VALTREX

Valtrex is a prescription medication taken by mouth that is effective in the treatment of genital infection, mouth ulcers, and lips blisters caused by the herpes simplex virus.

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Brand Name(s): Valtrex
Generic Name Valacyclovir
Phonetic: (val ay sye' kloe veer)

Who is this for?
Valacyclovir is used to treat herpes zoster (shingles), genital herpes, and cold sores (herpes labialis). It does not cure herpes infections but decreases pain and itching, helps sores to heal, and prevents new ones from forming. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

When should I be careful taking it?
Before taking valacyclovir,

tell your doctor and pharmacist if you are allergic to acyclovir (Zovirax), valacyclovir, or any other drugs.
tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially cimetidine (Tagamet), probenecid (Benemid), and vitamins.
tell your doctor if you have or have ever had kidney or liver disease, problems with your immune system, human immunodeficiency virus infection (HIV), or acquired immunodeficiency syndrome (AIDS).
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking valacyclovir, call your doctor.
What side effects should I watch for?
Although side effects from valacyclovir are not common, they can occur. Tell your doctor if any of these symptoms are severe or do not go away:

headache
upset stomach
vomiting
diarrhea or loose stools
constipation
If you experience any of the following side effects, call your doctor immediately:
rash
itching
How should I take it?
Valacyclovir comes as a tablet to take by mouth. It is usually taken every 8 hours (three times a day) for 7 days to treat shingles. To treat genital herpes it is usually taken twice a day for 5 days. For cold sores, valacyclovir is usually taken for one day only. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take valacyclovir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Use this medication as soon as possible after symptoms appear. Continue to take valacyclovir even if you feel well. Do not stop taking valacyclovir without talking to your doctor.

What happens if I miss a dose?
Take the missed dose as soon as you remember it, and take any remaining doses for that day at evenly spaced intervals. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Where should I keep it?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

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Valtrex Patient Monograph

CATEGORIES: Herpes genitalis; Herpes labialis; Herpes zoster; Infection, herpes simplex virus; Infection, varicella-zoster virus; Pregnancy Category B; FDA Approved 1995 Jun; Top 200 Drugs

Drug Classes: Antivirals

BRAND NAMES: Valtrex

FOREIGN BRAND AVAILABILITY:
Rapivir (Mexico)
Valcyclor (Colombia)
Zelitrex (France; South Africa)

COST OF THERAPY:
$89.84 (Genital Herpes; Valtrex; 1 g; 2 tablets/day; 10 day supply)
$94.33 (Herpes Zoster; Valtrex; 1 g; 3 tablets/day; 7 day supply)

DESCRIPTION
Valacyclovir hydrochloride is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir.

Valtrex caplets are for oral administration. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 g valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C blue no. 2 lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.

The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride.

Valacyclovir hydrochloride is a white to off-white powder with a molecular formula C13H20N6O4·HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/ml. The pKa's for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

CLINICAL PHARMACOLOGY

Microbiology

Mechanism of Antiviral Action

Valacyclovir HCl is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in vitro 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 vitro, acyclovir triphosphate stops 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 to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02-13.5 µg/ml for HSV-1 and from 0.01-9.9 µg/ml for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12-10.8 µg/ml. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 µg/ml.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.

Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.

After oral administration, valacyclovir HCl is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.

Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir have been investigated in 14 volunteer studies involving 283 adults.

Absorption and Bioavailability

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 intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 g of fat).

There was a lack of dose proportionality in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose administration of 100, 250, 500, 750 mg, and 1 g of valacyclovir to 8 healthy volunteers. The mean Cmax (±SD) was 0.83 (±0.14), 2.15 (±0.50), 3.28 (±0.83), 4.17 (±1.14), and 5.65 (±2.37) µg/ml, respectively; and the mean AUC (±SD) was 2.28 (±0.40), 5.76 (±0.60), 11.59 (±1.79), 14.11 (±3.54), and 19.52 (±6.04) h·µg/ml, respectively.

There was also a lack of dose proportionality in acyclovir Cmax and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 g of valacyclovir administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers. The mean Cmax (±SD) was 2.11 (±0.33), 3.69 (±0.87), and 4.96 (±0.64) µg/ml, respectively, and the mean AUC (±SD) was 5.66 (±1.09), 9.88 (±2.01), and 15.70 (±2.27) h·µg/ml, respectively.

There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in healthy volunteers with normal renal function.

Distribution

The binding of valacyclovir to human plasma proteins ranged from 13.5-17.9%.

Metabolism

After oral administration, valacyclovir HCl is rapidly absorbed from the gastrointestinal tract. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 µg/ml at all doses. After single-dose administration of 1 g of valacyclovir HCl, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 µg/ml in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.

Elimination

The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 g dose of radiolabeled valacyclovir to 4 healthy subjects, 45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively. Acyclovir accounted for 88.60% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 g dose of valacyclovir HCl to 12 healthy volunteers was approximately 255 ± 86 ml/min which represents 41.9% of total acyclovir apparent plasma clearance.

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

End-Stage Renal Disease (ESRD)

Following administration of valacyclovir HCl to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one-third of acyclovir in the body is removed by dialysis during a 4 hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 ml/min/1.73 m2, compared to 679.16 ± 162.76 ml/min/1.73 m2 in healthy volunteers.

Reduction in dosage is recommended in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Geriatrics

After single-dose administration of 1 g of valacyclovir HCl in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared to 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir HCl in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Pediatrics

Valacyclovir pharmacokinetics have not been evaluated in pediatric patients.

Liver Disease

Administration of valacyclovir HCl to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.

HIV Disease

In 9 patients with advanced HIV disease (CD4 cell counts <150 cells/mm3) who received valacyclovir HCl at a dosage of 1 g 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers (see WARNINGS).

Drug Interactions

The pharmacokinetics of digoxin was not affected by coadministration of valacyclovir HCl 1 g 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir HCl (1 g) was unchanged by coadministration of digoxin (2 doses of 0.75 mg), single doses of antacids (Al3+ or Mg++), or multiple doses of thiazide diuretics. Acyclovir Cmax and AUC following a single dose of valacyclovir HCl (1 g) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after probenecid (1 g), or by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. These effects are not considered to be of clinical significance in subjects with normal renal function. Therefore, no dosage adjustment is recommended when valacyclovir HCl is coadministered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function.

CLINICAL STUDIES

Herpes Zoster Infections

Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir HCl was compared to placebo in patients less than 50 years of age, and to acyclovir in patients greater than 50 years of age. 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 2 days for those treated with valacyclovir HCl compared to 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir HCl or acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir HCl and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7 day valacyclovir HCl, 14 day valacyclovir HCl, and 7 day acyclovir, respectively.

Genital Herpes Infections

Initial Episode

Six hundred and forty-three (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 HCl 1 g bid (n=323) or acyclovir 200 mg 5 times a day (n=320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.

Recurrent Episodes

Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir HCl 500 mg bid (n=360) or placebo (n=259). The median time to lesion healing was 4 days in the group receiving valacyclovir HCl 500 mg vs 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir HCl 500 mg vs 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir HCl 500 mg vs 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.

In a third study, patients were randomized to receive valacyclovir HCl 500 mg bid for 5 days (n=398) or valacyclovir 500 mg bid for 3 days (and matching placebo bid for 2 additional days) (n=402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.

Suppressive Therapy

One thousand, four hundred seventy-nine (1479) immunocompetent adults with a history of 6 or more recurrences/year were randomized into a double-blind, placebo-controlled study. Outcomes for the overall study population are shown in TABLE 1.

TABLE 1 Proportions of Patients Recurrence Free at 6 and 12 Months
Valacyclovir HCl Acyclovir
1 g qd 400 mg bid Placebo
Treatment Arm (n=269) (n=267) (n=134)
6 Months
Recurrence free 55% 54% 7%
Recurrences 35% 36% 83%
Unknowns 10% 10% 10%
12 Months
Recurrence free 34% 34% 4%
Recurrences 46% 46% 85%
Unknowns 19% 19% 10%

Subjects with 9 or fewer recurrences/year showed comparable results with valacyclovir HCl 500 mg once daily.

Cold Sores (herpes Labialis)

Two double-blind, placebo-controlled clinical trials were conducted in 1856 healthy adults and adolescents (³12 years old) with a history of recurrent cold sores. Patients self initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir HCl 2 g twice daily on day 1 followed by placebo on day 2, valacyclovir HCl 2 g twice daily on day 1 followed by 1 g twice daily on day 2, or placebo on days 1 and 2.

The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared to placebo. The 2 day regimen did not offer additional benefit over the 1 day regimen.

No significant difference was observed between subjects receiving valacyclovir HCl or placebo in the prevention of progression of cold sore lesions beyond the papular stage.

INDICATIONS AND USAGE

Herpes Zoster: Valacyclovir HCl is indicated for the treatment of herpes zoster (shingles).
Genital Herpes: Valacyclovir HCl is indicated for the treatment or suppression of genital herpes.
Cold Sores (herpes labialis): Valacyclovir HCl is indicated for the treatment of cold sores (herpes labialis).

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

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 allogenic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir HCl at doses of 8 g/day.

PRECAUTIONS
Dosage reduction is recommended when administering valacyclovir HCl 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 valacyclovir HCl for their level of renal function. Similar caution should be exercised when administering valacyclovir HCl 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 valacyclovir HCl 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 g 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. 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 valacyclovir HCl have not been established in immunocompromised patients (see WARNINGS), or for the treatment of disseminated herpes zoster.

Information for the Patient

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 valacyclovir HCl is not a cure for genital herpes. There are no data evaluating whether valacyclovir HCl will prevent transmission of infection to others. 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 can also be transmitted in the absence of symptoms through asymptomatic viral shedding. 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 of 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.

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 valacyclovir HCl is not a cure for cold sores (herpes labialis).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 g valacyclovir HCl 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 up to 120 mg/kg/day for mice and 100 mg/kg/day for rats. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors. Plasma concentrations of acyclovir were equivalent to human levels in the mouse bioassay and 1.4-2.3 times human levels in the rat bioassay.

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 at a single oral dose of 3000 mg/kg (8-9 times human plasma levels).

In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76-88% conversion to acyclovir), valacyclovir was mutagenic.

Valacyclovir was not mutagenic in a mouse micronucleus assay at 250 mg/kg but positive at 500 mg/kg (acyclovir concentrations 26-51 times human plasma levels).

Valacyclovir did not impair fertility or reproduction in rats at 200 mg/kg/day (6 times human plasma levels).

Pregnancy, Teratogenic Effects, Pregnancy Category B

Valacyclovir was not teratogenic in rats or rabbits given 400 mg/kg (which results in exposures of 10 and 7 times human plasma levels, respectively) during the period of major organogenesis.

There are no adequate and well-controlled studies of valacyclovir HCl or acyclovir 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. Valacyclovir HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

There is no experience with valacyclovir HCl. However, acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6-4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir as high as 0.3 mg/kg/day. Valacyclovir HCl should be administered to a nursing mother with caution and only when indicated.

Pediatric Use

Safety and effectiveness of valacyclovir HCl in pre-pubertal pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of valacyclovir HCl, 889 were 65 and over, and 350 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).

DRUG-INTERACTIONS
See CLINICAL PHARMACOLOGY, Pharmacokinetics.

ADVERSE REACTIONS
Frequently reported adverse events in clinical trials of valacyclovir HCl are listed in TABLE 2, TABLE 3A and TABLE 3B.

TABLE 2 Incidence (%) of Adverse Events in Herpes Zoster Study Populations
Valacyclovir HCl (1 g tid) Placebo
Adverse Event (n=967) (n=195)
Nausea 15% 8%
Headache 14% 12%
Vomiting 6% 3%
Dizziness 3% 2%
Abdominal pain 3% 2%

TABLE 3A Incidence (%) of Adverse Events in Genital Herpes Treatment Study Populations
Valacyclovir HCl
1 g bid 500 mg bid Placebo
Adverse Event (n=1194) (n=1159) (n=439)
Nausea 6% 5% 8%
Headache 16% 15% 14%
Vomiting 1% <1% <1%
Dizziness 3% 2% 3%
Abdominal pain 2% 1% 3%
Dysmenorrhea <1% <1% 1%
Arthralgia <1% <1% <1%
Depression 1% 0% <1%

TABLE 3B Incidence (%) of Adverse Events in Genital Herpes Suppression Study Populations
Valacyclovir HCl
1 g qd 500 mg qd Placebo
Adverse Event (n=269) (n=266) (n=134)
Nausea 11% 11% 8%
Headache 35% 38% 34%
Vomiting 3% 3% 2%
Dizziness 4% 2% 1%
Abdominal pain 11% 9% 6%
Dysmenorrhea 8% 5% 4%
Arthralgia 6% 5% 4%
Depression 7% 5% 5%

In clinical studies for the treatment of cold sores, the adverse events reported by patients receiving valacyclovir HCl (n=609) or placebo (n=609) included headache (valacyclovir HCl 14%, placebo 10%) and dizziness (valacyclovir HCl 2%, placebo 1%).

Laboratory abnormalities reported in clinical trials of valacyclovir HCl are listed in TABLE 4A, TABLE 4B, and TABLE 4C.

TABLE 4A Incidence (%) of Laboratory Abnormalities in Herpes Zoster Study Populations
Laboratory Abnormality Valacyclovir HCl (1 g tid) Placebo
Hemoglobin (<0.8 × LLN) 0.8% 0%
White blood cells (<0.75 × LLN) 1.3% 0.6%
Platelet count (<100, 000/mm3) 1.0% 1.2%
AST (SGOT) (>2 × ULN) 1.0% 0%
Serum creatinine (>1.5 × ULN) 0.2% 0%
LLN = Lower limit of normal.
ULN = Upper limit of normal.

TABLE 4B Incidence (%) of Laboratory Abnormalities in Genital Herpes Treatment Study Populations
Valacyclovir HCl
Laboratory Abnormality 1 g bid 500 mg bid Placebo
Hemoglobin (<0.8 × LLN) 0.3% 0.2% 0%
White blood cells (<0.75 × LLN) 0.7% 0.6% 0.2%
Platelet count (<100, 000/mm3) 0.3% 0.1% 0.7%
AST (SGOT) (>2 × ULN) 1.0% * 0.5%
Serum creatinine (>1.5 × ULN) 0.7% 0% 0%
* Data were not collected prospectively.
LLN = Lower limit of normal.
ULN = Upper limit of normal.

TABLE 4C Incidence (%) of Laboratory Abnormalities in Genital Herpes Suppression Study Populations
Valacyclovir HCl
Laboratory Abnormality 1 g qd 500 mg qd Placebo
Hemoglobin (<0.8 × LLN) 0% 0.8% 0.8%
White blood cells (<0.75 × LLN) 0.7% 0.8% 1.5%
Platelet count (<100, 000/mm3) 0.4% 1.1% 1.5%
AST (SGOT) (>2 × ULN) 4.1% 3.8% 3.0%
Serum creatinine (>1.5 × ULN) 0% 0% 0%
LLN = Lower limit of normal.
ULN = Upper limit of normal.

In clinical studies for the treatment of cold sores, the frequencies of abnormal ALT (>2 × ULN) were 1.8% for patients receiving valacyclovir HCl compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.

Observed During Clinical Practice

The following events have been identified during post-approval use of valcyclovir HCl in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to valacyclovir HCl, or a combination of these factors.

General: Facial edema, hypertension, tachycardia.
Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria.
CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations; seizures (see PRECAUTIONS).
Eye: Visual abnormalities.
Gastrointestinal: Diarrhea.
Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.
Renal: Elevated creatinine, renal failure.
Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis.
Skin: Erythema multiforme, rashes including photosensitivity.

Renal Impairment

Renal failure and CNS symptoms have been reported in patients with renal impairment who received valacyclovir HCl or acyclovir at greater than the recommended dose. Dose reduction is recommended in this patient population (see DOSAGE AND ADMINISTRATION).

OVERDOSAGE
Caution should be exercised to prevent inadvertent overdose (see PRECAUTIONS). 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 AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION
Valacyclovir HCl caplets may be given without regard to meals.

Herpes Zoster

The recommended dosage of valacyclovir HCl for the treatment of herpes zoster is 1 g orally 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of zoster rash. No data are available on efficacy of treatment started greater than 72 hours after rash onset.

Genital Herpes

Initial Episodes

The recommended dosage of valacyclovir HCl for treatment of initial genital herpes is 1 g twice daily for 10 days.

There are no data on the effectiveness of treatment with valacyclovir HCl when initiated more than 72 hours after the onset of signs and symptoms. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

Recurrent Episodes

The recommended dosages of valacyclovir HCl for the treatment of recurrent genital herpes is 500 mg twice daily for 3 days.

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 with valacyclovir HCl when initiated more than 24 hours after the onset of signs or symptoms.

Suppressive Therapy

The recommended dosage of valacyclovir HCl for chronic suppressive therapy of recurrent genital herpes is 1 g once daily. In patients with a history of 9 or fewer recurrences/year, an alternative dose is 500 mg once daily. The safety and efficacy of therapy with valacyclovir HCl beyond 1 year have not been established.

Cold Sores (herpes labialis)

The recommended dosage of valacyclovir HCl for the treatment of cold sores is 2 g twice daily for 1 day taken about 12 hours apart. Therapy should be initiated 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 With Acute or Chronic Renal Impairment

In patients with reduced renal function, reduction in dosage is recommended (see TABLE 5A and TABLE 5B).

TABLE 5A Dosages for Patients With Renal Impairment
Normal Dosage Regimen
Indications (creatinine clearance ³50)
Herpes Zoster 1 g q 8h
Genital Herpes
Initial treatment 1 g q 12h
Recurrent episodes 500 mg q 12h
Suppressive therapy 1 g q 24h
Suppressive therapy 500 mg q 24h
Herpes labialis (cold sores) Do not exceed 1 day of treatment Two 2 g doses taken about 12 hours apart

TABLE 5B Dosages for Patients With Renal Impairment
Creatinine Clearance (ml/min)
Indications 30-49 10-29 <10
Herpes Zoster 1 g q 12h 1 g q 24h 500 mg q 24h
Genital Herpes
Initial treatment no reduction 1 g q 24h 500 mg q 24h
Recurrent episodes no reduction 500 mg q 24h 500 mg q 24h
Suppressive therapy no reduction 500 mg q 24h 500 mg q 24h
Suppressive therapy no reduction 500 mg q 48h 500 mg q 48h
Herpes labialis (cold sores) Do not exceed 1 day of treatment Two 1 g doses taken about 12 hours apart Two 500 mg doses taken about 12 hours apart 500 mg single dose

Hemodialysis

During hemodialysis, the half-life of acyclovir after administration of valacyclovir HCl is approximately 4 hours. About one-third of acyclovir in the body is removed by dialysis during a 4 hour hemodialysis session. Patients requiring hemodialysis should receive the recommended dose of valacyclovir HCl after hemodialysis.

Peritoneal Dialysis

There is no information specific to administration of valacyclovir in patients receiving peritoneal dialysis. 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 HCl should not be required following CAPD or CAVHD.

HOW SUPPLIED
Valtrex Caplets

500 mg: Blue, film-coated, capsule-shaped tablets containing valacyclovir HCl equivalent to 500 mg valacyclovir and printed with "VALTREX 500 mg".
1 g: Blue, film-coated, capsule-shaped tablets containing valacyclovir HCl equivalent to 1 g valacyclovir and printed with "VALTREX 1 gram".

Storage: Store at 15-25°C (59-77°F).

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