Valacyclovir Hydrochloride: Package Insert and Label Information (Page 3 of 5)

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

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.

8.2 Lactation

Risk Summary

Although there is no information on the presence of valacyclovir in human milk, its metabolite, acyclovir, is present in human milk following oral administration of valacyclovir. Based on published data, a 500-mg maternal dose of valacyclovir hydrochloride twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day (see Data). There is no data on the effects of valacyclovir or acyclovir on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clincial need for valacyclovir hydrochloride and any potential adverse effects on the breastfed child from valacyclovir hydrochloride or from the underlying maternal condition.

Data

Following oral administration of a 500-mg dose of valacyclovir hydrochloride to 5 lactating women, peak acyclovir concentrations (Cmax ) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500-mg maternal dose of valacyclovir hydrochloride twice daily would provide a breastfed child with an oral acyclovir dosage of approximately 0.6 mg/kg/day. Unchanged valacyclovir was not detected in maternal serum, breast milk or infant urine.

8.4 Pediatric Use

Valacyclovir hydrochloride 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 [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 (aged greater than or equal to 12 years) with a history of recurrent cold sores [see Clinical Studies (14.1)].

The use of valacyclovir hydrochloride 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 [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:

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 [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].
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 (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.
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 (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 aged 1 to less than 12 years with recurrent genital herpes.

8.5 Geriatric Use

Of the total number of subjects in clinical trials of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical trial of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in subjects 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.3)].

8.6 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 equivalent to 500 mg or 1 gram valacyclovir. In addition, each tablet contains the following inactive ingredients: crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.

The chemical name of valacyclovir hydrochloride is L -valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H -purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:

structure formula
(click image for full-size original)

Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C13 H20 N6 O4 •HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pka s for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valacyclovir is an antiviral drug active against α-herpes viruses [see Microbiology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years.

Pharmacokinetics in Adults

Absorption and Bioavailability

After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L- valine by first-pass intestinal and/or hepatic metabolism.

The absolute bioavailability of acyclovir after administration of valacyclovir 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

*
Administered 4 times daily for 11 days.

Dose

Single-Dose Administration

(N = 8)

Multiple-Dose Administration *

(N = 24, 8 per treatment arm)

Cmax (±SD)

(mcg/mL)

AUC (±SD) (h●mcg/mL)

Cmax (±SD) (mcg/mL)

AUC (±SD) (h●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)

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 subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.

Elimination

The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of 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 subjects was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of valacyclovir hydrochloride in subjects with normal renal function.

Specific Populations

Patients with Renal Impairment

Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].

Following administration of valacyclovir hydrochloride to subjects 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 subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m2 compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy subjects.

Patients with Hepatic Impairment

Administration of valacyclovir hydrochloride to subjects with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.

Patients with HIV-1 Disease

In 9 subjects with HIV-1 disease and CD4+ cell counts less than 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 subjects.

Geriatric Patients

After single-dose administration of 1 gram of valacyclovir hydrochloride in healthy geriatric subjects, the half-life of acyclovir was 3.11 ± 0.51 hours compared with 2.91 ± 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir hydrochloride in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5, 8.6)].

Pediatric Patients

Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric subjects (aged 1 month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following 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 Subjects vs. 1-Gram Single Dose of Valacyclovir Hydrochloride to Adults

*
Historical estimates using pediatric pharmacokinetic sampling schedule.

Pediatric Subjects

(20 mg/kg Oral Suspension)

Adults 1-gram Solid Dose of Valacyclovir *

Hydrochloride (n = 15)

Parameter

1 to <2 year

(n = 6)

2 to <6 year

(n = 12)

6 to <12 year

(n = 8)

AUC (mcg•h/mL) Cmax (mcg/mL)

14.4 (±6.26) 4.03 (±1.37)

10.1 (±3.35) 3.75 (±1.14)

13.1 (±3.43) 4.71 (±1.20)

17.2 (±3.10) 4.72 (±1.37)

Drug Interaction Studies

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.

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