Valacyclovir Drug Information

Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cold Sores (Herpes Labialis) In clinical trials for the treatment of cold sores, the adverse reactions reported by subjects receiving valacyclovir tablets 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for subjects receiving valacyclovir 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 2 groups.

Genital Herpes Initial Episode In a clinical trial for the treatment of initial episodes of genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving valacyclovir tablets 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2. Recurrent Episodes In 3 clinical trials for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving valacyclovir tablets 500 mg twice daily for 3 days (n = 402), valacyclovir tablets 500 mg twice daily for 5 days (n = 1,136), or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2. Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults In a clinical trial for the suppression of recurrent genital herpes infections, the adverse reactions reported by subjects receiving valacyclovir tablets 1 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; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively. Reduction of Transmission In a clinical trial for the reduction of transmission of genital herpes, the adverse reactions reported by subjects receiving 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 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving valacyclovir tablets 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2. Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations LLN = Lower limit of normal. ULN = Upper limit of normal.

Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir Tablets 1 gram 3 Times Daily (n = 967) Placebo (n = 195) Valacyclovir Tablets 1 gram Twice Daily (n = 1,194) Valacyclovir Tablets 500 mg Twice Daily (n = 1,159) Placebo (n = 439) Valacyclovir Tablets 1 gram Once Daily (n = 269) Valacyclovir Tablets 500 mg Once Daily (n = 266) Placebo (n = 134) Hemoglobin (< 0.8 x LLN) 0.8% 0% 0.3% 0.2% 0% 0% 0.8% 0.8% White blood cells (< 0.75 x LLN) 1.3% 0.6% 0.7% 0.6% 0.2% 0.7% 0.8% 1.5% Platelet count (< 100,000/mm 3 ) 1.0% 1.2% 0.3% 0.1% 0.7% 0.4% 1.1% 1.5% AST (SGOT) (> 2 x ULN) 1.0% 0% 1.0% Data were not collected prospectively. 0.5% 4.1% 3.8% 3.0% Serum creatinine (> 1.5 x ULN) 0.2% 0% 0.7% 0% 0% 0% 0% 0%

Clinical Trials Experience in Pediatric Subjects

The safety profile of valacyclovir tablets has been studied in 177 pediatric subjects aged 1 month to less than 18 years. Sixty-five of these pediatric subjects, aged 12 to less than 18 years, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric subjects, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety trials and received valacyclovir oral suspension.

Fifty-one of these 112 pediatric subjects received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults. Pediatric Subjects Aged 12 to Less than 18 Years (Cold Sores) In clinical trials for the treatment of cold sores, the adverse reactions reported by adolescent subjects receiving valacyclovir tablets 2 grams twice daily for 1 day, or valacyclovir tablets 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%). Pediatric Subjects Aged 1 Month to Less than 12 Years Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials in children aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.

Postmarketing 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 a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir tablets.

General Facial edema, hypertension, tachycardia. Allergic Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria . 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. Eye Visual abnormalities.

Gastrointestinal Diarrhea. Hepatobiliary Tract and Pancreas Liver enzyme abnormalities, hepatitis. Renal Renal failure, renal pain (may be associated with renal failure) . Hematologic Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS . Skin and Subcutaneous Tissue Disorders Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), erythema multiforme (EM), rashes including photosensitivity, alopecia .

No clinically significant drug-drug or drug-food interactions with valacyclovir tablets are known.

Pregnancy Risk Summary Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, have not identified a drug associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes (see Data ). There are risks to the fetus associated with untreated herpes simplex during pregnancy (see Clinical Considerations ). In animal reproduction studies, no evidence of adverse developmental outcomes was observed with valacyclovir when administered to pregnant rats and rabbits at system exposures (AUC) 4 (rats) and 7 (rabbits) times the human exposure at the maximum recommended human dose (MRHD) (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk The risk of neonatal HSV infection varies from 30% to 50% for genital HSV acquired in late pregnancy (third trimester), whereas with HSV acquisition in early pregnancy, the risk of neonatal infection is about 1%. A primary herpes occurrence during the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and, in rare cases, skin lesions. In very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction, and stillbirth.

