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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Adult Patients

1.2 Pediatric Patients

1.3 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosing Recommendations

2.2 Pediatric Dosing Recommendations

2.3 Extemporaneous Preparation of Oral Suspension

2.4 Patients With Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)

5.2 Acute Renal Failure

5.3 Central Nervous System Effects

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience in Adult Subjects

6.2 Clinical Trials Experience in Pediatric Subjects

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Cold Sores (Herpes Labialis)

14.2 Genital Herpes Infections

14.3 Herpes Zoster

14.4 Chickenpox

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

 

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adult Patients

Cold Sores (Herpes Labialis): 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.

Genital Herpes: Initial Episode: 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.

Recurrent Episodes: 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.

Suppressive Therapy: 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.

Reduction of Transmission: 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] Sexually Transmitted Diseases Treatment Guidelines).

Herpes Zoster: 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.

1.2 Pediatric Patients

Cold Sores (Herpes Labialis): 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.

Chickenpox: 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 [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/mm3.

•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.

2 DOSAGE AND ADMINISTRATION

•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)].

2.1 Adult Dosing Recommendations

Cold Sores (Herpes Labialis): 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).

Genital Herpes: Initial Episode: 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.

Recurrent Episodes: 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.

Suppressive Therapy: 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.

In HIV─1─infected patients with a CD4+ cell count greater than or equal to 100 cells/mm3, the recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

Reduction of Transmission: 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.

Herpes Zoster: 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.

2.2 Pediatric Dosing Recommendations

Cold Sores (Herpes Labialis): 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).

Chickenpox: 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 [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

2.3 Extemporaneous Preparation of Oral Suspension

Ingredients and Preparation per USP─NF: 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.

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 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of VALTREX in pediatric patients with a creatinine clearance less than 50 mL/min/1.73 m2.

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

 

Hemodialysis: 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.

Peritoneal Dialysis: 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.

3 DOSAGE FORMS AND STRENGTHS

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."

4 CONTRAINDICATIONS

VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)].

5 WARNINGS AND PRECAUTIONS

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)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

•Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)].

•Acute Renal Failure [see Warnings and Precautions (5.2)].

•Central Nervous System Effects [see Warnings and Precautions (5.3)].

The most common adverse reactions reported in at least 1 indication by greater than 10% of adult subjects treated with VALTREX and observed more frequently with VALTREX compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric subjects aged less than 18 years was headache.

6.1 Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cold Sores (Herpes Labialis): In clinical trials for the treatment of cold sores, the adverse reactions reported by subjects receiving VALTREX 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for subjects receiving VALTREX 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.

Genital Herpes: Initial Episode: In a clinical trial for the treatment of initial episodes of genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving VALTREX 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2.

Recurrent Episodes: In 3 clinical trials for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving VALTREX 500 mg twice daily for 3 days (n = 402), VALTREX 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.

Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical trial for the suppression of recurrent genital herpes infections, the adverse reactions reported by subjects receiving VALTREX 1 gram once daily (n = 269), VALTREX 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2.

Suppression of Recurrent Genital Herpes in HIV─1-Infected Subjects: In HIV─1-infected subjects, frequently reported adverse reactions for VALTREX (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post─randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively.

Reduction of Transmission: In a clinical trial for the reduction of transmission of genital herpes, the adverse reactions reported by subjects receiving VALTREX 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%).

Herpes Zoster: In 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving VALTREX 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.

Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations

 

Laboratory Abnormality

Herpes Zoster

Genital Herpes Treatment

Genital Herpes Suppression

 

VALTREX

1 gram

3 Times Daily

(n = 967)

Placebo

(n = 195)

VALTREX

1 gram Twice Daily

(n = 1,194)

VALTREX

500 mg Twice Daily

(n = 1,159)

Placebo

(n = 439)

VALTREX

1 gram Once Daily

(n = 269)

VALTREX

500 mg Once Daily

(n = 266)

Placebo

(n = 134)

 

Hemoglobin

(<0.8 x LLN)

0.8%

0%

0.3%

0.2%

0%

0%

0.8%

0.8%

 

White blood cells

(<0.75 x LLN)

1.3%

0.6%

0.7%

0.6%

0.2%

0.7%

0.8%

1.5%

 

Platelet count (<100,000/mm3)

1.0%

1.2%

0.3%

0.1%

0.7%

0.4%

1.1%

1.5%

 

AST (SGOT)

(>2 x ULN)

1.0%

0%

1.0%

a

0.5%

4.1%

3.8%

3.0%

 

Serum creatinine

(>1.5 x ULN)

0.2%

0%

0.7%

0%

0%

0%

0%

0%

 

a Data were not collected prospectively.

 

LLN = Lower limit of normal.

 

ULN = Upper limit of normal.

 

6.2 Clinical Trials Experience in Pediatric Subjects

The safety profile of VALTREX has been studied in 177 pediatric subjects aged 1 month to less than 18 years. Sixty-five of these pediatric subjects, aged 12 to less than 18 years, received oral caplets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric subjects, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety trials and received valacyclovir oral suspension. Fifty-one of these 112 pediatric subjects received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.

Pediatric Subjects Aged 12 to Less Than 18 Years (Cold Sores): In clinical trials for the treatment of cold sores, the adverse reactions reported by adolescent subjects receiving VALTREX 2 grams twice daily for 1 day, or VALTREX 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).

Pediatric Subjects Aged 1 Month to Less Than 12 Years: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials in children aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.

6.3 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of VALTREX. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to VALTREX.

General: Facial edema, hypertension, tachycardia.

Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)].

CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6)].

Eye: Visual abnormalities.

Gastrointestinal: Diarrhea.

Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.

Renal: Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6)].

Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1)].

Skin: Erythema multiforme, rashes including photosensitivity, alopecia.

7 DRUG INTERACTIONS

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

8 USE IN SPECIFIC POPULATIONS

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 n

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Valtrex 500 Mg 42 Tablets

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