Foscarnet

Foscarnet is an intravenous pyrophosphate analogue that inhibits viral DNA polymerase directly, without activation by viral kinases. It is used for cytomegalovirus disease resistant to ganciclovir or complicated by marrow suppression, and for acyclovir-resistant herpes simplex and varicella zoster infection. Nephrotoxicity and electrolyte disturbance are dose-limiting, with boxed warnings for kidney impairment and seizures.

Class. Pyrophosphate analogue antiviral.

Mechanism. Binds the pyrophosphate site of viral DNA polymerase and blocks chain elongation. Resistance arises through UL54 mutations, and thymidine kinase deficiency does not affect it.

Pharmacokinetics. Intravenous only. Half life 3 to 7 hours initially with a prolonged terminal phase through bone deposition. About 80% to 90% excreted unchanged in urine. Cerebrospinal fluid penetration about 40% of plasma.

Cytomegalovirus retinitis and end-organ disease, ganciclovir-resistant (adults). - Induction: 60 mg/kg intravenously every 8 hours (or 90 mg/kg every 12 hours) for 14 to 21 days. - Maintenance: 90 to 120 mg/kg once daily. - Maximum: 180 mg/kg daily during induction.

Acyclovir-resistant herpes simplex or varicella zoster. 40 mg/kg every 8 to 12 hours for 2 to 3 weeks or until lesions heal.

Dose adjustment for kidney function (creatinine clearance in mL/min/kg; induction at 60 mg/kg every 8 hours). - Over 1.4: 60 mg/kg every 8 hours. Over 1.0 to 1.4: 45 mg/kg every 8 hours. - Over 0.8 to 1.0: 50 mg/kg every 12 hours. Over 0.6 to 0.8: 40 mg/kg every 12 hours. - Over 0.5 to 0.6: 60 mg/kg every 24 hours. 0.4 to 0.5: 50 mg/kg every 24 hours. - Under 0.4: not advised.

Hydration. Sodium chloride 0.9% 500 mL to 1 L before each dose, with further fluid with each dose, to protect the kidney.

Main alternatives. Cidofovir for ganciclovir resistance; ganciclovir when resistance is not an issue.

Contraindications. Hypersensitivity, CrCl under 0.4 mL/min/kg, and uncorrected hypocalcaemia.

Serious adverse effects. Acute kidney injury, seizures (linked to hypocalcaemia, hypomagnesaemia, hypokalaemia and phosphate disturbance), QT prolongation, anaemia, genital ulceration and thrombophlebitis.

Common adverse effects. Nausea, vomiting, headache, fever, paraesthesia and perioral tingling.

Interactions. Additive nephrotoxicity with amphotericin B, aminoglycosides, ciclosporin, tacrolimus, tenofovir disoproxil fumarate and NSAIDs; severe hypocalcaemia with intravenous pentamidine; additive QT effect with macrolides and other QT drugs.

Common prescribing errors. No pre-hydration, no electrolyte monitoring, full dose in kidney impairment, and rapid infusion.

Special groups.

• Pregnancy: avoid unless essential; animal skeletal effects.
• Breastfeeding: avoid.
• Children: limited data; bone deposition concern.
• Older adults: reduced clearance; adjust for kidney function.
• Kidney impairment: reduce the dose and lengthen the interval as CrCl in mL/min/kg falls; avoid when it is under 0.4.
• Liver impairment: no adjustment.

Formulations. Intravenous solution 24 mg/mL (6 g in 250 mL).

Administration. Central line: undiluted at 24 mg/mL; peripheral line: dilute to 12 mg/mL with 5% glucose or 0.9% sodium chloride. Use an infusion pump, with rates no faster than 1 mg/kg/min (over at least 1 hour for 60 mg/kg; 2 hours for 90 mg/kg).

Baseline. Creatinine, calcium (ionised), magnesium, potassium, phosphate, full blood count, ECG, pregnancy test.

Monitoring. Creatinine, ionised calcium, magnesium, potassium and phosphate before each dose for the first week, then at least twice weekly; full blood count weekly.

Stopping thresholds. Stop for seizures, ionised hypocalcaemia with symptoms, creatinine clearance falling under 0.4 mL/min/kg, or QTcF over 500 ms.

Referral and escalation. Specialist review for resistant cytomegalovirus or herpes infection and kidney injury.