Valtrex (as valacyclovir hydrochloride) 1000 MG Oral Tablet

DRUG INTERACTIONS

7 No clinically significant drug-drug or drug-food interactions with VALTREX are known [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 Caution should be exercised to prevent inadvertent overdose .

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 Use in Specific Populations (8.5, 8.6)] [see Dosage and Administration (2.4)]

DESCRIPTION

11 VALTREX (valacyclovir hydrochloride) is the hydrochloride salt of the ─valyl ester of the antiviral drug acyclovir.

L VALTREX Caplets are for oral administration.

Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No.

2 Lake, hypromellose, 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 -valine, 2-[(2-amino-1,6-dihydro-6-oxo-9 -purin-9-yl)methoxy]ethyl ester, monohydrochloride.

It has the following structural formula: L H Valacyclovir hydrochloride is a white to off─white powder with the molecular formula C H N O •HCl and a molecular weight of 360.80.

The maximum solubility in water at 25°C is 174 mg/mL.

The pk s for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

13 20 6 4 a valacyclovir hydrochloride chemical structure

CLINICAL STUDIES

14 14.1 Cold Sores (Herpes Labialis) Two double‑blind, placebo‑controlled clinical trials were conducted in 1,856 healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores.

Subjects self‑initiated therapy at the earliest symptoms and prior to any signs of a cold sore.

The majority of subjects initiated treatment within 2 hours of onset of symptoms.

Subjects were randomized to VALTREX 2 grams twice daily on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1 followed by 1 gram 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 with placebo.

The 2─day regimen did not offer additional benefit over the 1─day regimen.

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

14.2 Genital Herpes Infections Six hundred forty─three 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 VALTREX 1 gram twice daily (n = 323) or oral 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, and the median time to cessation of viral shedding was 3 days.

Initial Episode: Three double─blind trials (2 of them placebo─controlled) in immunocompetent adults with recurrent genital herpes were conducted.

Subjects self─initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

Recurrent Episodes: In 1 trial, subjects were randomized to receive 5 days of treatment with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259).

The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in subjects with at least 1 positive culture (42% of the overall trial population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group.

The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group.

Results supporting efficacy were replicated in a second trial.

In a third trial, subjects were randomized to receive VALTREX 500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3 days (and matching placebo twice daily 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.

Two clinical trials were conducted, one in immunocompetent adults and one in HIV-1─infected adults.

Suppressive Therapy: A double‑blind, 12‑month, placebo‑ and active‑controlled trial enrolled immunocompetent adults with a history of 6 or more recurrences per year.

Outcomes for the overall trial population are shown in Table 5.

Table 5.

Recurrence Rates in Immunocompetent Adults at 6 and 12 Months Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

a Outcome 6 Months 12 Months VALTREX 1 gram Once Daily (n = 269) Oral Acyclovir 400 mg Twice Daily (n = 267) Placebo (n = 134) VALTREX 1 gram Once Daily (n = 269) Oral Acyclovir 400 mg Twice Daily (n = 267) Placebo (n = 134) Recurrence free 55% 54% 7% 34% 34% 4% Recurrences 35% 36% 83% 46% 46% 85% Unknown a 10% 10% 10% 19% 19% 10% Subjects with 9 or fewer recurrences per year showed comparable results with VALTREX 500 mg once daily.

In a second trial, 293 HIV‑1-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano‑genital herpes per year were randomized to receive either VALTREX 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months.

The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5.

Overall, the median pretrial HIV‑1 RNA was 2.6 log copies/mL.

Among subjects who received VALTREX, the pretrial median CD4+ cell count was 336 cells/mm ; 11% had less than 100 cells/mm , 16% had 100 to 199 cells/mm , 42% had 200 to 499 cells/mm , and 31% had greater than or equal to 500 cells/mm .

Outcomes for the overall trial population are shown in Table 6.

10 3 3 3 3 3 Table 6.

Recurrence Rates in HIV─1-Infected Adults at 6 Months Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

a Outcome VALTREX 500 mg Twice Daily (n = 194) Placebo (n = 99) Recurrence free 65% 26% Recurrences 17% 57% Unknown a 18% 17% A double─blind, placebo─controlled trial to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples.

