Introduction
Valacyclovir is an oral antiviral prodrug that is rapidly converted to acyclovir in the body. It is a nucleoside analogue DNA polymerase inhibitor specifically designed for the treatment of herpesvirus infections. Valacyclovir offers improved bioavailability compared to its parent compound acyclovir, allowing for less frequent dosing and improved patient compliance.
Mechanism of Action
Valacyclovir is rapidly converted to acyclovir by first-pass intestinal and hepatic metabolism. Acyclovir is phosphorylated by viral thymidine kinase to acyclovir monophosphate, which is then converted to acyclovir triphosphate by cellular kinases. Acyclovir triphosphate inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate for incorporation into viral DNA. Incorporation into the growing DNA chain results in chain termination due to the lack of a 3'-hydroxyl group. The drug has greater affinity for viral thymidine kinase than cellular kinases, resulting in selective activation in infected cells.
Indications
- Treatment of herpes zoster (shingles) in immunocompetent adults
- Treatment of initial and recurrent genital herpes in immunocompetent adults
- Suppression of recurrent genital herpes in immunocompetent adults
- Treatment of herpes labialis (cold sores) in immunocompetent adults and children
- Treatment of chickenpox in immunocompetent children
- Reduction of cytomegalovirus infection and disease in adult transplant patients
Dosage and Administration
Herpes Zoster: 1 g orally three times daily for 7 days Genital Herpes (initial episode): 1 g orally twice daily for 10 days Recurrent Genital Herpes: 500 mg orally twice daily for 3 days Suppression of Genital Herpes: 1 g orally once daily (500 mg once daily in patients with <9 recurrences/year) Herpes Labialis: 2 g orally twice daily for 1 day (doses separated by 12 hours) Chickenpox: 20 mg/kg orally three times daily for 5 days (maximum 1 g three times daily) Renal Impairment Adjustments:CrCl 30-49 mL/min: Adjust dose to 1 g every 12 hours CrCl 10-29 mL/min: Adjust dose to 1 g every 24 hours CrCl <10 mL/min: Adjust dose to 500 mg every 24 hours
Pharmacokinetics
Absorption: Rapidly absorbed from GI tract and converted to acyclovir; bioavailability of acyclovir from valacyclovir is 54%, significantly higher than oral acyclovir (10-20%) Distribution: Widely distributed throughout body tissues and fluids; CSF concentrations approximately 50% of plasma concentrations Protein Binding: 13-18% (acyclovir) Metabolism: Rapidly hydrolyzed to acyclovir and L-valine by first-pass intestinal and hepatic metabolism Elimination: Primarily renal via glomerular filtration and tubular secretion; half-life 2.5-3.3 hours in adults with normal renal function Excretion: >80% recovered in urine as acyclovir and 9-carboxymethoxymethylguanine metaboliteContraindications
- Hypersensitivity to valacyclovir, acyclovir, or any component of the formulation
- Patients with HIV/AIDS and CD4 count <100 cells/mm³ (increased risk of thrombotic microangiopathy)
Warnings and Precautions
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): Reported in immunocompromised patients receiving higher doses; monitor for symptoms including fever, pallor, fatigue, unexplained bruising, and neurological changes Acute Renal Failure: May occur in elderly patients, those with renal impairment, or those receiving nephrotoxic drugs; ensure adequate hydration Neurological Symptoms: Agitation, confusion, hallucinations, seizures, and coma reported; more common in elderly patients and those with renal impairment Hepatic Impairment: Use with caution in patients with pre-existing liver disease Elderly Patients: Increased risk of neurological and renal adverse effects; adjust dose based on renal functionDrug Interactions
Probenecid: Increases acyclovir AUC and half-life by reducing renal clearance Nephrotoxic Drugs (aminoglycosides, cyclosporine, NSAIDs): May increase risk of renal toxicity Mycophenolate Mofetil: Potential for increased concentrations of both drugs Zidovudine: May cause increased fatigue and headacheAdverse Effects
Common (>10%): Headache, nausea, diarrhea, dizziness Less Common (1-10%): Abdominal pain, vomiting, fatigue, rash, arthralgia Rare (<1%): Thrombocytopenia, leukopenia, neurological symptoms (agitation, confusion, hallucinations), renal impairment, anaphylaxis, angioedema Serious but Rare: TTP/HUS, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysisMonitoring Parameters
- Renal function (serum creatinine, BUN) at baseline and during treatment
- CBC with differential in immunocompromised patients
- Signs and symptoms of TTP/HUS (fever, bruising, neurological changes)
- Hydration status, especially in elderly patients
- Neurological status in patients with renal impairment
- Signs of hypersensitivity reactions
Patient Education
- Complete the full course of treatment even if symptoms improve
- Maintain adequate hydration during treatment
- Start treatment at earliest signs of outbreak for best results
- For genital herpes suppression, continue daily therapy as prescribed
- Report any unusual bruising, bleeding, neurological symptoms, or signs of allergic reaction immediately
- Notify all healthcare providers of valacyclovir use
- Store at room temperature away from moisture and heat
References
1. Kimberlin DW, Whitley RJ. Antiviral therapy of HSV-1 and -2. In: Holmes KK, Sparling PF, Stamm WE, et al., eds. Sexually Transmitted Diseases. 4th ed. New York: McGraw-Hill; 2008. 2. Perrottet N, Decosterd LA, Meylan P, et al. Valacyclovir pharmacokinetics and early antiviral response in EBV-infected patients. J Clin Pharmacol. 2009;49(4):455-463. 3. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years of experience with acyclovir. J Infect Dis. 2002;186 Suppl 1:S40-S46. 4. Valacyclovir hydrochloride [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2021. 5. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the acyclovir prodrug valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther. 1993;54(6):595-605.