Ganciclovir

Ganciclovir is an intravenous guanosine analogue active against cytomegalovirus and, to a lesser degree, herpes simplex and varicella zoster viruses. It is used for treatment of cytomegalovirus retinitis, colitis, pneumonitis and other end-organ disease, for pre-emptive treatment and for prophylaxis in transplant recipients. Myelosuppression is the dominant toxicity. It carries boxed warnings for haematological toxicity, impaired fertility, foetal toxicity and carcinogenicity.

Class. Nucleoside analogue antiviral.

Mechanism. Phosphorylated first by the viral UL97 kinase and then by cellular kinases to the triphosphate, which inhibits the viral DNA polymerase (UL54) and terminates chain elongation. UL97 mutations cause resistance, and UL54 mutations cause wider cross-resistance.

Pharmacokinetics. Intravenous only. Half life about 3.5 hours in normal kidney function and over 24 hours in severe kidney failure. Penetrates cerebrospinal fluid and vitreous, with more than 90% excreted unchanged by the kidney.

Cytomegalovirus end-organ disease (adults, normal kidney function). - Induction: 5 mg/kg intravenously every 12 hours for 14 to 21 days. - Maintenance (secondary prophylaxis, for example retinitis): 5 mg/kg once daily until immune recovery (CD4 count over 100 cells/microlitre for at least 3 to 6 months in HIV infection). - Loading dose: none. Maximum: 10 mg/kg daily.

Prophylaxis in transplantation. 5 mg/kg once daily, usually for 100 days after solid organ transplantation (longer in lung transplantation), or pre-emptive treatment on a positive viral load.

Congenital cytomegalovirus infection (specialist). 6 mg/kg intravenously every 12 hours for 6 weeks, with oral valganciclovir preferred when feeding is established.

Dose adjustment for kidney function. - Induction: CrCl 50 to 69 mL/min 2.5 mg/kg every 12 hours; 25 to 49: 2.5 mg/kg every 24 hours; 10 to 24: 1.25 mg/kg every 24 hours; under 10: 1.25 mg/kg three times weekly after dialysis. - Maintenance: CrCl 50 to 69: 2.5 mg/kg every 24 hours; 25 to 49: 1.25 mg/kg every 24 hours; 10 to 24: 0.625 mg/kg every 24 hours; under 10: 0.625 mg/kg three times weekly after dialysis.

Dosing weight. Actual body weight; use adjusted weight in marked obesity.

Main alternatives. Oral valganciclovir for step-down; foscarnet or cidofovir for resistance or marrow toxicity.

Contraindications. Hypersensitivity to ganciclovir, valganciclovir, acyclovir or valaciclovir; neutrophils under 0.5 x 10^9/L, platelets under 25 x 10^9/L or haemoglobin under 80 g/L (relative, treated by transfusion and growth factor where benefit is clear).

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

Common adverse effects. Fever, nausea, diarrhoea, headache and phlebitis.

Interactions. Zidovudine and other marrow suppressants add haematological toxicity; imipenem raises seizure risk; mycophenolate and nephrotoxins increase risk; probenecid reduces clearance.

Common prescribing errors. Full dose in kidney impairment, no blood count monitoring, rapid bolus injection, and use in early pregnancy without clear need.

Special groups. - Pregnancy: avoid; teratogenic and embryotoxic in animals; effective contraception during treatment (women for 30 days and men for 90 days after). - Breastfeeding: avoid. - Children: weight-based dosing; neutropenia is common. - Older adults: reduced clearance; adjust for kidney function. - Kidney impairment: reduce the dose and lengthen the interval as CrCl falls under 70 mL/min, down to 1.25 mg/kg three times weekly (induction) after dialysis when CrCl is under 10 mL/min. - Liver impairment: no adjustment.

Regional points. In East Africa cytomegalovirus retinitis in advanced HIV infection is the main indication; availability of intravenous ganciclovir, intravitreal therapy and ophthalmology is limited, and antiretroviral therapy is essential for immune recovery.

Formulations. Intravenous powder 500 mg vial.

Administration. Reconstitute and dilute in 0.9% sodium chloride or 5% glucose to no more than 10 mg/mL; infuse over 1 hour into a large vein. The solution is alkaline (pH about 11) and is handled as a cytotoxic drug; never give as a bolus.

Baseline. Full blood count, creatinine, liver tests, pregnancy test, ophthalmology review.

Monitoring. Full blood count every 2 to 3 days for the first week and then weekly; creatinine twice weekly during induction; ophthalmology review during treatment of retinitis.

Stopping thresholds. Hold for neutrophils under 0.5 x 10^9/L or platelets under 25 x 10^9/L until neutrophils exceed 0.75 x 10^9/L; use growth factor where needed. Stop for seizures.

Referral and escalation. Specialist review for cytomegalovirus disease, suspected resistance (rising viral load after 2 weeks) or marrow failure.