ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling:oThrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)].oAcute Renal Failure [see Warnings and Precautions (5.2)].oCentral Nervous System Effects [see Warnings and Precautions (5.3)].The most common adverse reactions reported in at least indication by greater than 10% of adult subjects treated with valacyclovir tablets and observed more frequently with valacyclovir tablets 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.. oThrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)].. oAcute Renal Failure [see Warnings and Precautions (5.2)].. oCentral Nervous System Effects [see Warnings and Precautions (5.3)].. oThe most common adverse reactions reported in at least one indication by greater than 10% of adult subjects treated with valacyclovir tablets and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. (6.1)oThe 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe most common adverse reactions reported in at least one indication by greater than 10% of adult subjects treated with valacyclovir tablets and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. (6.1). oThe only adverse reaction occurring in greater than 10% of pediatric subjects aged less than 18 years was headache. (6.2). 6.1Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 tablets grams twice daily (n 609) or placebo (n 609) for day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (greater than x ULN) were 1.8% for subjects receiving valacyclovir tablets compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the groups.. Genital Herpes. Initial Episode In 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 valacyclovir tablets gram twice daily for 10 days (n 318) or oral acyclovir 200 mg 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 clinical trials for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving valacyclovir tablets 500 mg twice daily for days (n 402), valacyclovir tablets 500 mg twice daily for 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 clinical trial for the suppression of recurrent genital herpes infections, the adverse reactions reported by subjects receiving valacyclovir tablets gram once daily (n 269), valacyclovir tablets 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 valacyclovir tablets (500 mg twice daily; = 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 clinical trial for the reduction of transmission of genital herpes, the adverse reactions reported by subjects receiving valacyclovir tablets 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 clinical trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving valacyclovir tablets gram times daily for 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 PopulationsLLN Lower limit of normal.ULN Upper limit of normal.Laboratory AbnormalityHerpes ZosterGenital Herpes TreatmentGenital Herpes SuppressionValacyclovir Tablets1 gram3 Times Daily(n 967)Placebo(n 195)Valacyclovir Tablets1 gramTwice Daily(n 1,194)Valacyclovir Tablets500 mgTwice Daily(n 1,159)Placebo(n 439)Valacyclovir Tablets1 gramOnce Daily(n 269)Valacyclovir Tablets500 mgOnce Daily(n 266)Placebo(n 134)Hemoglobin (< 0.8 LLN)0.8%0%0.3%0.2%0%0%0.8%0.8%White blood cells(< 0.75 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)(> x ULN)1.0%0%1.0%Data were not collected prospectively.0.5%4.1%3.8%3.0%Serum creatinine(> 1.5 ULN) 0.2%0%0.7%0%0%0%0%0%. 6.2Clinical Trials Experience in Pediatric Subjects The safety profile of valacyclovir tablets has been studied in 177 pediatric subjects aged month to less than 18 years. Sixty-five of these pediatric subjects, aged 12 to less than 18 years, received oral tablets for to days for treatment of cold sores. The remaining 112 pediatric subjects, aged month to less than 12 years, participated in pharmacokinetic and safety trials and received valacyclovir oral suspension. Fifty-one of these 112 pediatric subjects received oral suspension for to 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 tablets grams twice daily for day, or valacyclovir tablets grams twice daily for day followed by gram twice daily for day (n 65, across both dosing groups), or placebo (n 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).. Pediatric Subjects Aged Month to Less Than 12 Years. Adverse events reported in more than subject across the pharmacokinetic and safety trials in children aged 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.. 6.3Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir tablets. Because they are reported voluntarily from population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir tablets.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 (8.5, 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The data presented below include references to the steady-state acyclovir AUC observed in humans treated with gram of valacyclovir tablets given orally times 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 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and rat cytogenetic study.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 mouse micronucleus assay.. Impairment of Fertility. Valacyclovir did not impair fertility or reproduction in male or female rats at acyclovir exposures (AUC) 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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Valacyclovir is an antiviral drug active against -herpes viruses [see Microbiology (12.4)]. 12.3 Pharmacokinetics The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir tablets have been investigated in 14 volunteer trials involving 283 adults and in trials involving 112 pediatric subjects aged month to less than 12 years.. Pharmacokinetics in Adults. Absorption and Bioavailability After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.The absolute bioavailability of acyclovir after administration of valacyclovir tablets is 54.5% +- 9.1% as determined following 1-gram oral dose of valacyclovir tablets and 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir tablets 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 tablets to healthy adult volunteers are presented in Table 3. There was less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir tablets from doses between 250 mg to gram.There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.Table 3. Mean (+- SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir Tablets to Healthy Adult VolunteersND not done.DoseSingle-Dose Administration(N 8)Multiple-Dose AdministrationAdministered times daily for 11 days.(N 24, per treatment arm)Cmax (+- SD)(mcg/mL)AUC (+- SD) (hr mcg/mL)Cmax (+- SD) (mcg/mL)AUC (+- SD) (hr mcg/mL)100 mg0.83 (+- 0.14)2.28 (+- 0.40)NDND250 mg2.15 (+- 0.50)5.76 (+- 0.60)2.11 (+- 0.33)5.66 (+- 1.09)500 mg3.28 (+- 0.83)11.59 (+- 1.79)3.69 (+- 0.87)9.88 (+- 2.01)750 mg4.17 (+- 1.14)14.11 (+- 3.54)NDND1,000 mg5.65 (+- 2.37)19.52 (+- 6.04)4.96 (+- 0.64)15.70 (+- 2.27). Distribution The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.. Metabolism Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of gram of valacyclovir tablets, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.. Elimination The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of single 1-gram dose of radiolabeled valacyclovir to healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of single 1-gram dose of valacyclovir tablets to 12 healthy subjects was approximately 255 +- 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of valacyclovir tablets in subjects with normal renal function.. Specific Populations. Patients with Renal Impairment Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)]. Following administration of valacyclovir tablets to subjects with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately hours. Approximately one-third of acyclovir in the body is removed by dialysis during 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in subjects on dialysis was 86.3 +- 21.3 mL/min/1.73 m2 compared with 679.16 +- 162.76 mL/min/1.73 m2 in healthy subjects.. Patients with Hepatic Impairment Administration of valacyclovir tablets to subjects with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.. Patients with HIV-1 Disease In subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm3 who received valacyclovir tablets at dosage of gram times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy subjects.. Geriatric Patients After single-dose administration of gram of valacyclovir tablets in healthy geriatric subjects, the half-life of acyclovir was 3.11 +- 0.51 hours compared with 2.91 +- 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir tablets in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].. Pediatric Patients Acyclovir pharmacokinetics have been evaluated in total of 98 pediatric subjects (aged month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4) ]. Acyclovir pharmacokinetic parameter estimates following 20-mg/kg dose are provided in Table 4.Table 4. 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 Tablets to AdultsParameterPediatric Subjects(20 mg/kg Oral Suspension)Adults1-gram Solid Dose of Valacyclovir TabletsHistorical estimates using pediatric pharmacokinetic sampling schedule.(N 15)1 < year(N 6)2 < year(N 12)6 < 12 year(N 8)AUC (mcgohr/mL)14.4 (+- 6.26)10.1 (+- 3.35)13.1 (+- 3.43)17.2 (+- 3.10)Cmax (mcg/mL)4.03 (+- 1.37)3.75 (+- 1.14)4.71 (+- 1.20)4.72 (+- 1.37). Drug Interaction Studies. When valacyclovir tablets are 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 tablets are coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.. Antacids The pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of single dose of antacids (Al3+ or Mg++).. Cimetidine Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 8% and 32%, respectively, after single dose of cimetidine (800 mg).. Cimetidine Plus Probenecid Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 30% and 78%, respectively, after combination of cimetidine and probenecid, primarily due to reduction in renal clearance of acyclovir. Digoxin The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir tablets gram times daily, and the pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).. Probenecid Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).. Thiazide Diuretics The pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.. 12.4Microbiology Mechanism of Action. Valacyclovir is deoxynucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV types (HSV-1) and (HSV-2) and VZV both in cell culture and in vivo.Acyclovir is synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK; pUL23) of HSV or VZV into acyclovir monophosphate, nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of -herpes viral DNA. This is accomplished in 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 (EC50), vary greatly depending upon number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 microM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 microM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 microM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with mean EC50 value of microM (1.35 mcg/mL).. Resistance. In Cell Culture Acyclovir-resistant HSV-1, HSV-2, and VZV strains were isolated in cell culture. Acyclovir-resistant HSV and VZV resulted from mutations in the viral thymidine kinase (TK, pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture, acyclovir resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 5).Table 5. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions in Cell CultureVirusGeneSubstitutionHSV-1TKP5A, 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, V348AHSV-2TKL69P, C172R, A175V, T288MHSV-1POLD368A, Y557S, E597D, V621S, L702H, A719V, S742N, N815S, V817M, Y818C, G841C/SHSV-2POLNo substitutions detected. HSV-Infected Patients Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their -herpes virus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 6). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in the HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.Table 6. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Observed in Treated PatientsNote: Many additional pathways to acyclovir resistance likely exist.VirusGeneSubstitutionHSV-1TKG6C, 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, A365THSV-2TKG25A, 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, C337YHSV-1POLK532T, S559L, Q570R, L583V, A605V, V621S, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, R842S, I890M, V958L, H1228DHSV-2POLE250Q, 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. 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).Table 7. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOSCross-Resistant DrugVirus/GeneSubstitutionPCV/FCVHSV-1 TKG6C, 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, V348AHSV-1 POLA657T, D672N, V715G, A719V, S724N, E798K, N815S, G841C/SHSV-2 TKG39E, R51W, Y53N, R86P, Y133F, R177W, R221H, T288MHSV-2 POLK533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934AFOSHSV-1 POLD368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890MHSV-2 POLK533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1Cold 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 history of recurrent cold sores. Subjects self-initiated therapy at the earliest symptoms and prior to any signs of cold sore. The majority of subjects initiated treatment within hours of onset of symptoms. Subjects were randomized to valacyclovir tablets grams twice daily on Day followed by placebo on Day 2, valacyclovir tablets grams twice daily on Day followed by gram twice daily on Day 2, or placebo on Days and 2.The mean duration of cold sore episodes was about 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 tablets or placebo in the prevention of progression of cold sore lesions beyond the papular stage.. 14.2Genital Herpes Infections Initial Episode. Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in double-blind trial to receive 10 days of valacyclovir tablets gram twice daily (n 323) or oral acyclovir 200 mg times day (n 320). For both treatment groups the median time to lesion healing was days, the median time to cessation of pain was days, and the median time to cessation of viral shedding was 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 recurrent genital herpes episode.In trial, subjects were randomized to receive days of treatment with either valacyclovir tablets 500 mg twice daily (n 360) or placebo (n 259). The median time to lesion healing was days in the group receiving valacyclovir tablets 500 mg versus days in the placebo group, and the median time to cessation of viral shedding in subjects with at least positive culture (42% of the overall trial population) was days in the group receiving valacyclovir tablets 500 mg versus days in the placebo group. The median time to cessation of pain was days in the group receiving valacyclovir tablets 500 mg versus days in the placebo group. Results supporting efficacy were replicated in second trial.In third trial, subjects were randomized to receive valacyclovir tablets 500 mg twice daily for days (n 398) or valacyclovir tablets 500 mg twice daily for days (and matching placebo twice daily for additional days) (n 402). The median time to lesion healing was about 1/2 days in both treatment groups. The median time to cessation of pain was about 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 history of or more recurrences per year. Outcomes for the overall trial population are shown in Table 8.Table 8. Recurrence Rates in Immunocompetent Adults at and 12 MonthsOutcome6 Months12 MonthsValacyclovir Tablets1 gramOnce Daily(n 269)Oral Acyclovir400 mgTwice Daily(n 267)Placebo(n 134)Valacyclovir Tablets1 gramOnce Daily(n 269)Oral Acyclovir400 mgTwice Daily(n 267)Placebo(n 134)Recurrence free 55%54%7%34%34%4%Recurrences 35%36%83%46%46%85%UnknownIncludes lost to follow-up, discontinuations due to adverse events, and consent withdrawn. 10%10%10%19%19%10%Subjects with or fewer recurrences per year showed comparable results with valacyclovir tablets 500 mg once daily.In second trial, 293 HIV-1-infected adults on stable antiretroviral therapy with history of or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir tablets 500 mg twice daily (n 194) or matching placebo (n 99) for months. The median duration of recurrent genital herpes in enrolled subjects was 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 log10 copies/mL. Among subjects who received valacyclovir tablets, the pretrial median CD4+ cell count was 336 cells/mm3; 11% had less than 100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had greater than or equal to 500 cells/mm3. Outcomes for the overall trial population are shown in Table 9.Table 9. Recurrence Rates in HIV-1-Infected Adults at MonthsOutcomeValacyclovir Tablets500 mg Twice Daily(n 194)Placebo(n 99)Recurrence free 65%26%Recurrences17%57%UnknownIncludes lost to follow-up, discontinuations due to adverse events, and consent withdrawn. 18%17%. Reduction of Transmission of Genital Herpes. 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 history of 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 tablets 500 mg once daily or placebo once daily for 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.Table 10. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary EndpointsEndpointValacyclovir TabletsResults show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with valacyclovir tablets versus placebo. Individual results may vary based on consistency of safer sex practices.(n 743)Placebo(n 741)Symptomatic HSV-2 acquisition (0.5%)16 (2.2%)HSV-2 seroconversion12 (1.6%)24 (3.2%)Overall HSV-2 acquisition14 (1.9%)27 (3.6%). 14.3Herpes Zoster Two randomized, double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir tablets were 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 days for those treated with valacyclovir tablets compared with days for those treated with placebo. In subjects aged greater than 50 years, the median time to cessation of new lesions was days in subjects treated with either valacyclovir tablets 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 tablets 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 tablets, 14-day valacyclovir tablets, and 7-day oral acyclovir, respectively.. 14.4Chickenpox The use of valacyclovir for treatment of chickenpox in pediatric subjects aged 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 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 to less than 12 years with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg times daily for 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 (Cmax: 13%, AUC: 30%) than the mean daily historical exposures in adults receiving valacyclovir gram times daily, but were higher (daily AUC: 50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 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 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 times day for days (not to exceed gram times daily) is recommended for the treatment of chickenpox in pediatric patients aged to less than 18 years. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children aged less than years have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children aged less than years with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to days duration are not available [see Use in Specific Populations (8.4) ].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Valacyclovir tablets are contraindicated in patients who have had demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)].. Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any component of the formulation. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Valacyclovir hydrochloride is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.Valacyclovir tablets, USP are for oral administration. Each tablet contains 556.2 mg or 1.112 grams of valacyclovir hydrochloride, USP (hydrous) equivalent to 500 mg or gram of valacyclovir, respectively, and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. The white, film-coated tablets are printed with edible black ink which contains black iron oxide, propylene glycol and shellac glaze.The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula: Valacyclovir hydrochloride, USP (hydrous) is white to off-white powder with the molecular formula C13H20N6O4oHCl and molecular weight of 360.80. The maximum solubility in water at 25C is 174 mg/mL. The pkas for valacyclovir hydrochloride are 7.47 and 9.43.Meets USP Dissolution Test 2. Valacyclovir Hydrochloride Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oValacyclovir tablets may be given without regard to meals.oValacyclovir 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 solid dosage form is not appropriate [see Dosage and Administration (2.3)].. oValacyclovir tablets may be given without regard to meals.. oValacyclovir 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 solid dosage form is not appropriate [see Dosage and Administration (2.3)].. Adult Dosage (2.1)Cold Sores2 grams every 12 hours for dayGenital Herpes Initial episode1 gram twice daily for 10 daysRecurrent episodes500 mg twice daily for daysSuppressive therapy Immunocompetent patients1 gram once daily Alternate dose in patients with less than or equal to recurrences/year500 mg once daily HIV-1-infected patients500 mg twice dailyReduction of transmission500 mg once dailyHerpes Zoster1 gram times daily for daysPediatric Dosage (2.2)Cold Sores (aged greater than or equal to 12 years)2 grams every 12 hours for dayChickenpox (aged to less than 18 years)20 mg/kg times daily for days; not to exceed gram times dailyValacyclovir oral suspension (25 mg/mL or 50 mg/mL) can be prepared from the 500 mg valacylovir tablets. (2.3). 