VALACYCLOVIR HYDROCHLORIDE_- valacyclovir hydrochloride_tablet, film coated

Valacyclovir is an antiviral drug active against alpha-herpes viruses [see Microbiology (12. 4) The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years. Pharmacokinetics in Adults Absorption and Bioavailability: L- The absolute bioavailability of acyclovir after administration of valacyclovir hydrochloride is 54. 1% as determined following a 1 gram oral dose of valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir hydrochloride is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat). Acyclovir pharmacokinetic parameter estimates following administration of valacyclovir hydrochloride to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C max There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function. Mean (+/-SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir Hydrochloride to Healthy Adult Volunteers a Dose Single-Dose Administration (N = 8) Multiple-Dose Administration a (N = 24, 8 per treatment arm) C max (mcg/mL) AUC (+/-SD) (hmcg/mL) C max AUC (+/-SD) (hmcg/mL) 100 mg 0. 4) ND ND 250 mg 2. 09) 500 mg 3. 01) 750 mg 4. 54) ND ND 1,000 mg 5. 27) Distribution: Metabolism: L Elimination: The plasma elimination half-life of acyclovir typically averaged 2. 3 hours in all trials of valacyclovir hydrochloride in subjects with normal renal function. Specific Populations Patients with Renal Impairment: [see Dosage and Administration (2. 4) Use in Specific Populations (8. Following administration of valacyclovir hydrochloride to subjects 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 subjects on dialysis was 86. 73 m 2 2 Patients with Hepatic Impairment: Patients with HIV-1 Disease: 3 Geriatric Patients: [see Dosage and Administration (2. 6) Pediatric Patients: [see Adverse Reactions (6. 2) Use in Specific Populations (8. Mean (+/-SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Subjects vs. 1 Gram Single Dose of Valacyclovir Hydrochloride to Adults a Parameter Pediatr ic Subjects (20 mg/kg Oral Suspension) Adults 1 gram Solid Dose of Valacyclovir Hydrochloride a (n = 15) 1 to <2 year (n = 6) 2 to <6 year (n = 12) 6 to <12 year (n = 8) AUC (mcgh/mL) max 14. 1) Drug Interaction Studies When valacyclovir hydrochloride is coadministered with antacids, cimetidine and/or probenecid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir hydrochloride is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended. Antacids: 3+ ++ Cimetidine: max Cimetidine plus Probenecid: max Digoxin: Probenecid: max Thiazide Diuretics: Mechanism of Action Valacyclovir is a deoxynucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo Acyclovir is a synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK; pUL23) of HSV or VZV 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 biochemical assays, acyclovir triphosphate inhibits replication of alpha-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 with VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activity The quantitative relationship between the cell culture 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 (EC 50 50 50 50 Resistance Table 5. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions in Cell Culture Virus Gene Substitution HSV-1 TK P5A, H7Q, L50V, G56V, G59R/V/W/A, G61A/V, K62I/N, T63A, E83K, P84L/S, R89W, D116N, P131S, P155R, F161I/C, R163H/P, A167V, P173L, R176Q/W, Q185R, A189L/V, G200S, G206R, R216S, R220H, L227F, Y239S, T245M, Q261stop, R281stop, T287M, M322K, C336Y, V348A HSV-2 TK L69P, C172R, A175V, T288M HSV-1 POL D368A, Y557S, E597D, V621S, L702H, A719V, S742N, N815S, V817M, Y818C, G841C/S HSV-2 POL No substitutions detected HSV-Infected Patients: Table 6. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Observed in Treated Patients Virus Gene Substitution HSV-1 TK G6C, R32H, R41H, R51W, Y53C/D/H, Y53stop, D55N, G56D/E/S, P57H, G58N/R, G59R, G61A/E/W, K62N, T63I, Q67stop, S74stop, Y80N, E83K, P84L, Y87H, E95stop, T103P, Q104H, Q104stop, H105P, M121K/L/R, Q125N, M128L, G129D, I143V, A156V, D162A/H/N, R163G/H, L170P, Y172C, P173L/R, A174P, A175V, R176Q/W, R176stop, L178R, S181N, A186P, V187M, A189V, V192A, G200C/D/S, T201P, T202A, V204G, A207P, L208F/H, R216C/H, R220C/H, R221C/H, R222C/H, E226K, D229H, L242P, T245M/P, L249P, Q250stop, C251G, E257K, Q261R, A265T, R281stop, T287M, L288stop, L291R, L297S, L315S, L327R, C336Y, C336stop, Q342stop, T354P, L364P, A365T HSV-2 TK G25A, R34C, G39E, R51W, Y53N/D, G59P, G61A/E/W, S66P, A72S, D78N, P85S, R86P, A94V, L98stop, N100H, I101S, Q103stop, Q105P, A125T, T131P, Y133F, D137stop, F140L, L158P, S169P, R177W, S182N, M183Istop, V192M, G201D, R217H, R221C/H, Q222stop, R223H, D229stop, Y239stop, D231N, L263stop, R271V, P272S, D273R, T287M, C337Y HSV-1 POL K532T, S559L, Q570R, L583V, A605V, V621S, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, R842S, I890M, V958L, H1228D HSV-2 POL E250Q, D307N, K533E, A606V, C625R, R628C, E678G, A724V, S725G, S729N, I731F, Q732R, D785N, M789K/T, V818A, N820S, Y823C, Q829R, T843A, M910T, D912N/V, A915V, F923L, T934A, R964H Note: Many additional pathways to acyclovir resistance likely exist. Cross-Resistance Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) (Table 7). Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS Cross-Resistant Drug Virus/Gene Substitution PCV/FCV HSV-1 TK G6C, R32H, R51W, Y53C/H/N, H58N, G61A, S74stop, E83K, P84L, T103P, Q104stop, D116N, M121R, I143V, P155R, R163G/H, A167V, L170P, Y172C, P173L, A174P, R176Q/W, Q185R, A186P, A189L/V, G200D/S, G206R, L208H, R216C, R220H, R222C/H, Y239S, T245M, Q250stop, Q261stop, R281stop, T287M, L315S, M322K, C336Y, V348A HSV-1 POL A657T, D672N, V715G, A719V, S724N, E798K, N815S, G841C/S HSV-2 TK G39E, R51W, Y53N, R86P, Y133F, R177W, R221H, T288M HSV-2 POL K533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934A FOS HSV-1 POL D368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890M HSV-2 POL K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H.

