VIRAVAL 500

Indications

• Herpes simplex virus infections (HSV-1 and HSV-2)
• Shingles (herpes zoster)
• Cold sores (herpes labialis)
• Cytomegalovirus infection

Mechanism of action

Valacyclovir is metabolized to aciclovir, which inhibits viral DNA synthesis. This occurs after aciclovir is phosphorylated to its active triphosphate form, primarily by viral thymidine kinase in virus-infected cells, followed by further phosphorylation by cellular kinases. Acyclovir triphosphate then competitively inhibits viral DNA polymerase, leading to DNA chain termination and cessation of viral replication. The selectivity of this action is due to the preferential uptake of the drug by infected cells.

Pharmacodynamics

Valacyclovir demonstrates antiviral effects against herpes simplex virus types 1 and 2, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. Clinical studies indicate that treatment with valacyclovir can shorten the duration of cold sore episodes in immunocompetent individuals. The efficacy of valacyclovir varies based on the viral strain and individual patient factors, with in vitro studies showing varying EC50 values.

Pharmacokinetics

Valacyclovir is rapidly absorbed and converted to aciclovir, with peak plasma concentrations occurring within 1 to 2 hours after oral administration. The bioavailability of valacyclovir is significantly higher than that of aciclovir. The elimination half-life of aciclovir is approximately 2.5 to 3 hours, and the drug is primarily excreted in urine, with a significant proportion being eliminated unchanged. Dosage adjustments may be necessary in patients with renal impairment.

Adverse effects

• Nausea
• Headache
• Dizziness
• Abdominal pain
• Diarrhea
• Fatigue
• Renal impairment
• Neurotoxicity
• Skin rash

Interactions

• Probenecid
• Cimetidine
• Mycophenolate mofetil
• Other nephrotoxic drugs

Precautions

• Renal impairment
• Dehydration
• Neurological disorders
• Elderly patients
• Concurrent use with other antiviral agents

Pregnancy

Valacyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies have shown adverse effects.

Breast-feeding

Valacyclovir is excreted in human breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store below 25°C in a tightly closed container, protect from moisture and light.

Formulations

• Tablets: 500 mg, 1000 mg

Mechanism of action

Valacyclovir is the L-valine ester of aciclovir. It is classified as a nucleoside analog DNA polymerase enzyme inhibitor. Aciclovir is a purine (guanine) nucleoside analog is a metabolite that heavily contributes to the pharmacological actions of valacyclovir. In fact, most of valacyclovir's activity is attributed to acyclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme _valacyclovir hydrolase_. Aciclovir is a selective inhibitor of the herpes viruses, possessing in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), as well as human herpesvirus 6 (HHV-6). Aciclovir has been shown to inhibit herpes virus DNA synthesis after it has been phosphorylated to the active triphosphate form. The first stage of drug phosphorylation for acyclovir requires activation by a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral _thymidine kinase_ (TK), which is only found in virus-infected cells. The process of phosphorylation is completed (conversion from mono- to triphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this agent results in DNA chain termination, stopping virus DNA synthesis and blocking virus replication. The inhibitory capabilities of acyclovir are highly selective due to the drug's strong affinity for _thymidine kinase_ (TK). In summary, the antiviral effects of valacyclovir are achieved in 3 ways: 1) competitive inhibition of viral DNA polymerase 2) incorporation and termination of the growing viral DNA chain 3) inactivation of the viral DNA polymerase. The higher level of antiviral activity of acyclovir against HSV compared with VZV is attributed to its more efficient phosphorylation by viral thymidine kinase (TK). Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in cell culture and in vivo. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Pharmacodynamics

**Antiviral effects** Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors. **Clinical study results** For the various conditions below, clinical study results are summarized as follows: _Cold sores_ Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration. _Initial genital herpes episodes_ 643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days. _Recurrent genital herpes episodes_ The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding. These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration. **A note on resistance** The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases.