Generic Name

Valacyclovir

Mechanism

• Rapid conversion: In the gastrointestinal tract, peptidases hydrolyze valacyclovir to active acyclovir.
• Selective activation: Acyclovir is phosphorylated by viral thymidine kinase (TK). This first‑step phosphorylation is virus‑dependent and restricts activity to infected cells.
• Inhibition of viral DNA synthesis: Triphosphorylated acyclovir competes with deoxyguanosine triphosphate and is incorporated into viral DNA, causing chain termination.
• Broad spectrum: Effective against HSV‑1, HSV‑2, varicella‑zoster virus (VZV), and some cytomegalovirus (CMV) strains.

Pharmacokinetics

• Absorption: Oral valacyclovir has ~54 % bioavailability vs. 15 % for oral acyclovir; peak plasma concentrations achieved 1–2 h post‑dose.
• Distribution: Volume of distribution ≈ 0.9 L/kg; crosses the blood‑brain barrier when excised.
• Metabolism: Converted to acyclovir by intestinal and hepatic peptidases; minimal first‑pass metabolism.
• Half‑life: 1.5–2 h (acyclovir) after conversion; overall effective half‑life extends due to sustained tissue levels.
• Elimination: Primarily renal (≈ 95 %) as unchanged drug and metabolites. Renal impairment necessitates dose adjustment; non‑renal clearance is negligible.
• Drug–drug interactions: Increases trough levels of drugs renally cleared or that compete for renal transporters (e.g., amphotericin B, amphotericin‑related nephroprotection).

Indications

• Herpes simplex virus (HSV)
• Primary and recurrent oral/genital HSV infections
• Immunocompetent adults: 500 mg × 2 daily; adjust for renal status
• Varicella‑zoster virus (VZV)
• Acute herpes zoster (shingles) management
• Post‑herpetic neuralgia prophylaxis (in select high‑risk pts)
• HSV prophylaxis
• Recurrent genital HSV in immunocompetent adults
• Chronic suppression in immunocompromised or patients with frequent recurrences
• Prophylaxis for VZV in high‑risk groups (e.g., chemotherapy, stem‑cell transplant recipients)

Contraindications

• Allergy: Hypersensitivity to valacyclovir or acyclovir.
• Pregnancy: Category C; use only when benefits outweigh risks (often first‑line for genital HSV in pregnancy).
• Renal impairment: Adjust dose per creatinine clearance; avoid in patients with CrCl < 10 mL/min absent dialysis.
• Neonatal prophylaxis: High risk of teratogenicity if administered during pregnancy; careful monitoring if used during labor.
• CNS depression: Use cautiously with alcohol or CNS depressants; CNS toxicity seen in renal failure.

Dosing

• Administration: With water, take with food if GI upset occurs. Avoid excessive alcohol consumption.

Adverse Effects

• Common (≤ 5 %)
• Nausea, vomiting, diarrhea
• Headache, mild dizziness
• Rash or pruritus
• Transient GI discomfort
• Serious (≤ 1 %)
• Nephrotoxicity: acute kidney injury, nephrogenic diabetes insipidus (especially in renal impairment, dehydration).
• Neurotoxicity: confusion, delirium, myoclonus, seizures in severe renal failure.
• Allergic reactions: anaphylaxis, Stevens–Johnson syndrome.
• Interstitial nephritis: rare but notable in long‑term use.

*Patients with reduced renal clearance should have serum creatinine and BUN monitored every 1–2 weeks during prolonged therapy.*

Monitoring

• Renal function: Creatinine clearance (CrCl) or eGFR before initiation and at least every 2 weeks if CrCl < 60 mL/min.
• Serum electrolytes: If concomitant nephrotoxic drugs or dialysis.
• Adverse reaction surveillance: Report skin rash, CNS changes; discontinue if severe.
• Pregnancy status: Counsel patients and document.
• Medication reconciliation: Identify potential drug‑drug interactions, particularly with CIs or other nephrotoxic agents.

Clinical Pearls

• Prodrug advantage: Valacyclovir’s ~3‑fold higher oral bioavailability allows a *twice‑daily regimen* that enhances adherence compared to acyclovir’s oral dosing of *five times daily* at lower doses.
• Renal mapping: Use the Cockcroft–Gault equation to adjust dosing; e.g., CrCl > 60 mL/min → standard dose; 30–59 mL/min → 250 mg BID; < 30 mL/min → 250 mg every 48 h or discontinue.
• In pregnancy: For genital HSV, valacyclovir (500 mg BID) is preferable to acyclovir due to better serum concentrations and lower total dose, but still must weigh risk–benefit.
• Transplant patients: Long‑term prophylaxis at 500 mg BID can reduce VZV‑associated morbidity; monitor renal function intensively.
• Dry mouth & dehydration: Encourage hydration during treatment to mitigate the risk of nephrotoxicity.
• Adherence bridging: For patients who miss a dose, give the next dose as soon as remembered; do not double‑dose.
• Pharmacologic synergy: Valacyclovir is synergistic with cidofovir and foscarnet in CMV treatment but should be avoided concurrently in routine HSV therapy.
• Drug‑response check: In cases of frequent recurrences despite therapy, consider switching to famciclovir or trifluridine to rule out acyclovir‑resistant HSV.

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• Key take‑away: Valacyclovir delivers high oral bioavailability, easier dosing schedules, and excellent antiviral activity against HSV and VZV, but requires careful renal monitoring and adjustment, especially in the elderly, pregnant, or immunocompromised populations.