Valacyclovir hydrochloride 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 valacyclovir tablets have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-1-infected patients. Cold Sores (Herpes Labialis) Genital Herpes Initial Episode: Sexually Transmitted Diseases Treatment Guidelines Herpes Zoster Cold Sores (Herpes Labialis) Valacyclovir tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years. The efficacy of valacyclovir tablets initiated after the development of clinical signs of a cold sore (e. , papule, vesicle, or ulcer) has not been established. Chickenpox Valacyclovir tablets are 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 valacyclovir tablets should be initiated within 24 hours after the onset of rash [see Clinical Studies (14. 4) The efficacy and safety of valacyclovir tablets 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.

Valacyclovir tablets may be given without regard to meals. Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500 mg valacyclovir 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 1 gram once 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 valacyclovir tablets. 3 Cold Sores (Herpes Labialis) The recommended dosage of valacyclovir tablets 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. , tingling, itching, or burning). Genital Herpes Initial Episode: Recurrent Episodes: Suppressive Therapy: In HIV-1-infected patients with a CD4+ cell count greater than or equal to 100 cells/mm 3 Reduction of Transmission: Herpes Zoster The recommended dosage of valacyclovir tablets 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. Cold Sores (Herpes Labialis) The recommended dosage of valacyclovir tablets 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. Chickenpox The recommended dosage of valacyclovir tablets 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) Ingredients and Preparation per USP-NF Valacyclovir 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 valacyclovir 500 mg tablets until a fine powder is produced (5 valacyclovir tablets for 25 mg/mL suspension; 10 valacyclovir tablets 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. Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) 2 Table 1. Valacyclovir Tablets Dosage Recommendations for Adults with Renal Impairment Indications Normal Dosage Regimen (Creatinine Clearance >=50 mL/min) Creatinine Clearance (mL/min) 30 to 49 10 to 29 <10 Cold sores (Herpes Labialis) Do not exceed 1 day of treatment. Two 2 gram doses taken Two 1 gram doses taken Two 500 mg doses taken 500 mg Genital herpes: Initial episode 1 gram every no reduction 1 gram every 500 mg every Genital herpes: 500 mg every no reduction 500 mg every 500 mg every Genital herpes: Immunocompetent patients 1 gram every no reduction 500 mg every 500 mg every Alternate dose for immunocompetent patients with less than or equal to 9 recurrences/year 500 mg every no reduction 500 mg every 500 mg every HIV-1-infected patients 500 mg every no reduction 500 mg every 500 mg every Herpes zoster 1 gram every 1 gram every 1 gram every 500 mg every Hemodialysis Patients requiring hemodialysis should receive the recommended dose of valacyclovir tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir tablets 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 valacyclovir tablets 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 valacyclovir tablets should not be required following CAPD or CAVHD.

