Adult Patients
Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of Valacyclovir hydrochloride tablets 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 hydrochloride tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with Valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established.
Recurrent Episodes: Valacyclovir hydrochloride tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with Valacyclovir hydrochloride tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established.
Suppressive Therapy: Valacyclovir hydrochloride tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of Valacyclovir hydrochloride tablets for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established.
Reduction of Transmission: Valacyclovir hydrochloride tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of Valacyclovir hydrochloride tablets for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of Valacyclovir hydrochloride 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 hydrochloride tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of Valacyclovir hydrochloride tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of Valacyclovir hydrochloride tablets for treatment of disseminated herpes zoster have not been established.
Pediatric Patients
Cold Sores (Herpes Labialis): Valacyclovir hydrochloride tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients ≥ 12 years of age. The efficacy of Valacyclovir hydrochloride tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established.
Labeling describing use of Valacyclovir HCL in pediatric patients with chickenpox (ages 2 to ≤ 18 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that pediatric use is not approved for this Valacyclovir HCL tablet product.
Limitations of Use
The efficacy and safety of Valacyclovir hydrochloride tablets have not been established in:
- Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count ≥ 100 cells/mm3.
- Patients < 12 years of age with cold sores (herpes labialis).
- Patients < 18 years of age with genital herpes.
- Patients < 18 years of age with herpes zoster.
- Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.
Labeling describing use of Valacyclovir HCL in pediatric patients with chickenpox (ages of 2 to ≤ 18 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that pediatric use is not approved for this Valacyclovir HCL tablet product.
Valacyclovir Dosage and Administration
- Valacyclovir hydrochloride tablets may be given without regard to meals.
Labeling describing use of Valacyclovir HCL in pediatric patients for whom a solid dosage form is not appropriate is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that information is not approved for this Valacyclovir HCL tablet product.
Adult Dosing Recommendations
Cold Sores (Herpes Labialis): The recommended dosage of Valacyclovir hydrochloride tablets for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
Genital Herpes:Initial Episode: The recommended dosage of Valacyclovir hydrochloride tablets for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.
Recurrent Episodes: The recommended dosage of Valacyclovir hydrochloride tablets for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.
Suppressive Therapy: The recommended dosage of Valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.
In HIV-infected patients with a CD4+ cell count ≥ 100 cells/mm3, the recommended dosage of Valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
Reduction of Transmission: The recommended dosage of Valacyclovir hydrochloride tablets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.
Herpes Zoster: The recommended dosage of Valacyclovir hydrochloride tablets for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.
Pediatric Dosing Recommendations
Cold Sores (Herpes Labialis): The recommended dosage of Valacyclovir hydrochloride tablets for the treatment of cold sores in pediatric patients ≥ 12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).
Patients With Renal Impairment
Dosage recommendations for adult patients with reduced renal function are provided in Table 1[see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of Valacyclovir hydrochloride tablets in pediatric patients with a creatinine clearance < 50 mL/min/1.73 m2.
| Indications | Normal Dosage Regimen (Creatinine Clearance ≥ 50 mL/min) | Creatinine Clearance (mL/min) | ||
| 30 to 49 | 10 to 29 | < 10 | ||
| Cold sores (Herpes labialis) Do not exceed 1 day of treatment. | Two 2 gram doses taken 12 hours apart | Two 1 gram doses taken 12 hours apart | Two 500 mg doses taken 12 hours apart | 500 mg single dose |
| Genital herpes: Initialepisode | 1 gram every 12 hours | no reduction | 1 gram every 24 hours | 500 mg every 24 hours |
| Genital herpes: Recurrent episode | 500 mg every 12 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours |
| Genital herpes: Suppressive therapy Immunocompetent patients | 1 gram every 24 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours |
| Alternate dose for immunocompetent patients with ≤ 9 recurrences/year | 500 mg every 24 hours | no reduction | 500 mg every 48 hours | 500 mg every 48 hours |
| HIV-infected patients | 500 mg every 12 hours | no reduction | 500 mg every 24 hours | 500 mg every 24 hours |
| Herpes zoster | 1 gram every 8 hours | 1 gram every 12 hours | 1 gram every 24 hours | 500 mg every 24 hours |
Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of Valacyclovir hydrochloride tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of Valacyclovir hydrochloride tablets is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.
