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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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Absorption: 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 1000 mg oral dose of valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers.

VALTREX® pharmacokinetics are not dose-proportional. The rate and extent of absorption decreases with increasing dose, resulting in a less than proportional increase in Cmax over the therapeutic dose range and a reduced bioavailability at doses above 500 mg.

Acyclovir pharmacokinetics are unaltered after multiple-dose administration.

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Metabolism: Following absorption, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir and L-valine, an essential amino acid, by first-pass metabolism.

This hydrolysis is mediated primarily by the enzyme valacyclovir hydrolase, and occurs predominantly in the liver.

Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Acyclovir is eliminated primarily by urinary excretion of unchanged drug. In all studies of valacyclovir hydrochloride, the half-life of acyclovir typically averages 2.5 to 3.3 hours in subjects with normal renal function.

Special Populations and Conditions Pediatrics: The pharmacokinetics of valacyclovir hydrochloride have not been evaluated in pediatric patients.

Geriatrics: The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir hydrochloride caplets in geriatric volunteers varied with renal function. Dosage reduction may be required in geriatric patients with reduced renal function (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

VALTREX® should be stored between 15° and 30°C and protected from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

VALTREX® 500 mg caplets are blue, film-coated, capsule-shaped tablets printed with "VALTREX 500 mg".

Each blue caplet contains valacyclovir hydrochloride equivalent to 500 mg valacyclovir and the inactive ingredients carnauba wax, cellulose, crospovidone, hydroxypropyl methylcellulose, Indigotine Aluminum Lake, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, silicon dioxide, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.

Page 18 of 39 VALTREX® 1000 mg caplets are white, film-coated, capsule-shaped tablets engraved with "GX CF2".

Each white caplet contains valacyclovir hydrochloride equivalent to 1000 mg valacyclovir and the inactive ingredients carnauba wax, cellulose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, silicon dioxide, and titanium dioxide. The white, film-coated caplets are engraved.

500 mg caplets are available in blister packs of 30 caplets.

1000 mg caplets are available in blister packs of 21 caplets.

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PHARMACEUTICAL INFORMATION

Drug Substance Proper name: Valacyclovir (as valacyclovir hydrochloride) Chemical name: L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) [USAN] methoxy]ethyl ester, monohydrochloride Molecular formula: C13H20N6O4•HCl

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Structural formula:

Physicochemical properties:

Valacyclovir hydrochloride is a white to off-white powder with a maximum solubility in water of 174 mg/mL at 25°C. Valacyclovir hydrochloride has no distinct melting point. It undergoes rapid decomposition above 200°C. A saturated solution (4.82 x 10-1) of valacyclovir HCl in distilled water has a pH of

3.5 at 25°C. The pKa values of valacyclovir are pKa1 = 1.90, pKa2 = 7.47 and pKa3 = 9.43.

Page 20 of 39CLINICAL TRIALS

Herpes Zoster Two randomized double-blind clinical trials in 1540 immunocompetent patients with localized herpes zoster were conducted. In patients less than 50 years of age, VALTREX® 1000 mg three times daily for 7 days was compared to placebo. In patients greater than 50 years of age, VALTREX® 1000 mg three times daily for 7 days or 14 days was compared to ZOVIRAX® (acyclovir) 800 mg five times daily for 7 days. All patients were treated within 72 hours of appearance of zoster rash.

In patients less than 50 years of age, the median time to cessation of new lesion formation was shorter for those treated with VALTREX® (2 days) compared with those treated with placebo (3 days, p=0.03). In patients greater than 50 years of age, the median time to cessation of new lesion formation was three days in patients treated with either VALTREX® or ZOVIRAX®.

In both studies, the median time to at least 50% crusting or healing was 5 days for all treatment groups.





These trials also included assessment of pain. The primary endpoint for pain was time to complete cessation of zoster-associated pain. Zoster-associated pain, as defined in these trials, combined acute pain (pain associated with zoster lesions) and post-herpetic neuralgia (pain after 100% crusting/healing of lesion rash), a definition that is not universally accepted; most experts consider each pain component to have different pathogenesis and different morbidity. The clinical trials were not designed to look specifically at post-herpetic neuralgia. However, a post-hoc analysis for post-herpetic neuralgia was requested and carried out.

In patients greater than 50 years of age, the median time to resolution of post-herpetic neuralgia for the study population (including those with zero post-herpetic neuralgia) was significantly shorter in patients treated with VALTREX® compared with patients treated with ZOVIRAX® (9 and 4 days shorter for patients treated with VALTREX® for 7 days and 14 days respectively, p 0.05). In patients greater than 50 years of age, the incidence of chronic pain after 100% crusting/healing of lesion rash was not significantly different among the three treatment groups (79% and 80% in patients treated with VALTREX® for 7 or 14 days and 85% in patients treated with ZOVIRAX®). In patients less than 50 years of age, there was no statistically significant difference in the median time to cessation of post-herpetic neuralgia between the recipients of VALTREX® and placebo.

There were no significant differences in secondary endpoints, such as use of analgesics or quality of life, for patients treated with VALTREX® compared to placebo or ZOVIRAX®. In addition, no significant differences were found among the three groups with respect to intensity of pain.

Page 21 of 39 Initial Episode of Genital Herpes 643 immunocompetent adults with first episode of genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of VALTREX® 1000 mg twice daily (n=323) or ZOVIRAX® 200 mg five times a day (n=320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to viral shedding was 3 days.

