valacyclovir
Brand: Valtrex
Prototype: acyclovir
Drug Class: antiviral — acyclovir prodrug
Drug Family: antiviral
Subclass: L-valyl ester prodrug of acyclovir
Organ Systems: infectious-disease
Mechanism of Action
Prodrug rapidly hydrolyzed to acyclovir; acyclovir is phosphorylated by viral thymidine kinase to acyclovir triphosphate, which inhibits viral DNA polymerase and acts as a chain terminator; selective because viral TK activity is required for activation.
herpesvirus thymidine kinaseviral DNA polymerase
Indications
- herpes labialis (cold sores) — episodic treatment and suppression
- genital herpes — episodic treatment and suppression
- herpes zoster (shingles)
- chickenpox (VZV) in immunocompromised
- CMV prophylaxis in transplant recipients (high doses)
Contraindications
- acyclovir/valacyclovir hypersensitivity
- thrombotic thrombocytopenic purpura/HUS in immunocompromised patients at very high doses
Adverse Effects
Common
- nausea
- headache
- diarrhea
Serious
- nephrotoxicity (crystalluria, acute kidney injury — especially dehydrated patients)
- thrombotic microangiopathy (TMA/TTP-HUS — only at very high doses in severely immunocompromised)
- CNS toxicity (confusion, hallucinations — with accumulation in renal failure)
Pharmacokinetics (ADME)
| Absorption | 54% bioavailability as valacyclovir (converted to acyclovir); 3–5x higher than oral acyclovir |
| Distribution | widely distributed; CSF levels ~50% of plasma; crosses placenta |
| Metabolism | rapidly converted to acyclovir by first-pass intestinal/hepatic hydrolysis |
| Excretion | renal (45–79% unchanged acyclovir + 9-carboxymethoxymethylguanine metabolite) |
| Half-life | 2.5–3.3 hours (acyclovir after valacyclovir conversion) |
| Onset | 0.5–1 hour |
| Peak | 1.5–2.5 hours |
| Duration | 8–12 hours |
| Protein Binding | 15% |
| Vd | moderate |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| nephrotoxic agents, probenecid, cimetidine | reduced renal tubular secretion of acyclovir; increased levels and nephrotoxicity risk | moderate |
| zidovudine | possible additive CNS toxicity (drowsiness, lethargy) | moderate |
Nursing Considerations
- Maintain adequate hydration (minimum 2 L/day) during therapy to prevent crystalluria and nephrotoxicity; check baseline and periodic BUN/creatinine.
- Dose reduction is required in renal impairment; very high-dose regimens (used for CMV prophylaxis) require close renal monitoring.
- Initiate therapy within 72 hours of symptom onset for shingles to maximize efficacy; earlier is better.
- Counsel patients with genital herpes that suppressive therapy reduces (but does not eliminate) viral shedding and transmission risk.
Clinical Pearls
- Valacyclovir's prodrug formulation achieves 3–5 times higher acyclovir bioavailability than oral acyclovir, enabling three-times-daily (vs. five-times-daily) dosing for herpes zoster — a major compliance advantage.
- At high doses used for CMV prophylaxis (2 g four times daily), valacyclovir can cause TTP-HUS in severely immunocompromised patients; this complication is extremely rare at doses used for HSV/VZV treatment.
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Not required
TDM Not required
Concordance Terms
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