Valtrex (Valacyclovir HCl)

VALTREX®

Glaxo Wellcome

Valacyclovir HCl

Antiviral Agent

Action And Clinical Pharmacology: Mechanism of Action: Valacyclovir is the L-valyl ester and a pro-drug of the antiviral drug acyclovir. Valacyclovir is rapidly converted to acyclovir, which has in vitro and in vivo inhibitory activity against human herpes viruses including herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its unique affinity for the 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 vitro, acyclovir triphosphate terminates growing chains of viral DNA. Once incorporated, acyclovir irreversibly binds to viral DNA polymerase, effectively inactivating the enzyme. Acyclovir triphosphate is a potent inhibitor of all of the human herpes virus DNA polymerases studied.

Acyclovir is virtually inactive in uninfected cells, since it is preferentially taken up and selectively converted to the active triphosphate form by herpes virus-infected cells. Additionally, the enzyme thymidine kinase of uninfected cells does not effectively use acyclovir as a substrate and cellular a-DNA polymerase is less sensitive than viral DNA polymerase to the effects of acyclovir.

A combination of the thymidine kinase specificity, competitive inhibition of DNA polymerase and incorporation and termination of the growing viral DNA chain results in inhibition of herpes virus replication. No effect on latent nonreplicating virus has been demonstrated. Inhibition of viral replication reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing. The pain of shingles is related to viral damage to neurons which takes place during viral replication.

Pharmacokinetics: After oral administration, valacyclovir is rapidly absorbed from the gastrointestinal tract. Following absorption, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir and L-valine, an essential amino acid, by first-pass metabolism. This hydrolysis is mediated primarily by the enzyme valacyclovir hydrolase, and occurs predominantly in the liver. The absolute bioavailability of acyclovir after administration of valacyclovir is 54.5±9.1% as determined following a 1 g oral dose of valacyclovir and a 350 mg i.v. acyclovir dose to 12 healthy volunteers. The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from i.v. and oral acyclovir.

Acyclovir is eliminated primarily by urinary excretion of unchanged drug. In all studies of valacyclovir, the half-life of acyclovir typically averages 2.5 to 3.3 hours in subjects with normal renal function. In a single-dose escalation study conducted in healthy volunteers with doses of 100 mg, 500 mg, and 1 g of valacyclovir, average (±SD) peak acyclovir concentrations (Cmax) were 0.83 (±0.14) to 5.6 (±2.4) g/mL, respectively. Area under the acyclovir concentration-time curve (AUC) was 2.3 (±0.4), 11.6 (±1.8), and 19.5 (±6.0) hrg/mL, respectively. Acyclovir pharmacokinetics are unaltered after multiple-dose administration.

Clinical Trials: Zoster: Two randomized double-blind clinical trials in 1 540 immunocompetent patients with localized herpes zoster were conducted. In patients less than 50 years of age, valacyclovir 1 000 mg 3 times daily for 7 days was compared to placebo. In patients greater than 50 years of age, valacyclovir 1 000 mg 3 times daily for 7 days or 14 days was compared to acyclovir 800 mg 5 times daily for 7 days. All patients were treated within 72 hours of appearance of zoster rash.

In patients less than 50 years of age, the median time to cessation of new lesion formation was shorter for those treated with valacyclovir (2 days) compared with those treated with placebo (3 days, p=0.03). In patients greater than 50 years of age, the median time to cessation of new lesion formation was 3 days in patients treated with either valacyclovir or acyclovir.

In both studies, the median time to at least 50% crusting or healing was 5 days for all treatment groups.

These trials also included assessment of pain. The primary endpoint for pain was time to complete cessation of zoster-associated pain. Zoster-associated pain, as defined in these trials, combined acute pain (pain associated with zoster lesions) and postherpetic neuralgia (pain after 100% crusting/healing of lesion rash), a definition that is not universally accepted; most experts consider each pain component to have different pathogenesis and different morbidity. The clinical trials were not designed to look specifically at postherpetic neuralgia. However, a posthoc analysis for postherpetic neuralgia was requested and carried out.