2.1Adult Dosing Recommendations Cold Sores (Herpes Labialis). The recommended dosage of valacyclovir tablets for treatment of cold sores is grams twice daily for day taken 12 hours apart. Therapy should be initiated at the earliest symptom of cold sore (e.g., tingling, itching, or burning).. Genital Herpes. Initial Episode The recommended dosage of valacyclovir tablets for treatment of initial genital herpes is 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 valacyclovir tablets for treatment of recurrent genital herpes is 500 mg twice daily for days. Initiate treatment at the first sign or symptom of an episode.. Suppressive Therapy The recommended dosage of valacyclovir tablets for chronic suppressive therapy of recurrent genital herpes is gram once daily in patients with normal immune function. In patients with history of or fewer recurrences per year, an alternative dose is 500 mg once daily.In HIV-1-infected patients with CD4+ cell count greater than or equal to 100 cells/mm3, the recommended dosage of valacyclovir tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.. Reduction of Transmission The recommended dosage of valacyclovir tablets for reduction of transmission of genital herpes in patients with history of or fewer recurrences per year is 500 mg once daily for the source partner.. Herpes Zoster. The recommended dosage of valacyclovir tablets for treatment of herpes zoster is gram times daily for 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.. 2.2Pediatric Dosing Recommendations 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 grams twice daily for day taken 12 hours apart. Therapy should be initiated at the earliest symptom of cold sore (e.g., tingling, itching, or burning).. Chickenpox. The recommended dosage of valacyclovir for treatment of chickenpox in immunocompetent pediatric patients aged to less than 18 years is 20 mg/kg administered times daily for days. The total dose should not exceed gram 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)]. 2.3Extemporaneous Preparation of Oral Suspension 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. oPrepare SSV according to the USP-NF.oUsing pestle and mortar, grind the required number of valacyclovir 500-mg tablets until fine powder is produced (5 valacyclovir tablets for 25-mg/mL suspension; 10 valacyclovir tablets for 50-mg/mL suspension).oGradually add approximately 5-mL aliquots of SSV to the mortar and triturate the powder until paste has been produced. Ensure that the powder has been adequately wetted.oContinue to add approximately 5-mL aliquots of SSV to the mortar, mixing thoroughly between additions, until concentrated suspension is produced, to minimum total quantity of 20 mL SSV and maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50- mg/mL suspensions.oTransfer the mixture to suitable 100-mL measuring flask.oTransfer the cherry flavor to the mortar and dissolve in approximately mL of SSV. Once dissolved, add to the measuring flask.oRinse the mortar at least times with approximately 5-mL aliquots of SSV, transferring the rinsing to the measuring flask between additions.oMake the suspension to volume (100 mL) with SSV and shake thoroughly to mix.oTransfer the suspension to an amber glass medicine bottle with child-resistant closure.oThe prepared suspension should be labeled with the following information Shake well before using. Store suspension between to 8C (36 to 46F) in refrigerator. Discard after 28 days.The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.. oPrepare SSV according to the USP-NF.. oUsing pestle and mortar, grind the required number of valacyclovir 500-mg tablets until fine powder is produced (5 valacyclovir tablets for 25-mg/mL suspension; 10 valacyclovir tablets for 50-mg/mL suspension).. oGradually add approximately 5-mL aliquots of SSV to the mortar and triturate the powder until paste has been produced. Ensure that the powder has been adequately wetted.. oContinue to add approximately 5-mL aliquots of SSV to the mortar, mixing thoroughly between additions, until concentrated suspension is produced, to minimum total quantity of 20 mL SSV and maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50- mg/mL suspensions.. oTransfer the mixture to suitable 100-mL measuring flask.. oTransfer the cherry flavor to the mortar and dissolve in approximately mL of SSV. Once dissolved, add to the measuring flask.. oRinse the mortar at least times with approximately 5-mL aliquots of SSV, transferring the rinsing to the measuring flask between additions.. oMake the suspension to volume (100 mL) with SSV and shake thoroughly to mix.. oTransfer the suspension to an amber glass medicine bottle with child-resistant closure.. oThe prepared suspension should be labeled with the following information Shake well before using. Store suspension between to 8C (36 to 46F) in refrigerator. Discard after 28 days.. 2.4Patients with Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of valacyclovir in pediatric patients with creatinine clearance less than 50 mL/min/1.73 m2.Table 1. Valacyclovir Tablets Dosage Recommendations for Adults with Renal ImpairmentIndicationsNormal DosageRegimen(Creatinine Clearance >= 50 mL/min)Creatinine Clearance (mL/min)30-4910-29< 10Cold sores (Herpes Labialis) Do not exceed day of treatment.Two 2-gram doses taken 12 hours apartTwo 1-gram doses taken 12 hours apartTwo 500-mg doses taken 12 hours apart500-mg single doseGenital herpes: Initial episode1 gram every 12 hoursno reduction1 gram every 24 hours500 mg every 24 hoursGenital herpes: Recurrent episode500 mg every 12 hoursno reduction500 mg every 24 hours500 mg every 24 hoursGenital herpes: Suppressive therapy Immunocompetent patients1 gram every 24 hoursno reduction500 mg every 24 hours500 mg every 24 hours Alternate dose for immunocompetent patients with less than or equal to recurrences/year500 mg every 24 hoursno reduction500 mg every 48 hours500 mg every 48 hours HIV-1-infected patients500 mg every 12 hoursno reduction500 mg every 24 hours500 mg every 24 hoursHerpes zoster1 gram every hours1 gram every 12 hours1 gram every 24 hours500 mg every 24 hours. Immunocompetent patients. Alternate dose for immunocompetent patients with less than or equal to recurrences/year. HIV-1-infected patients. 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 hours. About one-third of acyclovir in the body is removed by dialysis during 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Valacyclovir Tablets, USP are available containing 556.2 mg or 1.112 grams of valacyclovir hydrochloride, USP (hydrous) equivalent to 500 mg or gram of valacyclovir, respectively.oThe 500 mg tablets are white, film-coated, oval, unscored tablets with M122 imprinted with black ink on one side of the tablet and plain on the other side of the tablet.oThe gram tablets are white, film-coated, oval tablets with partial break line on both sides of the tablet and M123 imprinted with black ink on one side of the tablet.. oThe 500 mg tablets are white, film-coated, oval, unscored tablets with M122 imprinted with black ink on one side of the tablet and plain on the other side of the tablet.. oThe gram tablets are white, film-coated, oval tablets with partial break line on both sides of the tablet and M123 imprinted with black ink on one side of the tablet.. Tablets: 500 mg (unscored), gram (partial break line) (3).

DRUG INTERACTIONS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the total number of subjects in clinical trials of valacyclovir tablets, 906 were 65 and over, and 352 were 75 and over. In 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Valacyclovir Tablets, USP are available containing 556.2 mg or 1.112 grams of valacyclovir hydrochloride, USP (hydrous) equivalent to 500 mg or gram of valacyclovir, respectively.The 500 mg tablets are white, film-coated, oval, unscored tablets with M122 imprinted with black ink on one side of the tablet and plain on the other side of the tablet. They are available as follows:NDC 0378-4275-93bottles of 30 tabletsNDC 0378-4275-77bottles of 90 tabletsThe gram tablets are white, film-coated, oval tablets with partial break line on both sides of the tablet and M123 imprinted with black ink on one side of the tablet. They are available as follows:NDC 0378-4276-93bottles of 30 tabletsNDC 0378-4276-77bottles of 90 tabletsStorage: Store at 20o to 25oC (68o to 77oF). [See USP Controlled Room Temperature.] Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Valacyclovir tablets are deoxynucleoside analogue DNA polymerase inhibitor indicated for:Adult Patients (1.1)oCold Sores (Herpes Labialis)oGenital HerpesoTreatment in immunocompetent patients (initial or recurrent episode)oSuppression in immunocompetent or HIV-1-infected patientsoReduction of transmissionoHerpes ZosterPediatric Patients (1.2)oCold Sores (Herpes Labialis)oChickenpoxLimitations 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.. oCold Sores (Herpes Labialis). oGenital HerpesoTreatment in immunocompetent patients (initial or recurrent episode)oSuppression in immunocompetent or HIV-1-infected patientsoReduction of transmission. oTreatment in immunocompetent patients (initial or recurrent episode). oSuppression in immunocompetent or HIV-1-infected patients. oReduction of transmission. oHerpes Zoster. oCold Sores (Herpes Labialis). oChickenpox. 1.1Adult Patients Cold Sores (Herpes Labialis). Valacyclovir tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir tablets initiated after the development of clinical signs of cold sore (e.g., papule, vesicle, or ulcer) has not been established.. Genital Herpes. Initial Episode Valacyclovir tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established.. Recurrent Episodes Valacyclovir tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established.. Suppressive Therapy Valacyclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-1-infected adults. The efficacy and safety of valacyclovir tablets for the suppression of genital herpes beyond year in immunocompetent patients and beyond months in HIV-1-infected patients have not been established.. Reduction of Transmission Valacyclovir tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir tablets for the reduction of transmission of genital herpes beyond months in discordant couples has not been established. The efficacy of valacyclovir tablets 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. Valacyclovir tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of valacyclovir tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir tablets for treatment of disseminated herpes zoster have not been established.. 1.2Pediatric Patients 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 cold sore (e.g., papule, vesicle, or ulcer) has not been established.. Chickenpox. Valacyclovir is indicated for the treatment of chickenpox in immunocompetent pediatric patients aged to less than 18 years. Based on efficacy data from clinical trials with oral acyclovir, treatment with valacyclovir should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4)]. 1.3Limitations of Use The efficacy and safety of valacyclovir have not been established in:oImmunocompromised patients other than for the suppression of genital herpes in HIV-1-infected patients with CD4+ cell count greater than or equal to 100 cells/mm3.oPatients aged less than 12 years with cold sores (herpes labialis).oPatients aged less than years or greater than or equal to 18 years with chickenpox.oPatients aged less than 18 years with genital herpes.oPatients aged less than 18 years with herpes zoster.oNeonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection. oImmunocompromised patients other than for the suppression of genital herpes in HIV-1-infected patients with CD4+ cell count greater than or equal to 100 cells/mm3.. oPatients aged less than 12 years with cold sores (herpes labialis).. oPatients aged less than years or greater than or equal to 18 years with chickenpox.. oPatients aged less than 18 years with genital herpes.. oPatients aged less than 18 years with herpes zoster.. oNeonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Importance of Adequate Hydration: Patients should be advised to maintain adequate hydration.Missed Dose: Instruct patients that if they miss dose of valacyclovir tablets, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.Cold Sores (Herpes Labialis): Patients should be advised to initiate treatment at the earliest symptom of 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 cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir tablets are not cure for cold sores.Genital Herpes: Patients should be informed that valacyclovir tablets are not cure for genital herpes. Because genital herpes is 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 valacyclovir tablets. 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.Valacyclovir tablets have not been shown to reduce transmission of sexually transmitted infections other than HSV-2.If medical management of 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 first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of recurrent episode.There are no data on the safety or effectiveness of chronic suppressive therapy of more than years duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than months duration in HIV-1-infected patients.Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after diagnosis of herpes zoster.Chickenpox: Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.

LACTATION SECTION.

8.2 Lactation 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, 500-mg maternal dose of valacyclovir tablets twice daily would provide 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 mothers clinical need for valacyclovir tablets and any potential adverse effects on the breastfed child from valacyclovir or from the underlying maternal condition.. Data. Following oral administration of 500-mg dose of valacyclovir tablets to lactating women, peak acyclovir concentrations (Cmax) 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. 500-mg maternal dose of valacyclovir tablets twice daily would provide breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day. Unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Valacyclovir is an antiviral drug active against -herpes viruses [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4Microbiology Mechanism of Action. Valacyclovir is deoxynucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV types (HSV-1) and (HSV-2) and VZV both in cell culture and in vivo.Acyclovir is synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK; pUL23) of HSV or VZV into acyclovir monophosphate, nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of -herpes viral DNA. This is accomplished in 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 (EC50), vary greatly depending upon number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 microM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 microM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 microM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with mean EC50 value of microM (1.35 mcg/mL).. Resistance. In Cell Culture Acyclovir-resistant HSV-1, HSV-2, and VZV strains were isolated in cell culture. Acyclovir-resistant HSV and VZV resulted from mutations in the viral thymidine kinase (TK, pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture, acyclovir resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 5).Table 5. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions in Cell CultureVirusGeneSubstitutionHSV-1TKP5A, 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, V348AHSV-2TKL69P, C172R, A175V, T288MHSV-1POLD368A, Y557S, E597D, V621S, L702H, A719V, S742N, N815S, V817M, Y818C, G841C/SHSV-2POLNo substitutions detected. HSV-Infected Patients Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their -herpes virus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 6). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in the HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.Table 6. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Observed in Treated PatientsNote: Many additional pathways to acyclovir resistance likely exist.VirusGeneSubstitutionHSV-1TKG6C, 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, A365THSV-2TKG25A, 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, C337YHSV-1POLK532T, S559L, Q570R, L583V, A605V, V621S, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, R842S, I890M, V958L, H1228DHSV-2POLE250Q, 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. 