Zostavir

Uses

Valacyclovir is used for the treatment of Herpes zoster (shingles). It is used for the treatment or suppression of genital herpes in immuno-competent individuals and for the suppression of recurrent genital herpes in HIV infected individuals. It is also used for the treatment of cold sores (Herpes labialis).

Zostavir is also used to associated treatment for these conditions: Chickenpox, Cytomegalovirus (CMV) Infection, Genital Herpes, Genital herpes, initial episode, Herpes Labialis, Herpes Simplex Infection, Infection Transmission, Recurrent Genital Herpes (RGH), Shingles, Symptomatic for no more than 72 hours Herpes zoster, Safer sex practices, Chronic suppressive therapy of recurrent episodes of genital herpes

How Zostavir works

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).

Dosage

Zostavir dosage

Adult Dosage:

Cold Sores

: 2 grams every 12 hours for 1 day

Genital Herpes:

• Initial episode: 1 gram twice daily for 10 days
• Recurrent episodes: 500 mg twice daily for 3 days Suppressive therapy
• Immunocompetent patients: 1 gram once daily
• Alternate dose in patients with < 9 recurrences/year: 500 mg once daily
• HIV-infected patients: 500 mg twice daily
• Reduction of transmission: 500 mg once daily

Herpes Zoster

: 1 gram 3 times daily for 7 days

Pediatric Dosage:

• Cold Sores (> 12 years of age): 2 grams every 12 hours for 1 day
• Chickenpox (2 to < 18 years of age): 20 mg/kg 3 times daily for 5 days; not to exceed 1 gram 3 times daily

Side Effects

The most frequently reported adverse reactions were nausea (15%), headache (14%), vomiting (6%), dizziness (3%) and abdominal pain (3%).

Toxicity

LD50 Oral

Rat – 903.5 mg/kg

Carcinogenesis, Mutagenesis, Impairment of Fertility

Valacyclovir was noncarcinogenic in lifetime carcinogenicity assays at single daily gavage doses of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. No clinically significant difference in the incidence of tumors between treated and control animals was observed, and valacyclovir was not found to shorten the latency period of tumors. Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. An in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study was negative .

In the mouse lymphoma assay, valacyclovir was not found to be mutagenic without metabolic activation, however, in the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was also found to be mutagenic in a mouse micronucleus assay .

Valacyclovir did not impair fertility or reproduction in rats at 6 times the normal concentrations in human plasma .

Use in pregnancy

Valacyclovir is categorized as a pregnancy category B drug. There are insufficient well-controlled studies of valacyclovir in pregnant women. The general rate of birth defects in infants exposed to acyclovir in-utero is comparable to the rate for infants measured in the general population. This drug should be used during pregnancy only if the potential benefit justifies the possible fetal risk .

Use in nursing

Acyclovir, a major metabolite of valacyclovir, was excreted in breastmilk at lower concentrations when a normal therapeutic dose of valacyclovir was administered. Exercise caution when acyclovir is used while nursing .

A note on renal function and toxicity in elderly patients

Elderly patients and patients with decreased renal function are at increased risk of valacyclovir toxicity, which can sometimes lead to central nervous system effects, such as encephalopathy, agitation, dysarthria, mania, and psychosis, among other effects. Consider reducing the dose of this drug in these populations to decrease the risk of toxicity .

Precaution

Dosage reduction is recommended when administering valacyclovir to patients with renal impairment. Similar caution should be exercised when administering valacyclovir to geriatric patients and patients receiving potentially nephrotoxic agents. The safety and efficacy of valacyclovir have not been established in immuno compromised patients other than for the suppression of genital herpes in HIVinfected patients

Interaction

No dosage adjustment is recommended when valacyclovir is coadministered with digoxin, antacids, thiazide diuretics, cimetidine or probenecid in subjects with normal renal function.

Food Interaction

• Take with or without food.

Volume of Distribution

Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma AUC ratio, is approximately 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and approximately 2.5% for the metabolite 9-(carboxymethoxy)methylguanine .

In a study of immunocompromised pediatric patients, the volume of distribution of a 15 ml/kg dose of valacyclovir was 1.34 ± 0.65 L/kg .

Elimination Route

After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food .

Half Life

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function .

Clearance

Renal clearance of acyclovir following the administration of a single 1 gram dose of valacylcovir to 12 healthy 437 volunteers was approximately 255 ± 86 mL/min, which represents 42% of total acyclovir apparent plasma clearance .

Elimination Route

After oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was measured in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine .

Pregnancy & Breastfeeding use

Pregnancy category B. Valacyclovir was not teratogenic in rats or rabbits at 10 and 7 times human plasma levels, respectively, during the period of major organogenesis. There is no adequate and well-controlled studies of valacyclovir in pregnant women. Nursing Mothers: Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Valacyclovir should be administered to a nursing mother with caution and only when indicated.

Contraindication

Valacyclovir is contraindicated in patients with a known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation.

Special Warning

Pediatric Use: Safety and effectiveness of valacyclovir in pre-pubertal pediatric patients have not been established. Elderly Use (Over 65 yr.): Elderly patients may require a dose reduction of valacyclovir due to a low body weight or disorders (renal, CNS etc.) associated with aging.

Storage Condition

Store in cool & dry place, away from children.

Innovators Monograph

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