In patients greater than 50 years of age, the median time to resolution of postherpetic neuralgia for the study population (including those with zero postherpetic neuralgia) was significantly shorter in patients treated with valacyclovir compared with patients treated with acyclovir (9 and 4 days shorter for patients treated with valacyclovir for 7 and 14 days respectively, p£0.05). In patients greater than 50 years of age, the incidence of chronic pain after 100% crusting/healing of lesion rash was not significantly different among the 3 treatment groups (79 and 80% in patients treated with valacyclovir for 7 or 14 days and 85% in patients treated with acyclovir). In patients less than 50 years of age, there was no statistically significant difference in the median time to cessation of post-herpetic neuralgia between the recipients of valacyclovir and placebo.

There were no significant differences in secondary endpoints, such as use of analgesics or quality of life, for patients treated with valacyclovir compared to placebo or acyclovir. In addition, no significant differences were found among the 3 groups with respect to intensity of pain.

Genital Herpes: Two randomized, double-blind, placebo-controlled trials in 2 187 immunocompetent patients with recurrent genital herpes were conducted. In one study (004), patients were randomized to receive 5 days of treatment with either valacyclovir 1 000 mg bid, acyclovir 200 mg 5 times daily, or placebo. In a second study (028), patients were randomized to receive either valacyclovir 1 000 mg, valacyclovir 500 mg, or placebo, administered twice daily for 5 days. In both trials, patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

Valacyclovir significantly accelerated lesion healing and resolved episodes faster compared to placebo in both studies (p=0.0001). The median time to lesion healing was 4.8 days and 4.1 days for the valacyclovir groups versus 6.0 days and 6.0 days for the placebo groups, for studies 004 and 028 respectively. The median length of an episode was 4.8 days and 4.0 days for the valacyclovir groups versus 5.9 days and 5.9 days for the placebo groups, for studies 004 and 028, respectively (p=0.0001). There were no differences between active treatments groups in both studies.

In study 028, there was a significantly higher proportion of patients with aborted episodes in the valacyclovir 1 000 mg group (28%) and 500 mg group (31%) compared to placebo (21%) (p=0.042 and p=0.005 respectively). In study 004, the proportion of patients with aborted episodes was higher in the valacyclovir group (25.9%) than in the placebo group (19.8%), although this was not statistically significant (p=0.097).

The duration of lesion pain/discomfort was significantly shorter in the valacyclovir treatment groups compared to placebo (p=0.0014 for study 004 and p=0.0001 for study 028). In study 028, the median time to cessation of pain was 2.8 days in the valacyclovir 500 mg group versus 3.9 days for the placebo group. There were no differences between active treatments groups in either study.

In both studies, valacyclovir significantly shorten the duration of viral shedding compared to placebo (p=0.0001). The median time to cessation of viral shedding in patients with at least one positive culture was 2 days in the valacyclovir treatment groups versus 4 days in the placebo group, for both studies. There were no differences between active treatments groups in either study.

Indications And Clinical Uses: For the treatment of herpes zoster (shingles) and recurrent genital herpes in immunocompetent adults.

Contra-Indications: In patients with a known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS), in some cases resulting in death, has been reported in patients with advanced HIV disease and also in bone marrow transplant and renal transplant patients participating in clinical trials of valacyclovir. Valacyclovir caplets are not indicated for the treatment of immunocompromised patients. This syndrome has not been observed in immunocompetent patients treated with valacyclovir caplets in clinical trials.

Precautions: General: Caution should be exercised when administering valacyclovir to patients with significant renal impairment or those receiving potentially nephrotoxic agents, since this may increase the risk of renal dysfunction (see Dosage) and/or the risk of reversible CNS symptoms such as those that occur infrequently in patients treated with i.v. acyclovir.

Efficacy has not been studied in immunocompromised patients or in those with disseminated herpes zoster.

Geriatrics: Of the total number of patients included in clinical studies of valacyclovir 799 were age 65 or older, and 338 were age 75 or older. A total of 34 volunteers age 65 or older completed a pharmacokinetic trial of valacyclovir. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir caplets in geriatric volunteers varied with renal function. Dosage reduction may be required in geriatric patients depending on the underlying renal status of the patient (see Pharmacology and Dosage). Adequate hydration should be maintained.

Children: Safety and effectiveness in children have not been adequately studied.

Pregnancy : There are no adequate and well-controlled studies with either acyclovir or valacyclovir in pregnant women. Valacyclovir caplets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There has not been an increased incidence of birth defects in over 300 women exposed to acyclovir, during the first trimester of pregnancy, as compared with the incidence in the general population. Most women were exposed to acyclovir oral doses of 800 to 1 000 mg/day (approximately equivalent to the acyclovir exposure from 500 mg of valacyclovir once daily). The daily acyclovir area under the plasma concentration vs time curve (AUC) following valacyclovir 1 000 and 3 000 mg/day would be 2 to 4 times greater than that expected with oral acyclovir. The reported defects show no uniqueness or pattern to suggest a common etiology. However, the small size of patients registered is insufficient to evaluate the risk of less common defects or to permit reliable and definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.

