Valtrex (Valacyclovir Hydrochloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX have been investigated in 14 volunteer studies involving 283 adults.

Absorption and Bioavailability

The absolute bioavailability of acyclovir after administration of VALTREX is 54.5% ± 9.1% as determined following a 1-gram oral dose of VALTREX and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of VALTREX is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).

There was a lack of dose proportionality in acyclovir maximum concentration (C_max) and area under the acyclovir concentration-time curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of VALTREX to 8 healthy volunteers. The mean C_max (± SD) was 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) mcg/mL, respectively; and the mean AUC (± SD) was 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr•mcg/mL, respectively.

There was also a lack of dose proportionality in acyclovir C_max and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 gram of VALTREX administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers. The mean C_max (± SD) was 2.11 (± 0.33), 3.69 (± 0.87), and 4.96 (± 0.64) mcg/mL, respectively, and the mean AUC (± SD) was 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr•mcg/mL, respectively.

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

Distribution

The binding of valacyclovir to human plasma proteins ranged from 13.5% to 17.9%.

Metabolism

After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. 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 VALTREX, 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, 45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively. Acyclovir accounted for 88.60% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of VALTREX to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 41.9% 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 VALTREX in volunteers with normal renal function.

End-Stage Renal Disease (ESRD)

Following administration of VALTREX 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 m², compared with 679.16 ± 162.76 mL/min/1.73 m² in healthy volunteers.

Reduction in dosage is recommended in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Geriatrics

After single-dose administration of 1 gram of VALTREX in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Pediatrics

Valacyclovir pharmacokinetics have not been evaluated in pediatric patients.

Liver Disease

Administration of VALTREX to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate butnot 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 VALTREX 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 (see WARNINGS).

Drug Interactions

The pharmacokinetics of digoxin was not affected by coadministration of VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg), single doses of antacids (Al³⁺ or Mg⁺⁺), or multiple doses of thiazide diuretics. Acyclovir C_max and AUC following a single dose of VALTREX (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after probenecid (1 gram), or by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. These effects are not considered to be of clinical significance insubjects with normal renal function. Therefore, no dosage adjustment is recommended when VALTREX is coadministered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function.

CLINICAL TRIALS

Herpes Zoster

Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. VALTREX was compared with placebo in patients less than 50 years of age, and to ZOVIRAX in patients greater than 50 years of age. 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 2 days for those treated with VALTREX compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either VALTREX or ZOVIRAX. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of VALTREX and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day VALTREX, 14-day VALTREX, and 7-day ZOVIRAX, respectively.

Genital Herpes Infections

Initial Episode

Six hundred and forty-three immunocompetent adults with first episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of VALTREX 1 gram twice daily (n = 323) or ZOVIRAX 200 mg 5 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 cessation of viral shedding was 3 days.

Recurrent Episodes

Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

In 1 study, patients were randomized to receive 5 days of treatment with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.

In a third study, patients were randomized to receive VALTREX 500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.

Suppressive Therapy

Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.

A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 1.

Table 1. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months

	6 Months			12 Months
Treatment Arm	VALTREX 1 gram q.d. (n = 269)	ZOVIRAX 400 mg b.i.d. (n = 267)	Placebo (n = 134)	VALTREX 1 gram q.d. (n = 269)	ZOVIRAX 400 mg b.i.d. (n = 267)	Placebo (n = 134)
Recurrence free	55%	54%	7%	34%	34%	4%
Recurrences	35%	36%	83%	46%	46%	85%
Unknowns*	10%	10%	10%	19%	19%	10%

*Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

Subjects with 9 or fewer recurrences per year showed comparable results with VALTREX 500 mg once daily.

In a second study, 293 HIV-infected adults 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 duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log₁₀ copies/mL. Among patients who received VALTREX, the prestudy median CD4 cell count was 336 cells/mm³; 11% had <100 cells/mm³, 16% had 100 to 199 cells/mm³, 42% had 200 to 499 cells/mm³, and 31% had ≥500 cells/mm³. Outcomes for the overall study population are shown in Table 2.

Table 2. Recurrence Rates in HIV-Infected Adults at 6 Months

Treatment Arm	VALTREX 500 mg b.i.d. (n = 194)	Placebo (n = 99)
Recurrence free	65%	26%
Recurrences	17%	57%
Unknowns*	18%	17%

*Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

Reduction of Transmission of Genital Herpes

A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either VALTREX 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 3.

Table 3. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints

	VALTREX* (n = 743)	Placebo (n = 741)
Symptomatic HSV-2 acquisition	4 (0.5%)	16 (2.2%)
HSV-2 seroconversion	12 (1.6%)	24 (3.2%)
Overall HSV-2 acquisition	14 (1.9%)	27 (3.6%)

*Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with VALTREX versus placebo. Individual results may vary based on consistency of safer sex practices.

Cold Sores (Herpes Labialis)

Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to VALTREX 2 grams twice daily on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.

The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2-day regimen did not offer additional benefit over the 1-day regimen.

No significant difference was observed between subjects receiving VALTREX or placebo in the prevention of progression of cold sore lesions beyond the papular stage.