Peritoneal Dialysis: There is no information specific to administration of Valacyclovir hydrochloride 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 hydrochloride tablets should not be required following CAPD or CAVHD.
Dosage Forms and Strengths
- 500 mg: blue colored, capsule-shaped, film-coated tablets, debossed with "RX 904" on one side and plain on the other side.
- 1 gram: blue colored, capsule-shaped, film-coated tablets, debossed with "RX 905" on one side and partial scorebar on both sides.
Contraindications
Valacyclovir hydrochloride 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)].
Warnings and Precautions
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valacyclovir hydrochloride at doses of 8 grams per day. Treatment with Valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
Acute Renal Failure
Cases of acute renal failure have been reported in:
- Elderly patients with or without reduced renal function. Caution should be exercised when administering Valacyclovir hydrochloride 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 hydrochloride for their level of renal function. Dosage reduction is recommended when administering Valacyclovir hydrochloride 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 hydrochloride 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)].
Central Nervous System Effects
Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of Valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].
Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [seeWarnings and Precautions (5.1)].
- Acute Renal Failure [seeWarnings and Precautions (5.2)].
- Central Nervous System Effects [seeWarnings and Precautions (5.3)].
The most common adverse reactions reported in at least 1 indication by > 10% of adult patients treated with Valacyclovir hydrochloride and observed more frequently with Valacyclovir hydrochloride compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in > 10% of pediatric patients < 18 years of age was headache.
Clinical Trials Experience in Adult Patients
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 studies for the treatment of cold sores, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (> 2 x ULN) were 1.8% for patients receiving Valacyclovir hydrochloride compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.
Genital Herpes:Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥ 5% of patients receiving Valacyclovir hydrochloride 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 studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥ 5% of patients receiving Valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), Valacyclovir hydrochloride 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 study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 1 gram once daily (n = 269), Valacyclovir hydrochloride 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-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for Valacyclovir hydrochloride (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 study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 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 studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving Valacyclovir hydrochloride 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.
Clinical Trials Experience in Pediatric Patients
Sixty-five of these pediatric patients, 12 to < 18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults.
Pediatric Patients 12 to < 18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving Valacyclovir hydrochloride 2 grams twice daily for 1 day, or Valacyclovir hydrochloride 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%).
Labeling describing additional clinical trial adverse reactions in pediatric patients (ages of 1 month to ≤ 12 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those adverse reactions is not approved for this Valacyclovir HCL tablet product.
Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of Valacyclovir hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Valacyclovir hydrochloride.
General: Facial edema, hypertension, tachycardia.
Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)].
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)].
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.
Drug Interactions
No clinically significant drug-drug or drug-food interactions with Valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B. There are no adequate and well-controlled studies of Valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Valacyclovir hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity.
Nursing Mothers
Following oral administration of a 500 mg dose of Valacyclovir hydrochloride to 5 nursing mothers, 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. A 500 mg maternal dosage of Valacyclovir hydrochloride twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged Valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when Valacyclovir hydrochloride is administered to a nursing woman.
Pediatric Use
Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥ 12 years of age [seeIndications and Usage (1.2), Dosage and Administration (2.2)].
The use of Valacyclovir hydrochloride for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥ 12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)].
The efficacy and safety of Valacyclovir have not been established in pediatric patients:
- < 12 years of age with cold sores
- < 18 years of age with genital herpes
- < 18 years of age with herpes zoster
- for suppressive therapy following neonatal HSV infection.
In infants 1 month to < 3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of Valacyclovir in adults.