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 valacyclovir hydrochloride and observed more frequently with valacyclovir hydrochloride 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 valacyclovir hydrochloride and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. 1 The only adverse reaction occurring in greater than 10% of pediatric subjects aged less than 18 years was headache. 2 To report SUSPECTED ADVERSE REACTIONS, contact Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride 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: Recurrent Episodes: Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: Suppression of Recurrent Genital Herpes in HIV-1-Infected Subjects: Reduction of Transmission: Herpes Zoster In 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving valacyclovir hydrochloride 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. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations a Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Laboratory Abnormality Valacyclovir Hydro- chloride 1 gram 3 Times Daily (n = 967) Placebo (n = 195) Valacyclovir Hydro- chloride 1 gram Twice Daily (n = 1,194) Valacyclovir Hydro-chloride 500 mg Twice Daily (n = 1,159) Placebo (n = 439) Valacyclovir Hydro-chloride 1 gram Once Daily (n = 269) Valacyclovir Hydro-chloride 500 mg Once Daily (n = 266) Placebo (n = 134) Hemoglobin 0. 8% White blood cells 1. 5% Platelet count 3 1% 1. 5% AST (SGOT) 1% 0% 1% a 0. 8% 3% Serum creatinine 0. 7% 0% 0% 0% 0% 0% The safety profile of valacyclovir hydrochloride 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 tablets 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 valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 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. In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. 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 valacyclovir hydrochloride. General Facial edema, hypertension, tachycardia. Allergic Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4) Central Nervous System (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. 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. 6) Hematologic Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5. 1) Skin Erythema multiforme, rashes including photosensitivity, alopecia.

Valacyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e. , anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6. 3) ­Hypersensitivity to valacyclovir (e. , anaphylaxis), acyclovir, or any component of the formulation.

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). (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. 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: Data Human Data: 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%) and during any trimester of exposure was 2. 6% (95% CI: 1. 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. 9%) and during any trimester of exposure was 3. 9% (95% CI: 1. 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: In a pre/postnatal development study, valacyclovir was administered orally to pregnant rats (up to 200 mg/kg/day from Gestation Day 15 to Post-Partum Day 20) from late gestation through lactation. No significant adverse effects were observed in offspring exposed daily from before birth through lactation at maternal exposures (AUC) of approximately 6 times higher than human exposures at the MRHD. Risk Summary Although there is no information on the presence of valacyclovir in human milk, its metabolite, acyclovir, is present in human milk following oral administration of valacyclovir. Based on published data, a 500 mg maternal dose of valacyclovir hydrochloride twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0. 6 mg/kg/day (see Data). There is no data on the effects of valacyclovir or acyclovir on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for valacyclovir hydrochloride and any potential adverse effects on the breastfed child from valacyclovir hydrochloride or from the underlying maternal condition. Data Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 lactating women, peak acyclovir concentrations (C max Valacyclovir hydrochloride 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride 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. 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 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 max Of the total number of subjects in clinical trials of valacyclovir hydrochloride, 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. 3) Clinical Pharmacology (12. 3) Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment [see Dosage and Administration (2.

No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3)

