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 tablets, USP 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.
Valacyclovir hydrochloride, USP (hydrous) is a white to off-white powder with the molecular formula C 13 H20 N6 O4 •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 pka s for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
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 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.
|Dose||Single-Dose Administration (N = 8)||Multiple-Dose Administration* (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)|
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.
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 m 2 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.
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).
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