The couples were discordant for HSV─2 infection.

The source partner had a history of 9 or fewer genital herpes episodes per year.

Both partners were counseled on safer sex practices and were advised to use condoms throughout the trial period.

Source partners were randomized to treatment with either VALTREX 500 mg once daily or placebo once daily for 8 months.

The primary efficacy endpoint was symptomatic acquisition of HSV─2 in susceptible partners.

Overall HSV─2 acquisition was defined as symptomatic HSV─2 acquisition and/or HSV─2 seroconversion in susceptible partners.

The efficacy results are summarized in Table 7.

Reduction of Transmission of Genital Herpes: Table 7.

Percentage of Susceptible Partners Who Acquired HSV─2 Defined by the Primary and Selected Secondary Endpoints Results show reductions in risk of 75% (symptomatic HSV─2 acquisition), 50% (HSV─2 seroconversion), and 48% (overall HSV─2 acquisition) with VALTREX versus placebo.

Individual results may vary based on consistency of safer sex practices.

a Endpoint VALTREX a (n = 743) Placebo (n = 741) Symptomatic HSV─2 acquisition 4 (0.5%) 16 (2.2%) HSV─2 seroconversion 12 (1.6%) 24 (3.2%) Overall HSV─2 acquisition 14 (1.9%) 27 (3.6%) 14.3 Herpes Zoster Two randomized double‑blind clinical trials in immunocompetent adults with localized herpes zoster were conducted.

VALTREX was compared with placebo in subjects aged less than 50 years, and with oral acyclovir in subjects aged greater than 50 years.

All subjects were treated within 72 hours of appearance of zoster rash.

In subjects aged less than 50 years, the median time to cessation of new lesion formation was 2 days for those treated with VALTREX compared with 3 days for those treated with placebo.

In subjects aged greater than 50 years, the median time to cessation of new lesions was 3 days in subjects treated with either VALTREX or oral acyclovir.

In subjects aged less than 50 years, no difference was found with respect to the duration of pain after healing (post‑herpetic neuralgia) between the recipients of VALTREX and placebo.

In subjects aged greater than 50 years, 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 VALTREX, 14‑day VALTREX, and 7‑day oral acyclovir, respectively.

14.4 Chickenpox The use of VALTREX for treatment of chickenpox in pediatric subjects aged 2 to less than 18 years is based on single‑dose pharmacokinetic and multiple‑dose safety data from an open‑label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double‑blind, placebo‑controlled trials evaluating oral acyclovir in pediatric subjects.

The single‑dose pharmacokinetic and multiple‑dose safety trial enrolled 27 pediatric subjects aged 1 to less than 12 years with clinically suspected VZV infection.

Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days.

Acyclovir systemic exposures in pediatric subjects following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster.

The mean projected daily acyclovir exposures in pediatric subjects across all age‑groups (1 to less than 12 years) were lower (C : ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily.

The projected daily exposures in pediatric subjects were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric subjects receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox.

Based on the pharmacokinetic and safety data from this trial and the safety and extrapolated efficacy data from the acyclovir trials, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients aged 2 to less than 18 years.

Because the efficacy and safety of acyclovir for the treatment of chickenpox in children aged less than 2 years have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children aged less than 2 years with chickenpox.

Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available .

max [see Use in Specific Populations (8.4)]

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC:54569-5324-3 in a BOTTLE of 30 TABLET, FILM COATEDS

GERIATRIC USE

8.5 Geriatric Use [Of the total number of subjects in clinical trials of VALTREX, 906 were 65 and over, and 352 were 75 and over.

In a clinical trial of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in subjects 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 .

[see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.3)]

DOSAGE FORMS AND STRENGTHS

3 Caplets: 500-mg: blue, film─coated, capsule─shaped tablets printed with “VALTREX 500 mg.” • 1-gram: blue, film─coated, capsule─shaped tablets, with a partial scorebar on both sides, printed with “VALTREX 1 gram.” • Caplets: 500 mg (unscored), 1 gram (partially scored) ( ) 3

MECHANISM OF ACTION

12.1 Mechanism of Action Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

INDICATIONS AND USAGE

1 VALTREX is a nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients ( 1.1 ) Cold Sores (Herpes Labialis) • Genital Herpes • Treatment in immunocompetent patients (initial or recurrent episode) • Suppression in immunocompetent or HIV-1-infected patients • Reduction of transmission • Herpes Zoster • Pediatric Patients ( 1.2 ) Cold Sores (Herpes Labialis) • Chickenpox • Limitations of Use ( 1.3 ) The efficacy and safety of VALTREX have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-1─infected patients.