Co-infection with HSV increases the risk of perinatal HIV transmission in women who had a clinical diagnosis of genital herpes during pregnancy. Data Human Data Clinical data over several decades with valacyclovir and its metabolite, acyclovir, in pregnant women, based on published literature, have not identified a drug-associated risk of major birth defects. There are insufficient data on the use of valacyclovir regarding miscarriage or adverse maternal or fetal outcomes.

The Acyclovir and the Valacyclovir Pregnancy Registries, both population-based international prospective studies, collected pregnancy data through April 1999. The Acyclovir Registry documented outcomes of 1,246 infants and fetuses exposed to acyclovir during pregnancy (756 with earliest exposure during the first trimester, 197 during the second trimester, 291 during the third trimester, and 2 unknown). The occurrence of major birth defects during first-trimester exposure to acyclovir was 3.2% (95% CI: 2.0% to 5.0%) and during any trimester of exposure was 2.6% (95% CI: 1.8% to 3.8%). The Valacyclovir Pregnancy Registry documented outcomes of 111 infants and fetuses exposed to valacyclovir during pregnancy (28 with earliest exposure in the first trimester, 31 during the second trimester, and 52 during the third trimester).The occurrence of major birth defects during first-trimester exposure to valacyclovir was 4.5% (95% CI: 0.24% to 24.9%) and during any trimester of exposure was 3.9% (95% CI: 1.3% to 10.7%). Available studies have methodological limitations including insufficient sample size to support conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Animal Data Valacyclovir was administered orally to pregnant rats and rabbits (up to 400 mg/kg/day) during organogenesis (Gestation Days 6 through 15, and 6 through 18, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at acyclovir exposures (AUC) of up to approximately 4 (rats) and 7 (rabbits) times the exposure in humans at the MRHD. Early embryo death, fetal growth retardation (weight and length), and variations in fetal skeletal development (primarily extra ribs and delayed ossification of sternebrae) were observed in rats and associated with maternal toxicity (200 mg/kg/day; approximately 6 times higher than human exposure at the MRHD). In a pre/postnatal development study, valacyclovir was administered orally to pregnant rats (up to 200 mg/kg/day from Gestation Day 15 to Post-Partum Day 20) from late gestation through lactation. No significant adverse effects were observed in offspring exposed daily from before birth through lactation at maternal exposures (AUC) of approximately 6 times higher than human exposures at the MRHD.

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 2 to less than 18 years . The use of valacyclovir tablets for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores . The use of valacyclovir for treatment of chickenpox in pediatric patients aged 2 to less than 18 years is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric subjects with chickenpox . The efficacy and safety of valacyclovir have not been established in pediatric patients: aged less than 12 years with cold sores aged less than 18 years with genital herpes aged less than 18 years with herpes zoster aged less than 2 years with chickenpox for suppressive therapy following neonatal HSV infection. The pharmacokinetic profile and safety of valacyclovir oral suspension in children aged less than 12 years were studied in 3 open-label trials. No efficacy evaluations were conducted in any of the 3 trials.

Trial 1 was a single-dose pharmacokinetic, multiple-dose safety trial in 27 pediatric subjects aged 1 to less than 12 years with clinically suspected varicella-zoster virus (VZV) infection . Trial 2 was a single-dose pharmacokinetic and safety trial in pediatric subjects aged 1 month to less than 6 years who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children aged 3 months to less than 6 years, this dose provided comparable systemic acyclovir exposures to that from a 1-gram dose of valacyclovir in adults (historical data). In infants aged 1 month to less than 3 months, mean acyclovir exposures resulting from a 25-mg/kg dose were higher (C max : ↑ 30%, AUC: ↑ 60%) than acyclovir exposures following a 1-gram dose of valacyclovir in adults.

Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore, valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir. Trial 3 was a single-dose pharmacokinetic, multiple-dose safety trial in 28 pediatric subjects aged 1 to less than 12 years with clinically suspected HSV infection. None of the subjects enrolled in this trial had genital herpes.

Each subject was dosed with valacyclovir oral suspension 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric subjects following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric subjects across all age-groups (1 to less than 12 years) were lower (C max : ↓ 20%, AUC: ↓ 33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily but were higher (daily AUC: ↑ 16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily.

Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children aged 1 to less than 12 years with recurrent genital herpes.

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

Caution should be exercised to prevent inadvertent overdose . Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored .