Valacyclovir is a deoxynucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients (1.1)
Cold Sores (Herpes Labialis)
Genital Herpes
Treatment in immunocompetent patients (initial or recurrent episode)
Suppression in immunocompetent or HIV-1-infected patients
Reduction of transmission
Herpes Zoster Pediatric Patients (1.2)
Cold Sores (Herpes Labialis)
Chickenpox Limitations of Use (1.3) The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-1-infected patients.
1.1Adult Patients Cold Sores (Herpes Labialis)
Valacyclovir is indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Genital Herpes Initial Episode: Valacyclovir is indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir when initiated more than 72 hours after the onset of signs and symptoms has not been established.
Recurrent Episodes: Valacyclovir is indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir when initiated more than 24 hours after the onset of signs and symptoms has not been established. Suppressive Therapy: Valacyclovir is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-1-infected adults.
The efficacy and safety of valacyclovir for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-1-infected patients have not been established. Reduction of Transmission: Valacyclovir is indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established.
The efficacy of valacyclovir 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 is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults.
The efficacy of valacyclovir when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir for treatment of disseminated herpes zoster have not been established.
Valacyclovir is indicated for the treatment of cold sores (herpes labialis) in pediatric patients aged greater than or equal to 12 years. The efficacy of valacyclovir initiated after the development of clinical signs of a 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 2 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:
Immunocompromised patients other than for the suppression of genital herpes HIV-1-infected patients with a CD4+ cell count greater than or equal to 100 cells/mm 3 .
Patients aged less than 12 years with cold sores (herpes labialis).
Patients aged less than 2 years or greater than or equal to 18 years with chickenpox.
Patients aged less than 18 years with genital herpes.
Patients aged less than 18 years with herpes zoster.
Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.
Contraindications
Valacyclovir is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)]. Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any component of the formulation. (4)
Warnings and precautions
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV-1 disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (5.1)
Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher-than-recommended doses of valacyclovir for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients and reduce dosage in patients with renal impairment. ( 2.4 , 5.2 )
Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher-than-recommended doses of valacyclovir 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 )
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 at doses of 8 grams per day. Treatment with valacyclovir 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:
Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir to geriatric patients, and dosage reduction is recommended for those with impaired renal function [ see Dosage and Administration (2.4), Use in Specific Populations (8.5)].
Patients with underlying renal disease who received higher than recommended doses of valacyclovir for their level of renal function. Dosage reduction is recommended when administering valacyclovir to patients with renal impairment [ see Dosage and Administration (2.4), Use in Specific Populations (8.6)].
Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir to patients receiving potentially nephrotoxic drugs.
Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [ see Dosage and Administration (2.4) , Adverse Reactions (6.3)].
5.3Central 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 for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions.
Valacyclovir should be discontinued if central nervous system adverse reactions occur [ see Adverse Reactions (6.3), Use in Specific Populations ( 8.5, 8.6 )].
Interactions
No clinically significant drug-drug or drug-food interactions with valacyclovir are known [see Clinical Pharmacology (12.3)].
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)].
Acute Renal Failure [see Warnings and Precautions (5.2)].
Central Nervous System Effects [see Warnings and Precautions (5.3)]. The most common adverse reactions reported in at least 1 indication by greater than 10% of adult subjects treated with valacyclovir and observed more frequently with valacyclovir compared with placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric subjects aged less than 18 years was headache.
The most common adverse reactions reported in at least one indication by greater than 10% of adult subjects treated with valacyclovir and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. (6.1)
The only adverse reaction occurring in less than 10% of pediatric subjects aged less than 18 years was headache. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Time- Cap Labs, Inc. at 1-877-376-4271 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
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 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 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 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 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 500 mg twice daily for 3 days (n = 402), valacyclovir 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 1 gram once daily (n = 269), valacyclovir 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 (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 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 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%).
For the incidence of laboratory abnormalities see Table 2. Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir 1 gram 3 times daily (n=967) Placebo (n=195) Valacyclovir 1 gram twice daily (n=1,194) Valacyclovir 500 mg twice daily (n=1,159) Placebo (n=439) Valacyclovir 1 gram once daily (n=269) Valacyclovir 500 mg once daily (n=266) Placebo (n=134) Hemoglobin (<0.8xLLN) 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% a 0.5% 4.1% 3.8% 3.0% Serum creatinine (>1.5 x ULN) 0.2% 0% 0.7% 0% 0% 0% 0% 0% a Data were not collected prospectively.
LLN = Lower limit of normal. ULN = Upper limit of normal.
6.2Clinical Trials Experience in Pediatric Subjects
The safety profile of valacyclovir 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 2 grams twice daily for 1 day, or valacyclovir 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
Pediatric Subjects Aged 1 Month to Less than 12 Years Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials in children aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.
6.3Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir. 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. General Facial edema, hypertension, tachycardia.
Allergic Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)]. Central Nervous System (CNS) Symp
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Composition
Active ingredients
VALACYCLOVIR HYDROCHLORIDE EQ 500MG BASE
Strengths and forms
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