Valacyclovir: Package Insert and Label Information (Page 2 of 4)

6.2 Clinical Trials Experience in Pediatric Patients

The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients 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 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%).Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed.

6.3 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)].
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.

7 DRUG INTERACTIONS

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy: Teratogenic Effects


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.

8.3 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.

8.4 Pediatric Use

Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age [see Indications and Usage(1.2, Dosage and Administration (2.2)].
The use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)].
The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age 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 patients 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:
• <12 years of age with cold sores
• <18 years of age with genital herpes
• <18 years of age with herpes zoster
• <2 years of age with chickenpox
• for suppressive therapy following neonatal HSV infection.
The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.
Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age 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)].
Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age 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 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). 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. 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.Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study 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 patients 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 patients across all age-groups (1 to <12 years of age) 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 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 1 to <12 years of age with recurrent genital herpes.

8.5 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)].

8.6 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)].

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)].

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 valacyclovir hydrochloride USP equivalent to 500 mg or 1gm valacyclovir and the inactive ingredients crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. In addition to this 500 mg contains FD&C blue #2/ indigo carmine aluminum lake.
The chemical name of valacyclovir hydrochloride is L -valine2-[(2-amino-1,6-dihydro-6-oxo-9H -purin-9-yl)methoxy]ethyl ester hydrochloride monohydrate. It has the following structural formula:

Structure

Valacyclovir hydrochloride USP (monohydrate)is a white or almost white powder with the molecular formula C13 H23 N6 O5 Cl and a molecular weight of 378.81. Valacyclovir hydrochloride USP is freely soluble in water and practically insoluble in 1-octanol. The pka for valacyclovir hydrochloride is 5.95. Valacyclovir Tablets USP, 500 gm and 1 g complies with USP dissolution test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics


The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.
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 Table 3. 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.Table 3. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir Hydrochloride to Healthy Adult Volunteers

Dose Single-Dose Administration(N = 8) Multiple-Dose Administrationa (N = 24, 8 per treatment arm)
Cmax (±SD)(mcg/mL) AUC (±SD)(hr●mcg/mL) Cmax (±SD) (mcg/mL) AUC (±SD) (hr●mcg/mL)
100 mg 0.83 (±0.14) 2.28 (±0.40) ND ND
250 mg 2.15 (±0.50) 5.76 (±0.60) 2.11 (±0.33) 5.66 (±1.09)
500 mg 3.28 (±0.83) 11.59 (±1.79) 3.69 (±0.87) 9.88 (±2.01)
750 mg 4.17 (±1.14) 14.11 (±3.54) ND ND
1,000 mg 5.65 (±2.37) 19.52 (±6.04) 4.96 (±0.64) 15.70 (±2.27)

a Administered 4 times daily for 11 days.
ND = not done.
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)].
Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) 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 a 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 Patients vs. 1 Gram Single Dose of Valacyclovir Hydrochloride to Adults

Parameter Pediatric Patients (20 mg/kg Oral Suspension) Adults 1 gram SolidDose of Valacyclovir Hydrochloride(N = 15)
1 — <2 yr (N = 6) 2 — <6 yr (N = 12) 6 — <12 yr (N = 8)
AUC (mcg•hr/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)

a Historical estimates using pediatric pharmacokinetic sampling schedule.
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.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.