Valacyclovir was not teratogenic in rats or rabbits given 400 mg/kg (which results in 10 and 7 times human plasma levels, respectively) during the period of major organogenesis. However, in a nonstandard test in rats given 3 s.c. doses of 100 mg/kg acyclovir (20 times human plasma levels) on gestation day 10, there were fetal abnormalities, such as head and tail anomalies, and maternal toxicity.

Lactation : There is no experience with valacyclovir. However, acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. Caution should be exercised when valacyclovir is administered to a nursing woman. Consideration should be given to temporary discontinuation of nursing, as the safety of valacyclovir has not been established in infants.

Drug Interactions: Coadministration of probenecid with i.v. acyclovir has been shown to increase the mean elimination half-life, and the AUC of acyclovir. Urinary excretion and renal clearance of acyclovir were correspondingly reduced. An additive increase in acyclovir AUC with concomitant administration of valacyclovir, cimetidine, and probenecid has also been observed. Acyclovir Cmax was increased 8.4±27.8%, 22.5±25.3%, and 29.6±27.5% by cimetidine, probenecid, and combination treatment (concomitant cimetidine and probenecid administration), respectively. Acyclovir AUC (0 to 24 hours) was increased 31.9±22.9%, 49.0±27.9%, and 77.9±38.6% by cimetidine, probenecid, and combination treatment, respectively. There are no known drug interactions that require dosage adjustment in patients with normal renal function. Other drugs which affect renal physiology could affect plasma levels of acyclovir.

Hepatic Impairment: Dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advance cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment. However, clinical experience is limited.

Information for the Patient: Patients should be informed that valacyclovir is not a cure for genital herpes.

Adverse Reactions: Adverse events were not significantly different in recipients of valacyclovir (n=967) compared to placebo (n=195) or acyclovir (n=376) in the 2 double-blind, randomized clinical trials of treatment of herpes zoster (shingles). In addition, adverse events were not significantly different in recipients of valacyclovir (n=1 235) compared to placebo (n=439) in the two double-blind, randomized trials of treatment of recurrent genital herpes. The most frequent adverse events reported in recipients of valacyclovir are listed.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdosage from the administration of valacyclovir. However, it is known that precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see Dosage).

Dosage And Administration: Caplets may be given without regard to meals.

Herpes Zoster: The recommended dosage is 1 g (2 caplets) orally 3 times daily for 7 days. Treatment with valacyclovir should be initiated within 72 hours of the onset of rash.

Recurrent Genital Herpes: The recommended dosage is 500 mg orally twice daily for 5 days. Therapy should be initiated at the earliest sign or symptom of recurrence. Valacyclovir can prevent lesion development when taken at the first signs and symptoms of a genital herpes recurrence.

Patients with Acute or Chronic Renal Impairment: Pharmacokinetic and safety evaluations following administration of oral valacyclovir have been performed in patients with renal impairment and volunteers with end-stage renal disease (ESRD) managed by hemodialysis. Based on these studies and extensive experience with acyclovir, the following dosage adjustments are recommended.

Hemodialysis: During hemodialysis, the half-life of acyclovir after administration of valacyclovir is approximately 4 hours. About 1/3 of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. These patients should receive the daily dose of valacyclovir recommended for patients with creatinine clearance of
Peritoneal Dialysis: There is no information specific to administration of valacyclovir. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with ESRD not receiving hemodialysis. Therefore, supplemental doses of valacyclovir should not be required following CAPD or CAVHD.

Availability And Storage: Each blue, film-coated, capsule-shaped tablet (caplet), printed with edible white ink with “VALTREX 500 mg”, contains: valacyclovir HCl equivalent to 500 mg valacyclovir. Nonmedicinal ingredients: carnauba wax, cellulose, crospovidone, hydroxypropyl methylcellulose, Indigotine Aluminum Lake, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, silicon dioxide and titanium dioxide. Bottles of 42, blister packs of 10. Store between 15 and 25°C and protect from light.

VALTREX® Glaxo Wellcome Valacyclovir HCl Antiviral Agent

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