Recurrent Episodes of Genital Herpes Three randomized, double-blind trials (2 of them placebo-controlled) in immunocompetent patients with recurrent genital herpes were conducted. Patients selfinitiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

In one study (004), patients were randomized to receive five days of treatment with either VALTREX® 1000 mg twice daily, ZOVIRAX® 200 mg five times daily, or placebo. In a second study (028), patients were randomized to receive either VALTREX® 1000 mg, VALTREX® 500 mg, or placebo, administered twice daily for 5 days.

VALTREX® significantly accelerated lesion healing and resolved episodes faster compared to placebo in both studies (p=0.0001). The median time to lesion healing was

4.8 days and 4.1 days for the groups receiving VALTREX® versus 6.0 days and 6.0 days for the placebo groups, for studies 004 and 028 respectively. The median length of an episode was 4.8 days and 4.0 days for the groups receiving VALTREX® versus 5.9 days and 5.9 days for the placebo groups, for studies 004 and 028, respectively (p=0.0001).

There were no differences between active treatment groups in both studies.

In study 028, there was a significantly higher proportion of patients with aborted episodes in the groups receiving VALTREX® 1000 mg (28%) and 500 mg (31%) compared to placebo (21%) (p=0.042 and p=0.005 respectively). In study 004, the proportion of patients with aborted episodes was higher in the group receiving VALTREX® (25.9%) than in the placebo group (19.8%), although this was not statistically significant (p=0.097).

The duration of lesion pain/discomfort was significantly shorter in the groups receiving VALTREX® compared to placebo (p=0.0014 for study 004 and p=0.0001 for study 028).

In study 028, the median time to cessation of pain was 2.8 days in the group treated with VALTREX® 500 mg versus 3.9 days for the placebo group. There were no differences between active treatments groups in either study.

In studies 028 and 004, VALTREX® significantly shortened the duration of viral shedding compared to placebo (p=0.0001). The median time to cessation of viral shedding in patients with at least one positive culture was two days in the groups receiving VALTREX® versus four days in the placebo group, for both studies. There were no differences between active treatments groups in either study.

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Suppression of Genital Herpes Two randomized, double blind trials for the suppression of recurrent genital herpes were conducted in immunocompetent patients. In one study, 1479 immunocompetent patients received suppressive therapy daily for 1 year. This study included three once-daily regimens of VALTREX® (250 mg, 500 mg, and 1000 mg) and VALTREX® 250 mg twice daily which were compared with ZOVIRAX® (400 mg twice daily) and placebo.

All regimens of VALTREX® were significantly better than placebo (p 0.0001) in preventing or delaying recurrences of genital herpes during the 1-year study period. The once-daily regimens of VALTREX® showed a strong dose relationship in the efficacy parameters. Analysis of the time to first recurrence revealed that the 250 mg, 500 mg, and 1000 mg once-daily regimens and 250 mg twice daily regimen of VALTREX® prevented or delayed recurrences compared to placebo by 54%, 71%, 78%, and 79% respectively. The proportions of patients recurrence free at 1 year from a time-to-event analysis were 22%, 40%, 48% and 51% for the 250 mg, 500 mg, and 1000 mg once-daily doses and 250 mg twice daily dosing respectively. The proportion of patients recurrence free was 5% in the placebo group. In patients with a history of nine or fewer recurrences per year, VALTREX® 250 mg twice daily and 500 mg once daily provided comparable clinical efficacy (59% and 46% of patients were recurrence free at 1 year respectively).

In patients with ten or more recurrences per year, 40% of patients receiving 250 mg twice daily were recurrence free at 1 year, while 30% of patients receiving 500 mg once daily were recurrence free at 1 year.

In the second study, 382 immunocompetent patients received daily suppressive therapy for 16 weeks. VALTREX® 500 mg once daily was shown to prevent or delay 85% of the recurrences experienced by patients receiving placebo. At the end of the 16 weeks, the proportions of patients recurrence free were 69% for the patients receiving VALTREX® 500 mg once daily and 9.5% for those receiving placebo.

In an open-label suppression study, 1018 patients received VALTREX® 500 mg once daily suppressive therapy for 12 months after receiving either VALTREX® 500 mg or placebo during the 8 month double-blind phase of the study (see CLINICAL TRIALS, Reduction of Transmission of Genital Herpes). During the 12 month open-label phase, 44% of source partners had a recurrence of genital HSV. This was similar to that observed in the VALTREX group (39%) during the 8 month double-blind phase of the study. In the combined double-blind/open-label suppression phases, the median time to first recurrence of genital HSV was 49 days for source partners originally randomized to placebo and 405 days for source partners originally randomized to VALTREX®.

In a randomized, double-blind, placebo-controlled trial for the suppression of recurrent ano-genital herpes in subjects infected with Human Immunodeficiency Virus (HIV), a Page 23 of 39 total of 293 adult subjects on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either VALTREX® 500 mg twice daily (n=194) or matching placebo (n=99) for 6 months. The median pre-study HIV-1 RNA was 2.6 log10 copies/mL (range: 2.6 - 5.9 log10 copies/mL) in both treatment groups. Among the 194 subjects who received VALTREX®, the prestudy median CD4 cell count was 336 cells/mm3; 11% had 100 cells/mm3, 16% had 100-199 cells/mm3, 42% had 200-499 cells/mm3, and 31% had 500 cells/mm3. The proportions of patients who were recurrence free at 6 months were 65% in the group receiving VALTREX® versus 26% in the placebo group. Any subject who experienced a breakthrough episode of genital herpes received VALTREX® 1000 mg twice daily for 5 to 10 days. Ten percent (10/99) of subjects receiving placebo compared to four percent (7/194) of subjects receiving VALTREX® reported an oral HSV outbreak during the double-blind phase of the study. Time to first oral HSV outbreak was significantly shorter in the placebo group (p 0.001).



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