OVERDOSAGE
Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5 8.6) [see Dosage and Administration (2.4)
NONCLINICAL TOXICOLOGY
The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram of valacyclovir hydrochloride 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 (12.3) Carcinogenesis Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors. Mutagenesis 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 In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was mutagenic in a mouse micronucleus assay. Impairment of Fertility Valacyclovir did not impair fertility or reproduction in male or female rats at acyclovir exposures (AUC) 6 times higher than in humans given the MRHD. Testicular atrophy occurred in male rats (orally dosed for 97 days at 18 times the MRHD) and was reversible.
CLINICAL STUDIES
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 valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 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 valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage. Initial Episode 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 valacyclovir hydrochloride 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. Recurrent Episodes 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. In 1 trial, subjects were randomized to receive 5 days of treatment with either In a third trial, subjects were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 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. Suppressive Therapy Two clinical trials were conducted, one in immunocompetent adults and one in HIV-1-infected adults. 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 8. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months a Outcome 6 Months 12 Months Valacyclovir Hydrochloride Once Daily (n = 269) Oral Acyclovir 400 mg Twice Daily (n = 267) Placebo (n = 134) Valacyclovir Hydrochloride Once Daily (n = 269) Oral Acyclovir 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride 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 10 3 3 3 3 3 Table 9. Recurrence Rates in HIV-1-Infected Adults at 6 Months a Outcome Valacyclovir Hydrochloride 500 mg (n = 194) Placebo (n = 99) Recurrence free 65% 26% Recurrences 17% 57% Unknown a 18% 17% Reduction of Transmission of Genital Herpes 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 valacyclovir hydrochloride 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 10. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints a Endpoint Valacyclovir Hydrochloride a (n = 743) Placebo (n = 741) Symptomatic HSV-2 acquisition 4 (0. 2%) HSV-2 seroconversion 12 (1. 2%) Overall HSV-2 acquisition 14 (1. 6%) Two randomized, double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride 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 valacyclovir hydrochloride 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% CI) in days was: 40 (31, 51), 43 (36, 55), and 59 (41, 77) for 7-day valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively. The use of valacyclovir hydrochloride 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 max [see Use in Specific Populations (8.
PATIENT INFORMATION
Valacyclovir Tablets, USP (val’’ ay sye’ kloe vir) What are valacyclovir tablets? Valacyclovir tablets are a prescription medicine used in adults: to treat cold sores (herpes labialis). to treat or control genital herpes outbreaks in adults with normal immune systems. to control genital herpes outbreaks in adults with human immunodeficiency virus-1 (HIV-1). with safer sex practices to lower the chance of spreading genital herpes to others, in adults with normal immune systems. Even with safer sex practices, it is still possible to spread genital herpes. Do not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. Use a condom made of latex or polyurethane whenever you have sexual contact. Ask your healthcare provider for more information about safer sex practices. to treat shingles (herpes zoster) in adults with normal immune systems. Valacyclovir tablets are used in children to treat: cold sores in children 12 years of age and older. chickenpox in children with normal immune systems 2 years of age to less than 18 years of age. Valacyclovir tablets do not cure It is not known if valacyclovir tablets are safe and effective in people with weakened immune systems, other than for control of outbreaks of genital herpes in people with It is not known if valacyclovir tablets are safe and effective in people 18 years of age and older with chickenpox. It is not known if valacyclovir tablets are safe and effective in children: less than 12 years of age with cold sores less than 2 years of age with chickenpox less than 18 years of age with genital herpes or shingles Do not take valacyclovir tablets Before you take valacyclovir tablets, tell your healthcare provider about all of your medical conditions, including if you: have had a bone marrow transplant or kidney transplant, or if you have advanced HIV-1 infection or acquired immune deficiency syndrome (AIDS). have kidney problems, including if you receive dialysis. are pregnant or plan to become pregnant. It is not known if valacyclovir tablets will harm your unborn baby. You and your healthcare provider will decide if you will take valacyclovir tablets if you are pregnant. are breastfeeding or plan to breastfeed. Valacyclovir hydrochloride may pass into your breastmilk. Talk with your healthcare provider about the best way to feed your child if you take valacyclovir tablets. Tell your healthcare provider about all the medicines you take, How should I take valacyclovir tablets? Take valacyclovir tablets exactly as your healthcare provider tells you to take it. Your dose of valacyclovir tablets and length of treatment will depend on the type of infection that you have and any other medical problems that you have. Do not stop valacyclovir tablets or change your treatment without talking to your healthcare provider. Take valacyclovir tablets with or without food. Tell your healthcare provider if your child cannot swallow valacyclovir tablets. Your healthcare provider can prescribe valacyclovir tablets as an oral suspension for your child. If you are taking valacyclovir tablets to treat outbreaks of cold sores, chickenpox, shingles, or genital herpes, take valacyclovir tablets as soon as you have the first symptoms of infection such as tingling, itching, or burning, or when the sore appears. It is important for you to stay well hydrated during treatment with valacyclovir tablets. Be sure to drink plenty of fluids during this time. If you miss a dose of valacyclovir tablets, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time or take more valacyclovir tablets than prescribed. If you take too much valacyclovir hydrochloride, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of valacyclovir tablets? Valacyclovir tablets can cause serious side effects including: Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS). kidney failure. nervous system problems. aggressive behavior unsteady movement shaky movements confusion speech problems hallucinations (seeing or hearing things that are really not there) seizures coma Elderly people are more likely to get certain side effects. Talk to your healthcare provider if this is a concern for you. The most common side effects of valacyclovir tablets in adults include: headache nausea stomach (abdominal) pain The most common side effect of valacyclovir tablets in children less than 18 years of age is headache. These are not all the possible side effects of valacyclovir tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store valacyclovir tablets? Store valacyclovir tablets at 20º to 25ºC (68º to 77ºF). Store valacyclovir suspension between 2º to 8ºC (36º to 46ºF) in a refrigerator. Throw away (discard) any remaining valacyclovir suspension after 28 days. Shake valacyclovir suspension bottle well before using. Keep valacyclovir tablets in a tightly closed container. Keep valacyclovir tablets and all medicines out of the reach of children. General information about the safe and effective use of valacyclovir tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use valacyclovir tablets for a condition for which it was not prescribed. Do not give valacyclovir tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about valacyclovir tablets that is written for health professionals. What are the ingredients in valacyclovir tablets? Active ingredient: Inactive ingredients: This Patient Information has been approved by the U.S. Food and Drug Administration. Made in India

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