Valaciclovir precautions

List of precautions
Warnings Precautions for patients with renal failure Immunocompromised patients Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use
 * Dosage reduction
 * Elderly patients with cold sores
 * Precipitation of acyclovir

Warnings
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valaciclovir at doses of 8 grams per day. Return to top

Dosage reduction
Dosage reduction is recommended when administering Valaciclovir to patients with renal impairment. Acute renal failure and central nervous system symptoms have been reported in patients with underlying renal disease who have received inappropriately high doses of Valaciclovir for their level of renal function. Similar caution should be exercised when administering Valaciclovir to geriatric patients (see Geriatric Use) and patients receiving potentially nephrotoxic agents. Return to top

Elderly patients with cold sores
Given the dosage recommendations for treatment of cold sores, special attention should be paid when prescribing Valaciclovir for cold sores in patients who are elderly or who have impaired renal function (see DOSAGE AND ADMINISTRATION and Geriatric Use). Treatment should not exceed 1 day (2 doses of 2 grams in 24 hours). Therapy beyond 1 day does not provide additional clinical benefit. Return to top

Precipitation of acyclovir
Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored. Return to top

Immunocompromised patients
The safety and efficacy of Valaciclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. The safety and efficacy of Valaciclovir for suppression of recurrent genital herpes in patients with advanced HIV disease (CD4 cell count <100 cells/mm3) have not been established. The efficacy of Valaciclovir for the treatment of genital herpes in HIV-infected patients has not been established. The safety and efficacy of Valaciclovir have not been established for the treatment of disseminated herpes zoster. Return to top

Carcinogenesis
Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) 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. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors. Return to top

Mutagenesis
Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study. In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was mutagenic in a mouse micronucleus assay. Return to top

Impairment of fertility
Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels. Return to top

Pregnancy
Pregnancy category B Teratogenic Effects Valacyclovir was not teratogenic in rats or rabbits at 10 and 7 times human plasma levels, respectively, during the period of major organogenesis. There are no adequate and well-controlled studies of Valaciclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Valaciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Return to top

Nursing mothers
Following oral administration of a 500-mg dose of Valaciclovir to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500-mg maternal dosage of Valaciclovir twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Valaciclovir should be administered to a nursing mother with caution and only when indicated. Return to top

Pediatric use
Safety and effectiveness of Valaciclovir in pre-pubertal pediatric patients have not been established. Return to top

Geriatric use
Of the total number of subjects in clinical studies of Valaciclovir, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, agitation, hallucinations, confusion, delirium, and encephalopathy were reported more frequently in elderly patients. Return to top