injury, seizures, retinal detachment, and impaired fertility.

Common adverse effects. Diarrhoea, nausea, headache, fever and insomnia.

Interactions. Zidovudine, mycophenolate, co-trimoxazole and other marrow suppressants add toxicity; imipenem raises seizure risk; nephrotoxins raise levels.

Common prescribing errors. Not adjusting for CrCl, splitting or crushing tablets, taking without food, and not counselling on contraception.

Special groups. - Pregnancy: avoid; contraception for women during and for 30 days after treatment, and for men for 90 days after. - Breastfeeding: avoid. - Children: dosing by body surface area and kidney function; oral solution available. - Older adults: reduced clearance; adjust for kidney function. - Kidney impairment: 450 mg twice daily for induction at CrCl 40 to 59 mL/min and lower doses at CrCl under 40 mL/min; tablets are not advised on haemodialysis. - Liver impairment: no adjustment.

Formulations. Tablets 450 mg; powder for oral solution 50 mg/mL.

Administration. With food. Swallow tablets whole; do not break or crush. Handle as a cytotoxic drug.

Baseline. Full blood count, creatinine (and CrCl), liver tests, pregnancy test, ophthalmology review.

Monitoring. Full blood count weekly for the first month and then monthly; creatinine regularly; viral load in transplantation.

Stopping thresholds. Hold for neutrophils under 0.5 x 10^9/L or platelets under 25 x 10^9/L until recovery; stop for seizures.

Referral and escalation. Specialist review for end-organ disease, resistance or marrow failure.