VALTREX

1 INDICATIONS AND USAGE VALTREX is a deoxynucleoside 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 Cold Sores (Herpes Labialis) VALTREX is 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/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.

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 tablets 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 tablets. ( 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/mm 3 , 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 tablets 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. Instructions for Preparing Suspension at Time of Dispensing • Prepare SSV according to the USP-NF. • Using a pestle and mortar, grind the required number of VALTREX 500-mg tabl…

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 ) • Severe cutaneous adverse reactions (SCARs): Including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS) have been reported during the postmarketing experience with valacyclovir. Discontinue VALTREX immediately if a painful rash with mucosal involvement or a progressive severe rash develops, and closely monitor clinical status. ( 5.4 ) 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 …

4 CONTRAINDICATIONS VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction [e.g., anaphylaxis, severe cutaneous adverse reactions (SCARs)] to valacyclovir, acyclovir, or any component of the formulation [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.3 )] . Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any component of the formulation. ( 4 )

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

8.1 Pregnancy Risk Summary Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified a drug associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes (see Data) . There are risks to the fetus associated with untreated herpes simplex during pregnancy (see Clinical Considerations). In animal reproduction studies, no evidence of adverse developmental outcomes was observed with valacyclovir when administered to pregnant rats and rabbits at system exposures (AUC) 4 (rats) and 7 (rabbits) times the human exposure at the maximum recommended human dose (MRHD) (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: The risk of neonatal HSV infection varies from 30% to 50% for genital HSV acquired in late pregnancy (third trimester), whereas with HSV acquisition in early pregnancy, the risk of neonatal infection is about 1%. A primary herpes occurrence during the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and, in rare cases, skin lesions. In very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth. Co-infection with HSV increases the risk of perinatal HIV transmission in women who had a clinical diagnosis of genital herpes during pregnancy. Data Human Data : Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, based on published literature, have not identified a drug-associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes. The Acyclovir and the Valacyclovir Pregnancy Registries, both population-based international prospective studies, collected pregnancy data through April 1999. The Acyclovir Registry documented outcomes of 1,246 infants and fetuses exposed to acyclovir during pregnancy (756 with earliest exposure during the first trimester, 197 during the second trimester, 291 during the third trimester, and 2 unknown). The occurrence of major birth defects during first-trimester exposure to acyclovir was 3.2% (95% CI: 2.0% to 5.0%) and during any trimester of exposure was 2.6% (95% CI: 1.8% to 3.8%). The Valacyclovir Pregnancy Registry documented outcomes of 111 infants and fetuses exposed to valacyclovir during pregnancy (28 with earliest exposure in the first trimester, 31 during the second trimester, and 52 during the third trimester).The occurrence of major birth defects during first-trimester exposure to valacyclovir was 4.5% (95% CI: 0.24% to 24.9%) and during any trimester of exposure was 3.9% (95% CI: 1.3% to 10.7%). Available studies have methodological limitations including insufficient sample size to support conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Animal Data : Valacyclovir was administered orally to pregnant rats and rabbits (up to 400 mg/kg/day) during organogenesis (Gestation Days 6 through 15, and 6 through 18, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (AUC) of up to approximately 4 (rats) and 7 (rabbits) times the exposure in humans at the MRHD. Early embryo death, fetal growth retardation (weight and length), and variations in fetal skeletal development (primarily extra ribs and delayed ossificatio…

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 )] . • Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.4 )] . 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 with 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. • The most common adverse reactions reported in at least one indication by greater than 10% of adult subjects treated with VALTREX and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. ( 6.1 ) • The only adverse reaction occurring in greater than 10% of pediatric subjects aged less than 18 years was headache. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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…