• 1.1 Adult Patients VALTREX (valacyclovir hydrochloride) Caplets are indicated for treatment of cold sores (herpes labialis).

The efficacy of VALTREX initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.

Cold Sores (Herpes Labialis): ® VALTREX is indicated for treatment of the initial episode of genital herpes in immunocompetent adults.

The efficacy of treatment with VALTREX when initiated more than 72 hours after the onset of signs and symptoms has not been established.

Genital Herpes: Initial Episode: VALTREX is indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults.

The efficacy of treatment with VALTREX when initiated more than 24 hours after the onset of signs and symptoms has not been established.

Recurrent Episodes: VALTREX is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-1─infected adults.

The efficacy and safety of VALTREX for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-1─infected patients have not been established.

Suppressive Therapy: VALTREX is indicated for the reduction of transmission of genital herpes in immunocompetent adults.

The efficacy of VALTREX for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established.

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

Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] ).

Reduction of Transmission: Sexually Transmitted Diseases Treatment Guidelines VALTREX is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults.

The efficacy of VALTREX when initiated more than 72 hours after the onset of rash and the efficacy and safety of VALTREX for treatment of disseminated herpes zoster have not been established.

Herpes Zoster: 1.2 Pediatric Patients VALTREX is indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years.

The efficacy of VALTREX initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.

Cold Sores (Herpes Labialis): VALTREX is indicated for the treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years.

Based on efficacy data from clinical trials with oral acyclovir, treatment with VALTREX should be initiated within 24 hours after the onset of rash .

Chickenpox: [see Clinical Studies (14.4)] 1.3 Limitations of Use The efficacy and safety of VALTREX have not been established in: Immunocompromised patients other than for the suppression of genital herpes in HIV─1─infected patients with a CD4+ cell count greater than or equal to 100 cells/mm .

• 3 Patients aged less than 12 years with cold sores (herpes labialis).

• Patients aged less than 2 years or greater than or equal to 18 years with chickenpox.

• Patients aged less than 18 years with genital herpes.

• Patients aged less than 18 years with herpes zoster.

• Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

PEDIATRIC USE

8.4 Pediatric Use VALTREX is indicated for treatment of cold sores in pediatric patients aged greater than or equal to 12 years and for treatment of chickenpox in pediatric patients aged 2 to less than 18 years .

[see Indications and Usage (1.2), Dosage and Administration (2.2)] The use of VALTREX for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores .

[see Clinical Studies (14.1)] The use of VALTREX for treatment of chickenpox in pediatric patients aged 2 to less than 18 years is based on single─dose pharmacokinetic and multiple─dose safety data from an open─label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double─blind, placebo─controlled trials evaluating oral acyclovir in pediatric subjects with chickenpox .

[see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)] The efficacy and safety of valacyclovir have not been established in pediatric patients: aged less than 12 years with cold sores • aged less than 18 years with genital herpes • aged less than 18 years with herpes zoster • aged less than 2 years with chickenpox • for suppressive therapy following neonatal HSV infection.

• The pharmacokinetic profile and safety of valacyclovir oral suspension in children aged less than 12 years were studied in 3 open‑label trials.

No efficacy evaluations were conducted in any of the 3 trials.

Trial 1 was a single‑dose pharmacokinetic, multiple‑dose safety trial in 27 pediatric subjects aged 1 to less than 12 years with clinically suspected varicella─zoster virus (VZV) infection [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

Trial 2 was a single‑dose pharmacokinetic and safety trial in pediatric subjects aged 1 month to less than 6 years who had an active herpes virus infection or who were at risk for herpes virus infection.

Fifty─seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension.

In infants and children aged 3 months to less than 6 years, this dose provided comparable systemic acyclovir exposures to that from a 1─gram dose of valacyclovir in adults (historical data).

