Valacyclovir Hydrochloride (Page 7 of 13)

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 556.2 mg or 1.112 grams of valacyclovir hydrochloride, USP (hydrous), which are equivalent to 500 mg or 1 gram of valacyclovir, on the anhydrous basis, respectively, and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. The white, film-coated tablets are printed with edible black ink which contains black iron oxide, propylene glycol and shellac glaze.

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 Structural Formula
(click image for full-size original)

Valacyclovir hydrochloride, USP (hydrous) is a white to off-white powder with the molecular formula C 13 H 20 N 6 O 4 •HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pk a s for valacyclovir hydrochloride are 7.47 and 9.43.

Meets USP Dissolution Test 2.

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 tablets 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 tablets is 54.5% ± 9.1% as determined following a 1-gram oral dose of valacyclovir tablets and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir tablets 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 tablets to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C max ) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir tablets 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 Tablets to Healthy Adult Volunteers
ND = not done.
*
Administered 4 times daily for 11 days.

Dose

Single-Dose Administration

(N = 8)

Multiple-Dose Administration *

(N = 24, 8 per treatment arm)

C max (± SD)

(mcg/mL)

AUC (± SD) (hr • mcg/mL)

C max (± 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)

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