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«PRODUCT MONOGRAPH Pr VALTREX® valacyclovir caplets, 500 mg and 1000 mg valacyclovir (as valacyclovir hydrochloride) Antiviral Agent Date of ...»

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Reduction of Transmission of Genital Herpes A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partners had a history of 9 or fewer genital herpes episodes per year. Both partners were counselled on safer sex practices and supplied with condoms for use throughout the study period. Source partners were randomized to treatment with either VALTREX® 500 mg once daily or placebo once daily for 8 months.

In the double-blind phase of the study, transmission of genital herpes to the susceptible partner (as measured by the proportion of susceptible partners with clinical evidence of a first episode of genital herpes) was 2.2% (16/741) in the placebo group and 0.5% (4/743) in the group receiving VALTREX®, a reduction of 75%. The proportions of susceptible partners with acquisition of genital herpes infection were 3.6% (27/741) in the placebo group and 1.9% (14/743) in the group receiving VALTREX®, a reduction of 48%.

After successful completion of the 8 month double-blind phase of the study, 1018 patients (499 from the placebo group and 519 from the VALTREX® group) entered into an open-label phase of the study where they were treated with VALTREX® 500 mg once daily for up to 12 months. The 519 patients formerly in the VALTREX® group of the double-blind study received VALTREX® 500 mg once daily for a total of up to 20 months in the combined double-blind/open-label phases. The safety profile of VALTREX® in the open-label suppression phase of this study (12 months) was similar to that observed during the double-blind phase of this study (8 months). The safety and tolerability of VALTREX® 500 mg once daily has been established for up to 20 months.

Cold Sores (Herpes Labialis) Two double-blind, placebo-controlled clinical trials were conducted in 1856 immunocompetent adults and adolescents ( 12 years old) with a history of cold sores.

Patients were randomized to one of 3 treatment arms: VALTREX® 2000 mg twice daily on Day 1 followed by placebo on Day 2; VALTREX® 2000 mg twice daily on Day 1 followed by 1000 mg twice daily on Day 2; or, Placebo on Days 1 and 2. Patients selfPage 24 of 39 initiated therapy at the earliest symptom of a cold sore (e.g., tingling, itching or burning).

The majority of patients initiated treatment within two hours after onset of symptoms.

The mean duration of episode, measured as the time from initiation of treatment to the day the lesion was assessed as being healed (loss of crust in patients whose lesions progressed to the vesicular stage; return to normal skin and/or cessation of all signs and symptoms in patients whose lesions were not vesicular in nature) by the physician, was

1.1 days shorter (5.0 days vs. 6.1 days) in subjects treated with VALTREX® 2000 mg twice daily for 1 day (n=311) compared with subjects treated with placebo (n=292) in one study, and 1.0 days shorter (5.3 days vs. 6.3 days) in subjects treated with VALTREX® 2000 mg twice daily for 1 day (n=298) compared with subjects treated with placebo (n=317) in the second study. The 2-day regimen did not provide additional benefit overall.

There was no significant difference between subjects receiving VALTREX® or placebo in the prevention of cold sore lesions beyond the papular stage.

For those patients whose lesions progressed to the vesicular stage (VALTREX® 2000 mg twice daily for 1 day, 53% in one study and 54% in the second study; placebo, 59% and 61%), the mean time to lesions healing (loss of crust) was 4.8 days vs. 6.1 days in one study, and 5.1 days vs. 6.4 days in the second study in patients treated with VALTREX 2000 mg twice daily for 1 day (n=164 and n=161) compared with placebo (n=171 and n=192).

The mean time to cessation of pain/discomfort was 2.1 days vs. 2.9 days in one study, and 2.3 days vs. 3.1 days in the second study in patients treated with VALTREX® 2000 mg twice daily for 1 day (n=311 and n=298) compared with placebo (n=292 and n=317).

DETAILED PHARMACOLOGY

Pharmacokinetics The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX® have been investigated in 12 volunteer studies involving 253 adults.

Absorption and Bioavailability: The absolute bioavailability of acyclovir after administration of VALTREX® is 54.5% ± 9.1% as determined following a 1000 mg 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 (3654 Kj) breakfast, which included 51 grams of fat].

There was a lack of proportionality in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve after single-dose administration of 100 to 1000 mg of valacyclovir hydrochloride, in eight healthy volunteers. The mean Cmax (± S.D.) ranged from 0.83 (± 0.14) to 5.65 (± 2.37) µg/mL, and the mean AUC (± SD) ranged from 2.28 (± 0.40) to 19.52 (± 6.04) hr•µg/mL. There was also a lack of dose

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There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in healthy volunteers with normal renal function.





Metabolism: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. Valacyclovir is rapidly and nearly completely 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 metabolism is associated with liver microsomal enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally less than 0.5 µg/mL at all doses. After single-dose administration of 1000 mg of valacyclovir hydrochloride, average plasma valacyclovir concentrations observed were 0.5, 0.4 and 0.8 µg/mL in patients with hepatic dysfunctions, 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 1000 mg dose of radiolabeled valacyclovir to four healthy subjects, 45.6% and 47.1% of administered radioactivity was recovered in urine and feces over 96 hours, respectively. Acyclovir accounted for 88.6% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1000 mg dose of valacyclovir hydrochloride to 12 healthy volunteers was approximately 255 ± 86 mL/min, which represents 41.9% of the 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.

Geriatrics: Following administration of valacyclovir hydrochloride, the half-life of acyclovir in geriatric patients is slightly longer and a 35% to 50% increase in AUC is observed relative to estimates in young healthy volunteers. These differences are consistent with the age-related decline in renal function. Population pharmacokinetic results obtained in efficacy trials are consistent with these observations. Dosage modification may be necessary in geriatric patients with reduced renal function (see

DOSAGE AND ADMINISTRATION).