In infants aged 1 month to less than 3 months, mean acyclovir exposures resulting from a 25─mg/kg dose were higher (C : ↑30%, AUC: ↑60%) than acyclovir exposures following a 1─gram dose of valacyclovir in adults.

Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir.

max Trial 3 was a single‑dose pharmacokinetic, multiple‑dose safety trial in 28 pediatric subjects aged 1 to less than 12 years with clinically suspected HSV infection.

None of the subjects enrolled in this trial had genital herpes.

Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days.

Acyclovir systemic exposures in pediatric subjects following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes.

The mean projected daily acyclovir systemic exposures in pediatric subjects across all age‑groups (1 to less than 12 years) were lower (C : ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily.

Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age‑group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible.

Moreover, valacyclovir has not been studied in children aged 1 to less than 12 years with recurrent genital herpes.

max

PREGNANCY

8.1 Pregnancy Pregnancy Category B.

There are no adequate and well─controlled trials of VALTREX or acyclovir in pregnant women.

Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population.

VALTREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.

NUSRING MOTHERS

8.3 Nursing Mothers Following oral administration of a 500─mg dose of VALTREX to 5 nursing mothers, peak acyclovir concentrations (C ) 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.

Caution should be exercised when VALTREX is administered to a nursing woman.

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WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV-1 disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of VALTREX in clinical trials.

Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur.

( ) • 5.1 Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher than recommended doses of VALTREX for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients.

Use with caution in elderly patients and reduce dosage in patients with renal impairment.

( , ) • 2.4 5.2 Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher than recommended doses of VALTREX for their level of renal function.

Elderly patients are more likely to have central nervous system adverse reactions.

Use with caution in elderly patients and reduce dosage in patients with renal impairment.

( ) • 2.4, 5.3 5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV─1 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.

Treatment with VALTREX should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.

5.2 Acute Renal Failure Cases of acute renal failure have been reported in: Elderly patients with or without reduced renal function.

Caution should be exercised when administering VALTREX to geriatric patients, and dosage reduction is recommended for those with impaired renal function • [see Dosage and Administration (2.4), Use in Specific Populations (8.5)].

Patients with underlying renal disease who received higher-than-recommended doses of VALTREX for their level of renal function.

Dosage reduction is recommended when administering VALTREX to patients with renal impairment • [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].

Patients receiving other nephrotoxic drugs.

Caution should be exercised when administering VALTREX to patients receiving potentially nephrotoxic drugs.

• Patients without adequate hydration.

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 for all patients.

• In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored .

[see Dosage and Administration (2.4), Adverse Reactions (6.3)] 5.3 Central Nervous System Effects Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher-than-recommended doses of VALTREX for their level of renal function.

Elderly patients are more likely to have central nervous system adverse reactions.

VALTREX should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION ‑ Advise the patient to read the FDA Approved Patient Labeling (Patient Information).

Patients should be advised to maintain adequate hydration.

Importance of Adequate Hydration: 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.

Cold Sores (Herpes Labialis): 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.

Genital Herpes: 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‑1-infected patients.

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.

Herpes Zoster: : Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.

Chickenpox VALTREX is a registered trademark of the GlaxoSmithKline group of companies.

Distributed by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline group of companies.

All rights reserved.

VTX:6PI PHARMACIST‑DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

DOSAGE AND ADMINISTRATION

2 VALTREX may be given without regard to meals.

• Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg VALTREX Caplets for use in pediatric patients for whom a solid dosage form is not appropriate .

• [see Dosage and Administration (2.3)] ( ) Adult Dosage 2.1 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 less than or equal to 9 recurrences/year 500 mg once daily HIV-1─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 2.2 Cold Sores (aged greater than or equal to 12 years) 2 grams every 12 hours for 1 day Chickenpox (aged 2 to less than 18 years) 20 mg/kg 3 times daily for 5 days; not to exceed 1 gram 3 times daily Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) can be prepared from the 500 mg VALTREX Caplets.

( ) 2.3 2.1 Adult Dosing Recommendations The recommended dosage of VALTREX for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart.

Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

Cold Sores (Herpes Labialis): The recommended dosage of VALTREX for treatment of initial genital herpes is 1 gram twice daily for 10 days.

Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

Genital Herpes: Initial Episode: The recommended dosage of VALTREX for treatment of recurrent genital herpes is 500 mg twice daily for 3 days.

Initiate treatment at the first sign or symptom of an episode.

Recurrent Episodes: The recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function.

In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.

Suppressive Therapy: In HIV─1─infected patients with a CD4+ cell count greater than or equal to 100 cells/mm , the recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

3 The recommended dosage of VALTREX for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.

Reduction of Transmission: The recommended dosage of VALTREX for treatment of herpes zoster is 1 gram 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 rash.

Herpes Zoster: 2.2 Pediatric Dosing Recommendations The recommended dosage of VALTREX for the treatment of cold sores in pediatric patients aged greater than or equal to 12 years is 2 grams twice daily for 1 day taken 12 hours apart.

Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

Cold Sores (Herpes Labialis): The recommended dosage of VALTREX for treatment of chickenpox in immunocompetent pediatric patients aged 2 to less than 18 years is 20 mg/kg administered 3 times daily for 5 days.

The total dose should not exceed 1 gram 3 times daily.

Therapy should be initiated at the earliest sign or symptom .

Chickenpox: [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)] 2.3 Extemporaneous Preparation of Oral Suspension VALTREX Caplets 500 mg, cherry flavor, and Suspension Structured Vehicle USP─NF (SSV).

Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of 100 mL.

Ingredients and Preparation per USP─NF: Prepare Suspension at Time of Dispensing as Follows: Prepare SSV according to the USP-NF.

• Using a pestle and mortar, grind the required number of VALTREX 500 mg Caplets until a fine powder is produced (5 VALTREX Caplets for 25 mg/mL suspension; 10 VALTREX Caplets for 50 mg/mL suspension).

• Gradually add approximately 5-mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced.

Ensure that the powder has been adequately wetted.

• Continue to add approximately 5-mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50─mg/mL suspensions.

• Transfer the mixture to a suitable 100-mL measuring flask.

• Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV.

Once dissolved, add to the measuring flask.

• Rinse the mortar at least 3 times with approximately 5-mL aliquots of SSV, transferring the rinsing to the measuring flask between additions.

• Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix.

• Transfer the suspension to an amber glass medicine bottle with a child─resistant closure.

• The prepared suspension should be labeled with the following information “Shake well before using.

Store suspension between 2° to 8°C (36° to 46°F) in a refrigerator.

Discard after 28 days.” • *The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.

2.4 Patients With Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table 1 .

Data are not available for the use of VALTREX in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m .

[see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)] 2 Table 1.

VALTREX Dosage Recommendations for Adults With Renal Impairment Indications Normal Dosage Regimen (Creatinine Clearance ≥50 mL/min) Creatinine Clearance (mL/min) 30-49 10-29 <10 Cold sores (Herpes labialis) Do not exceed 1 day of treatment.

Two 2 gram doses taken 12 hours apart Two 1 gram doses taken 12 hours apart Two 500 mg doses taken 12 hours apart 500 mg single dose Genital herpes: Initial episode 1 gram every 12 hours no reduction 1 gram every 24 hours 500 mg every 24 hours Genital herpes: Recurrent episode 500 mg every 12 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Genital herpes: Suppressive therapy Immunocompetent patients 1 gram every 24 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Alternate dose for immunocompetent patients with less than or equal to 9 recurrences/year 500 mg every 24 hours no reduction 500 mg every 48 hours 500 mg every 48 hours HIV─1─infected patients 500 mg every 12 hours no reduction 500 mg every 24 hours 500 mg every 24 hours Herpes zoster 1 gram every 8 hours 1 gram every 12 hours 1 gram every 24 hours 500 mg every 24 hours Patients requiring hemodialysis should receive the recommended dose of VALTREX after hemodialysis.

During hemodialysis, the half─life of acyclovir after administration of VALTREX is approximately 4 hours.

About one-third of acyclovir in the body is removed by dialysis during a 4─hour hemodialysis session.

Hemodialysis: There is no information specific to administration of VALTREX 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 end─stage renal disease (ESRD) not receiving hemodialysis.

Therefore, supplemental doses of VALTREX should not be required following CAPD or CAVHD.

Peritoneal Dialysis: