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)].
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)].
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 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-9 H -purin-9-yl)methoxy]ethyl ester hydrochloride monohydrate. It has the following structural formula:
Valacyclovir hydrochloride USP (monohydrate)is a white or almost white powder with the molecular formula C 13 H 23 N 6 O 5 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.
Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].
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 (C max ) 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 Administration a (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)|
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 m 2 compared with 679.16 ± 162.76 mL/min/1.73 m 2 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/mm 3 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 Solid Dose 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 (Al 3+ or Mg ++).
Cimetidine: Acyclovir C max 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 C max 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 C max 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.
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
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK )encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1)competitive inhibition of viral DNA polymerase, 2)incorporation and termination of the growing viral DNA chain, and 3)inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC 50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC 50 values against herpes simplex virus isolates range from 0.09 to 60 µM (0.02 to 13.5 mcg/mL)for HSV-1 and from 0.04 to 44 µM (0.01 to 9.9 mcg/mL)for HSV-2. The EC 50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 µM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC 50 of 6 µM (1.35 mcg/mL).
Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered. Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
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