Labeling describing pediatric use information in pediatric patients with chickenpox (ages 2 to ≤18 years) and additional pharmacokinetic studies in pediatric patients (ages 3 months to < 12 years) treated with Valacyclovir HCL is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, that additional pediatric information is not approved for this Valacyclovir HCL tablet product.
Geriatric Use
Of the total number of subjects in clinical studies of Valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 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)].
Renal Impairment
Dosage reduction is recommended when administering Valacyclovir hydrochloride to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].
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)].
Valacyclovir Description
Valacyclovir hydrochloride is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir.
Valacyclovir hydrochloride tablets are for oral administration. Each film-coated tablet contains Valacyclovir hydrochloride, USP (hydrous) equivalent to 500 mg or 1 gram Valacyclovir and the inactive ingredients crospovidone, FD&C blue #2/indigo carmine aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 6000, polysorbate 80, povidone, and titanium dioxide.
The chemical name of Valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9 H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:
Valacyclovir hydrochloride, USP (hydrous) is a white to off-white powder with the molecular formula C13H20N6O4•HCl and a molecular weight of 360.80. Valacyclovir hydrochloride, USP (hydrous) is soluble in water and insoluble in dichloromethane, the maximum solubility in water at 25° C is 174 mg/mL. The pkas for Valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
Valacyclovir - Clinical Pharmacology
Mechanism of Action
Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].
Pharmacokinetics
The pharmacokinetics of Valacyclovir and acyclovir after oral administration of Valacyclovir hydrochloride have been investigated in 14 volunteer studies involving 283 adults.
Labeling describing use of Valacyclovir in pediatric patients with chickenpox (ages 1 month to < 12 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, that additional pediatric information is not approved for this Valacyclovir HCL tablet product.
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 hydrochloride is 54.5% ± 9.1% as determined following a 1 gram oral dose of Valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valacyclovir hydrochloride is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
Acyclovir pharmacokinetic parameter estimates following administration of Valacyclovir hydrochloride to healthy adult volunteers are presented in Table3. There was a 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 hydrochloride from doses between 250 mg to 1 gram.
There is no accumulation of acyclovir after the administration of Valacyclovir at the recommended dosage regimens in adults with normal renal function.
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 a 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 3 hours after administration. Peak plasma Valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of Valacyclovir hydrochloride, average plasma Valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers 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 a single 1 gram dose of radiolabeled Valacyclovir to 4 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 a single 1 gram dose of Valacyclovir hydrochloride to 12 healthy volunteers 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 studies of Valacyclovir hydrochloride in volunteers with normal renal function.
Specific Populations: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 hydrochloride to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Hepatic Impairment: Administration of Valacyclovir hydrochloride to patients 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.
HIV Disease: In 9 patients with HIV disease and CD4+ cell counts < 150 cells/mm3 who received Valacyclovir hydrochloride at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of Valacyclovir and acyclovir were not different from that observed in healthy volunteers.
Geriatrics: After single-dose administration of 1 gram of Valacyclovir hydrochloride in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of Valacyclovir hydrochloride in geriatric volunteers 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)].
Labeling describing additional pharmacokinetic studies with Valacyclovir HCL in pediatric patients (ages of 1 month to < 12 years) is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those pharmacokinetic studies is not approved for this Valacyclovir HCL tablet product.
Drug Interactions: When Valacyclovir hydrochloride is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when Valacyclovir hydrochloride is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
Antacids: The pharmacokinetics of acyclovir after a single dose of Valacyclovir hydrochloride (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
Cimetidine: Acyclovir Cmax and AUC following a single dose of Valacyclovir hydrochloride (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a single dose of Valacyclovir hydrochloride (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.
Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of Valacyclovir hydrochloride 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of Valacyclovir hydrochloride (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
Probenecid: Acyclovir Cmax and AUC following a single dose of Valacyclovir hydrochloride (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of Valacyclovir hydrochloride (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.
Microbiology
Mechanism of Action: Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.
The inhibitory activity of acyclovir is highly selective due to its affinity