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).Table 7. Summary of Acyclovir Resistance-Associated Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOSCross-Resistant DrugVirus/GeneSubstitutionPCV/FCVHSV-1 TKG6C, 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, V348AHSV-1 POLA657T, D672N, V715G, A719V, S724N, E798K, N815S, G841C/SHSV-2 TKG39E, R51W, Y53N, R86P, Y133F, R177W, R221H, T288MHSV-2 POLK533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934AFOSHSV-1 POLD368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890MHSV-2 POLK533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The data presented below include references to the steady-state acyclovir AUC observed in humans treated with gram of valacyclovir tablets given orally times 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 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and rat cytogenetic study.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 mouse micronucleus assay.. Impairment of Fertility. Valacyclovir did not impair fertility or reproduction in male or female rats at acyclovir exposures (AUC) 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5, 8.6)]. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 500 mg NDC 0378-4275-93ValacyclovirTablets, USP500 mgRx only 30 TabletsEach film-coated tablet contains 500 mgof valacyclovir equivalent to 556.2 mg ofvalacyclovir hydrochloride, USP (hydrous) per tablet.Usual Dosage: See accompanyingprescribing information.Keep this and all medication out ofthe reach of children.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Do not use if safety seal under cap isbroken or missing.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX4275H7Dispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Code No.: MH/DRUGS/25/NKD/89. Valacyclovir Tablets 500 mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Valacyclovir 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 to less than 18 years [see Indications and Usage (1.2), Dosage and Administration (2.2)]. The use of valacyclovir tablets for treatment of cold sores is based on double-blind, placebo-controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with history of recurrent cold sores [see Clinical Studies (14.1)].The use of valacyclovir for treatment of chickenpox in pediatric patients aged 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 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:oaged less than 12 years with cold soresoaged less than 18 years with genital herpesoaged less than 18 years with herpes zosteroaged less than years with chickenpoxofor 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 open-label trials. No efficacy evaluations were conducted in any of the trials.Trial was single-dose pharmacokinetic, multiple-dose safety trial in 27 pediatric subjects aged 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 was single-dose pharmacokinetic and safety trial in pediatric subjects aged month to less than years who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received single dose of 25 mg/kg valacyclovir oral suspension. In infants and children aged months to less than years, this dose provided comparable systemic acyclovir exposures to that from 1-gram dose of valacyclovir in adults (historical data). In infants aged month to less than months, mean acyclovir exposures resulting from 25-mg/kg dose were higher (Cmax: 30%, AUC: 60%) than acyclovir exposures following 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.Trial was single-dose pharmacokinetic, multiple-dose safety trial in 28 pediatric subjects aged 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 to 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 (Cmax: 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 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 to less than 12 years with recurrent genital herpes.. oaged less than 12 years with cold sores. oaged less than 18 years with genital herpes. oaged less than 18 years with herpes zoster. oaged less than years with chickenpox. ofor suppressive therapy following neonatal HSV infection.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir tablets have been investigated in 14 volunteer trials involving 283 adults and in trials involving 112 pediatric subjects aged month to less than 12 years.. Pharmacokinetics in Adults. Absorption and Bioavailability After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.The absolute bioavailability of acyclovir after administration of valacyclovir tablets is 54.5% +- 9.1% as determined following 1-gram oral dose of valacyclovir tablets and 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir tablets 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 tablets to healthy adult volunteers are presented in Table 3. There was less than dose-proportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir tablets from doses between 250 mg to gram.There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.Table 3. Mean (+- SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir Tablets to Healthy Adult VolunteersND not done.DoseSingle-Dose Administration(N 8)Multiple-Dose AdministrationAdministered times daily for 11 days.(N 24, per treatment arm)Cmax (+- SD)(mcg/mL)AUC (+- SD) (hr mcg/mL)Cmax (+- SD) (mcg/mL)AUC (+- SD) (hr mcg/mL)100 mg0.83 (+- 0.14)2.28 (+- 0.40)NDND250 mg2.15 (+- 0.50)5.76 (+- 0.60)2.11 (+- 0.33)5.66 (+- 1.09)500 mg3.28 (+- 0.83)11.59 (+- 1.79)3.69 (+- 0.87)9.88 (+- 2.01)750 mg4.17 (+- 1.14)14.11 (+- 3.54)NDND1,000 mg5.65 (+- 2.37)19.52 (+- 6.04)4.96 (+- 0.64)15.70 (+- 2.27). Distribution The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.. Metabolism Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of gram of valacyclovir tablets, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.. Elimination The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of single 1-gram dose of radiolabeled valacyclovir to healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of single 1-gram dose of valacyclovir tablets to 12 healthy subjects was approximately 255 +- 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of valacyclovir tablets in subjects with normal renal function.. Specific Populations. Patients with Renal Impairment Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)]. Following administration of valacyclovir tablets to subjects with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately hours. Approximately one-third of acyclovir in the body is removed by dialysis during 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in subjects on dialysis was 86.3 +- 21.3 mL/min/1.73 m2 compared with 679.16 +- 162.76 mL/min/1.73 m2 in healthy subjects.. Patients with Hepatic Impairment Administration of valacyclovir tablets to subjects with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.. Patients with HIV-1 Disease In subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm3 who received valacyclovir tablets at dosage of gram times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy subjects.. Geriatric Patients After single-dose administration of gram of valacyclovir tablets in healthy geriatric subjects, the half-life of acyclovir was 3.11 +- 0.51 hours compared with 2.91 +- 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir tablets in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].. Pediatric Patients Acyclovir pharmacokinetics have been evaluated in total of 98 pediatric subjects (aged month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4) ]. Acyclovir pharmacokinetic parameter estimates following 20-mg/kg dose are provided in Table 4.Table 4. 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 Tablets to AdultsParameterPediatric Subjects(20 mg/kg Oral Suspension)Adults1-gram Solid Dose of Valacyclovir TabletsHistorical estimates using pediatric pharmacokinetic sampling schedule.(N 15)1 < year(N 6)2 < year(N 12)6 < 12 year(N 8)AUC (mcgohr/mL)14.4 (+- 6.26)10.1 (+- 3.35)13.1 (+- 3.43)17.2 (+- 3.10)Cmax (mcg/mL)4.03 (+- 1.37)3.75 (+- 1.14)4.71 (+- 1.20)4.72 (+- 1.37). Drug Interaction Studies. When valacyclovir tablets are 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 tablets are coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.. Antacids The pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of single dose of antacids (Al3+ or Mg++).. Cimetidine Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 8% and 32%, respectively, after single dose of cimetidine (800 mg).. Cimetidine Plus Probenecid Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 30% and 78%, respectively, after combination of cimetidine and probenecid, primarily due to reduction in renal clearance of acyclovir. Digoxin The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir tablets gram times daily, and the pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).. Probenecid Acyclovir Cmax and AUC following single dose of valacyclovir tablets (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).. Thiazide Diuretics The pharmacokinetics of acyclovir after single dose of valacyclovir tablets (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified 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) (rats) and (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 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%. 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 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 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 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 through 15, and through 18, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (AUC) of up to approximately (rats) and (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 ossification of sternebrae) were observed in rats and associated with maternal toxicity (200 mg/kg/day; approximately times higher than human exposure at the MRHD).In 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 times higher than human exposures at the MRHD.