Renal Impairment: The elimination of acyclovir is correlated to renal function, and exposure to acyclovir will increase with increased renal impairment. In patients with endstage renal disease, the average elimination half-life of acyclovir after valacyclovir administration is approximately 14 hours, compared with about 3 hours for normal renal

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Liver Disease: Administration of valacyclovir hydrochloride to patients with moderate or severe 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.

HIV Disease: In patients with advanced HIV disease (CD4 cell counts 150 cells/mm3) who received a dose of valacyclovir hydrochloride of 1000 mg or 2000 mg four times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir are not different from that observed in healthy volunteers (see WARNINGS AND PRECAUTIONS, General).

Drug Interactions

Cimetidine and Probenecid: Co-administration of probenecid with intravenous acyclovir has been shown to increase the mean elimination half-life, and the AUC of acyclovir. Urinary excretion and renal clearance of acyclovir were correspondingly reduced. The administration of cimetidine and probenecid, separately or together, reduced the rate but not the extent of conversion of valacyclovir to acyclovir. Reductions in the renal clearance of acyclovir were observed, resulting in higher acyclovir plasma concentrations. In volunteers with normal renal function, the renal clearance of acyclovir was reduced by approximately 22% and 33%, respectively, with concomitant cimetidine or probenecid administration. Renal clearance of acyclovir was reduced by approximately 46% in patients receiving cimetidine, probenecid, and valacyclovir hydrochloride.

An additive increase in acyclovir AUC with concomitant administration of valacyclovir hydrochloride, cimetidine, and probenecid has also been observed. Acyclovir Cmax was increased 8.4% ± 27.8%, 22.5% ± 25.3%, and 29.6% ± 27.5% by cimetidine, probenecid, and combination treatment (concomitant cimetidine and probenecid administration), respectively. Acyclovir AUC (0 to 24 hours) was increased 31.9% ± 22.9%, 49.0% ± 27.9%, and 77.9% ± 38.6% by cimetidine, probenecid, and combination treatment, respectively.

Digoxin: The pharmacokinetics of digoxin (two 0.75 mg doses, 12 hours apart) were not affected by multiple dose administration of VALTREX® (1000 mg every 8 hours for 8 days beginning 12 hours before digoxin dosing) in a study with 12 volunteers. Acyclovir pharmacokinetics after single dose administration of VALTREX® (1000 mg) remained unchanged when the same dose was administered immediately after the second of two

0.75 mg doses of digoxin given 12 hours apart.

Antacids: The administration of an aluminum hydroxide and magnesium hydroxide containing antacid either 30 minutes before or 65 minutes after administration of

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Thiazide diuretics: Thiazide diuretics do not affect acyclovir pharmacokinetics after administration of valacyclovir hydrochloride in a geriatric population.

MICROBIOLOGY

The quantitative relationship between the in vitro susceptibility of herpes viruses 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 (IC50), vary greatly depending upon the particular assay used, the cell type employed, and the laboratory performing the test. Using a plaque-reduction assay, the IC50 for acyclovir against VZV ranges from 0.12 to 4.0 μg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 μg/mL. The IC50 against herpes isolates ranges from 0.02 to 13.5 μg/mL for HSV-1 and from 0.01 to 9.9 μg/mL for HSV-2.

Resistance Resistance of VZV to antiviral nucleosides analogues can result from qualitative or quantitative changes in the viral TK or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered rarely from patients with AIDS.

In these cases, the TK-deficient phenotype was predominantly responsible.

Resistance of HSV to antiviral nucleoside analogues occurs by the same mechanisms as resistance to VZV. 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 acyclovir) should be considered in patients who show poor clinical response during therapy.

TOXICOLOGY

Acute Toxicity The acute toxicity of valacyclovir hydrochloride is low. Single oral doses give approximate lethal dose values 2000 mg/kg for male mice, between 1000 and 2000 mg/kg for female mice and 5000 mg/kg for male and female rats. All of the deaths occurred within 3 days of dose administration. The target organ in the acute studies was the kidney, as was expected. The valacyclovir hydrochloride tested produced obstructive nephropathy due to the precipitation of crystals of acyclovir in kidney tubules.

Page 28 of 39 Long-Term Toxicity Male and female rats were dosed with a single daily dose of 50, 150 and 300 mg/kg of valacyclovir hydrochloride for 97 days. Obstructive nephropathy, characterized by increased values for BUN and creatinine, dilated renal tubules, cellular debris and casts in renal collecting ducts, accumulations of a mixed population of inflammatory cells in the interstitium and the presence of crystals of precipitated acyclovir, was observed in rats given 150 and 300 mg/kg/day. Additional findings consisted of reversible decreases in values for erythrocyte counts, packed cell volume and hemoglobin at 150 mg/kg/day (minimal and inconsistent) and at 300 mg/kg/day. Reversible thymic involution and inconsistent, minimal atrophy of testes were limited to high dose males where renal damage was severe and not fully reversible. No toxicological effects were seen at 50 mg/kg/day valacyclovir hydrochloride.

Monkeys given oral doses of valacyclovir hydrochloride for three months also had obstructive nephropathy. Male and female cynomolgus monkeys were dosed at 200, 400 and 600 mg/kg/day. The daily dose was divided into two equal doses given six hours apart. Reversible obstructive nephropathy was observed at 400 and 600 mg/kg/day. The no-effect level was 200 mg/kg/day.



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