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 VALTREX at doses of 8 grams per day.

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

Given the dosage recommendations for treatment of cold sores, special attention should be paid when prescribing VALTREX 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.

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 (see DOSAGE AND ADMINISTRATION).

The safety and efficacy of VALTREX have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. The safety and efficacy of VALTREX 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 VALTREX for the treatment of genital herpes in HIV-infected patients has not been established. The safety and efficacy of VALTREX have not been established for the treatment of disseminated herpes zoster.

The efficacy of VALTREX for reducing transmission of genital herpes has not been established in individuals with multiple partners and non-heterosexual couples.

Information for Patients: Patients should be advised to maintain adequate hydration.

Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

Genital Herpes: Patients should be informed that VALTREX is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with VALTREX. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.

VALTREX has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.

If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.

There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year's duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months' duration in HIV-infected patients.

Cold Sores (Herpes Labialis): Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that VALTREX is not a cure for cold sores (herpes labialis).

Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram VALTREX given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

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.

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.

Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

Pregnancy: Teratogenic Effects: 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 are no adequate and well-controlled studies of VALTREX or ZOVIRAX 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. VALTREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Following oral administration of a 500-mg dose of VALTREX 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 VALTREX 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. VALTREX should be administered to a nursing mother with caution and only when indicated.

Pediatric Use: Safety and effectiveness of VALTREX in pre-pubertal pediatric patients have not been established.

Geriatric Use: Of the total number of subjects in clinical studies of VALTREX, 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 (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION).

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