RISKS.

Risk Summary. Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified 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) (rats) and (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 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Valacyclovir Tablets, USP(val ay sye kloe vir)What are valacyclovir tabletsValacyclovir tablets are prescription medicine used in adults:oto treat cold sores (herpes labialis).oto treat or control genital herpes outbreaks in adults with normal immune systems.oto control genital herpes outbreaks in adults with human immunodeficiency virus-1 (HIV-1).owith 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.oDo not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. oUse condom made of latex or polyurethane whenever you have sexual contact.oAsk your healthcare provider for more information about safer sex practices.oto treat shingles (herpes zoster) in adults with normal immune systems.Valacyclovir tablets are used in children to treat:ocold sores in children 12 years of age and older.ochickenpox in children with normal immune systems years of age to less than 18 years of age.Valacyclovir tablets do not cure cold sores, chickenpox, shingles, or genital herpes. oIt 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 HIV-1.oIt is not known if valacyclovir tablets are safe and effective in people 18 years of age and older with chickenpox.oIt is not known if valacyclovir tablets are safe and effective in children:oless than 12 years of age with cold soresoless than years of age with chickenpoxoless than 18 years of age with genital herpes or shinglesDo not take valacyclovir tablets if you are allergic to valacyclovir, acyclovir, or any of the ingredients in valacyclovir tablets. See the end of this leaflet for complete list of ingredients in valacyclovir tablets.Before you take valacyclovir tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave had bone marrow transplant or kidney transplant, or if you have advanced HIV-1 infection or acquired immune deficiency syndrome (AIDS). ohave kidney problems, including if you receive dialysis. oare pregnant or plan to become pregnant. It is not known if valacyclovir will harm your unborn baby. You and your healthcare provider will decide if you will take valacyclovir tablets if you are pregnant. oare breastfeeding or plan to breastfeed. Valacyclovir 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, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take valacyclovir tabletsoTake valacyclovir tablets exactly as your healthcare provider tells you to take them.oYour 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.oDo not stop valacyclovir tablets or change your treatment without talking to your healthcare provider.oTake valacyclovir tablets with or without food.oTell your healthcare provider if your child cannot swallow valacyclovir tablets. Your healthcare provider can prescribe valacyclovir as an oral suspension for your child.oIf 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.oIt is important for you to stay well hydrated during treatment with valacyclovir tablets. Be sure to drink plenty of fluids during this time.oIf you miss 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 doses at the same time or take more valacyclovir tablets than prescribed.oIf you take too many valacyclovir tablets 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:oThrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS). TTP and HUS have happened in people with weakened immune systems taking valacyclovir tablets and have led to death. TTP and HUS are disorders that can cause small blood clots to form throughout the body and decrease blood flow to body organs such as the brain, heart, and kidneys. Your healthcare provider will stop treatment with valacyclovir tablets if you have signs or symptoms of TTP and HUS.okidney failure.onervous system problems. Tell your healthcare provider right away if you get any of these signs or symptoms of nervous system problems during treatment with valacyclovir tablets:oaggressive behaviorounsteady movementoshaky movementsoconfusionospeech problemsohallucinations (seeing or hearing things that are really not there)oseizuresocomaElderly people are more likely to get certain side effects. Talk to your healthcare provider if this is concern for you. The most common side effects of valacyclovir tablets in adults include:oheadacheonauseaostomach (abdominal) painThe 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 store valacyclovir tabletsoStore valacyclovir tablets at 20o to 25oC (68o to 77oF).oStore valacyclovir oral suspension between 2o to 8oC (36o to 46oF) in refrigerator. Throw away (discard) any remaining valacyclovir oral suspension after 28 days.oShake valacyclovir oral suspension bottle well before using. oKeep valacyclovir tablets in 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 Patient Information leaflet. Do not use valacyclovir tablets for condition for which they were not prescribed. Do not give valacyclovir tablets to other people, even if they have the same symptoms that you have. They 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 tabletsActive Ingredient: valacyclovir hydrochlorideInactive Ingredients: hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. The white, film-coated tablets are printed with edible black ink which contains black iron oxide, propylene glycol and shellac glaze. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited, Hyderabad -- 500 096, IndiaThis Patient Information has been approved by the U.S. Food and Drug Administration.For more information, call Mylan at 1-877-446-3679 (1-877-INFO-RX).Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India75080542Revised: 6/2021MX:VLCY:R10pt/MX:PL:VLCY:R7pt. oto treat cold sores (herpes labialis).. oto treat or control genital herpes outbreaks in adults with normal immune systems.. oto control genital herpes outbreaks in adults with human immunodeficiency virus-1 (HIV-1).. owith 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.oDo not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. oUse condom made of latex or polyurethane whenever you have sexual contact.oAsk your healthcare provider for more information about safer sex practices.. oDo not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. oUse condom made of latex or polyurethane whenever you have sexual contact.. oAsk your healthcare provider for more information about safer sex practices.. oto treat shingles (herpes zoster) in adults with normal immune systems.. ocold sores in children 12 years of age and older.. ochickenpox in children with normal immune systems years of age to less than 18 years of age.. oIt 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 HIV-1.. oIt is not known if valacyclovir tablets are safe and effective in people 18 years of age and older with chickenpox.. oIt is not known if valacyclovir tablets are safe and effective in children:oless than 12 years of age with cold soresoless than years of age with chickenpoxoless than 18 years of age with genital herpes or shingles. oless than 12 years of age with cold sores. oless than years of age with chickenpox. oless than 18 years of age with genital herpes or shingles. ohave had bone marrow transplant or kidney transplant, or if you have advanced HIV-1 infection or acquired immune deficiency syndrome (AIDS). ohave kidney problems, including if you receive dialysis. oare pregnant or plan to become pregnant. It is not known if valacyclovir will harm your unborn baby. You and your healthcare provider will decide if you will take valacyclovir tablets if you are pregnant. oare breastfeeding or plan to breastfeed. Valacyclovir may pass into your breastmilk. Talk with your healthcare provider about the best way to feed your child if you take valacyclovir tablets. oTake valacyclovir tablets exactly as your healthcare provider tells you to take them.. oYour 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.. oDo not stop valacyclovir tablets or change your treatment without talking to your healthcare provider.. oTake valacyclovir tablets with or without food.. oTell your healthcare provider if your child cannot swallow valacyclovir tablets. Your healthcare provider can prescribe valacyclovir as an oral suspension for your child.. oIf 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.. oIt is important for you to stay well hydrated during treatment with valacyclovir tablets. Be sure to drink plenty of fluids during this time.. oIf you miss 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 doses at the same time or take more valacyclovir tablets than prescribed.. oIf you take too many valacyclovir tablets call your healthcare provider or go to the nearest hospital emergency room right away.. oThrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS). TTP and HUS have happened in people with weakened immune systems taking valacyclovir tablets and have led to death. TTP and HUS are disorders that can cause small blood clots to form throughout the body and decrease blood flow to body organs such as the brain, heart, and kidneys. Your healthcare provider will stop treatment with valacyclovir tablets if you have signs or symptoms of TTP and HUS.. okidney failure.. onervous system problems. Tell your healthcare provider right away if you get any of these signs or symptoms of nervous system problems during treatment with valacyclovir tablets:. oaggressive behavior. ounsteady movement. oshaky movements. oconfusion. ospeech problems. ohallucinations (seeing or hearing things that are really not there). oseizures. ocoma. oheadache. onausea. ostomach (abdominal) pain. oStore valacyclovir tablets at 20o to 25oC (68o to 77oF).. oStore valacyclovir oral suspension between 2o to 8oC (36o to 46oF) in refrigerator. Throw away (discard) any remaining valacyclovir oral suspension after 28 days.. oShake valacyclovir oral suspension bottle well before using. oKeep valacyclovir tablets in tightly closed container.

SPL UNCLASSIFIED SECTION.

1.1Adult Patients Cold Sores (Herpes Labialis). Valacyclovir tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir tablets initiated after the development of clinical signs of cold sore (e.g., papule, vesicle, or ulcer) has not been established.. Genital Herpes. Initial Episode Valacyclovir tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established.. Recurrent Episodes Valacyclovir tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established.. Suppressive Therapy Valacyclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-1-infected adults. The efficacy and safety of valacyclovir tablets for the suppression of genital herpes beyond year in immunocompetent patients and beyond months in HIV-1-infected patients have not been established.. Reduction of Transmission Valacyclovir tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir tablets for the reduction of transmission of genital herpes beyond months in discordant couples has not been established. The efficacy of valacyclovir tablets 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. Valacyclovir tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of valacyclovir tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir tablets for treatment of disseminated herpes zoster have not been established.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary. Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified 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) (rats) and (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 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%. 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 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 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 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 through 15, and through 18, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (AUC) of up to approximately (rats) and (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 ossification of sternebrae) were observed in rats and associated with maternal toxicity (200 mg/kg/day; approximately times higher than human exposure at the MRHD).In 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 times higher than human exposures at the MRHD. 8.2 Lactation 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, 500-mg maternal dose of valacyclovir tablets twice daily would provide 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 mothers clinical need for valacyclovir tablets and any potential adverse effects on the breastfed child from valacyclovir or from the underlying maternal condition.. Data. Following oral administration of 500-mg dose of valacyclovir tablets to lactating women, peak acyclovir concentrations (Cmax) 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. 500-mg maternal dose of valacyclovir tablets twice daily would provide breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day. Unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine. 8.4 Pediatric Use Valacyclovir 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 to less than 18 years [see Indications and Usage (1.2), Dosage and Administration (2.2)]. The use of valacyclovir tablets for treatment of cold sores is based on double-blind, placebo-controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with history of recurrent cold sores [see Clinical Studies (14.1)].The use of valacyclovir for treatment of chickenpox in pediatric patients aged 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 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:oaged less than 12 years with cold soresoaged less than 18 years with genital herpesoaged less than 18 years with herpes zosteroaged less than years with chickenpoxofor 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 open-label trials. No efficacy evaluations were conducted in any of the trials.Trial was single-dose pharmacokinetic, multiple-dose safety trial in 27 pediatric subjects aged 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 was single-dose pharmacokinetic and safety trial in pediatric subjects aged month to less than years who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received single dose of 25 mg/kg valacyclovir oral suspension. In infants and children aged months to less than years, this dose provided comparable systemic acyclovir exposures to that from 1-gram dose of valacyclovir in adults (historical data). In infants aged month to less than months, mean acyclovir exposures resulting from 25-mg/kg dose were higher (Cmax: 30%, AUC: 60%) than acyclovir exposures following 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.Trial was single-dose pharmacokinetic, multiple-dose safety trial in 28 pediatric subjects aged 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 to 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 (Cmax: 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 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 to less than 12 years with recurrent genital herpes.. oaged less than 12 years with cold sores. oaged less than 18 years with genital herpes. oaged less than 18 years with herpes zoster. oaged less than years with chickenpox. ofor suppressive therapy following neonatal HSV infection.. 8.5 Geriatric Use Of the total number of subjects in clinical trials of valacyclovir tablets, 906 were 65 and over, and 352 were 75 and over. In 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)].. 8.6Renal Impairment Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oThrombotic 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 grams per day of valacyclovir tablets in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (5.1)oAcute 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 valacyclovir tablets 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)oCentral 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 valacyclovir tablets 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). oThrombotic 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 grams per day of valacyclovir tablets in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (5.1). oAcute 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 valacyclovir tablets 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). oCentral 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 valacyclovir tablets 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). 5.1Thrombotic 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 valacyclovir tablets at doses of grams per day. Treatment with valacyclovir tablets should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.. 5.2Acute Renal Failure Cases of acute renal failure have been reported in:oElderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir tablets 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)].oPatients with underlying renal disease who received higher-than-recommended doses of valacyclovir tablets for their level of renal function. Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].oPatients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir tablets to patients receiving potentially nephrotoxic drugs.oPatients 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)].. oElderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir tablets 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)].. oPatients with underlying renal disease who received higher-than-recommended doses of valacyclovir tablets for their level of renal function. Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].. oPatients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir tablets to patients receiving potentially nephrotoxic drugs.. oPatients 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.. 5.3Central 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 valacyclovir tablets for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir tablets should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].