valtrex
Generic Name: (
valacyclovir hydrochloride)
Dosage Type: tablet Organization: GlaxoSmithKline
DESCRIPTION
VALTREX (valacyclovir hydrochloride) is the hydrochloride
salt of L-valyl ester of the antiviral
drug acyclovir (ZOVIRAX® Brand, GlaxoSmithKline).
VALTREX
Caplets are for oral administration. Each caplet contains valacyclovir hydrochloride
equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients
carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2
Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated
caplets are printed with edible white ink.
The chemical
name of valacyclovir hydrochloride is L-valine,
2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
ester, monohydrochloride. It has the following structural formula:
Valacyclovir
hydrochloride is a white to off-whitepowder
with the molecular formula C13H20N6O4•HCl
and a molecular weight of 360.80. 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.
MICROBIOLOGY
Mechanism of Antiviral Action
Valacyclovir hydrochloride
is rapidly converted to acyclovir which has demonstrated antiviral activity
against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster
virus (VZV) both in vitro and in vivo.
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 vitro, acyclovir triphosphate stops 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 to VZV is due to its more efficient
phosphorylation by the viral TK.
Antiviral Activities
The quantitative relationship between the in vitro 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 (IC50), vary
greatly depending upon a number of factors. Using plaque-reduction assays,
the IC50 against herpes simplex virus isolates ranges from 0.02
to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2.
The IC50 for acyclovir against most laboratory strains and clinical
isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates
activity against the Oka vaccine strain of VZV with a mean IC50 of
1.35 mcg/mL.
Drug 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.
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 (Cmax)
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 Cmax (± 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 Cmax 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 Cmax (± 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 to 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 to 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 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 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 Cmax 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 in subjects 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 to
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 to 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%
|
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 enrolledsubjects 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%
|
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%)
|
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 to 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.
INDICATIONS AND USAGE
Herpes Zoster
VALTREX is indicated for the treatment of herpes zoster
(shingles).
Genital Herpes
VALTREX is indicated for the treatment or suppression of
genital herpes in immunocompetent individuals and for the suppression of recurrent
genital herpes in HIV-infected individuals.
When VALTREX
is used as suppressive therapy in immunocompetent individuals with genital
herpes, the risk of heterosexual transmission to susceptible partners is reduced.
Safer sex practices should be used with suppressive therapy (see current Centers
for Disease Control and Prevention (CDC) Sexually
Transmitted Diseases Treatment Guidelines).
Cold Sores (Herpes Labialis)
VALTREX is indicated for the treatment of cold sores (herpes
labialis).
CONTRAINDICATIONS
VALTREX is contraindicated in patients with a known hypersensitivity
or intolerance to valacyclovir, acyclovir, or any component of the formulation.
WARNINGS
Thrombotic thrombocytopenic purpura/hemolytic
uremic syndrome (TTP/HUS), in some cases resulting in death, has occurred
in patients with advanced HIV disease and also in allogeneic bone marrow transplant
and renal transplant recipients participating in clinical trials of VALTREX
at doses of 8 grams per day.
PRECAUTIONS
Dosage reduction is recommended
when administering VALTREX to patients with renal impairment (see DOSAGE AND
ADMINISTRATION). Acute renal failure and central nervous system
symptoms have been reported in patients with underlying renal disease who
have received inappropriately high doses of VALTREX for their level of renal
function. Similar caution should be exercised when administering VALTREX to
geriatric patients (see Geriatric Use) and patients receiving potentially
nephrotoxic agents.
Given the dosage recommendations
for treatment of cold sores, special attention should be paid when prescribing
VALTREX for cold sores in patients who are elderly or who have impaired renal
function (see DOSAGE AND ADMINISTRATION and Geriatric Use). Treatment should
not exceed 1 day (2 doses of 2 grams in 24 hours). Therapy
beyond 1 day does not provide additional clinical benefit.
Precipitation
of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL)
is exceeded in the intratubular fluid. Adequate hydration should be maintained.
In the event of acute renal failure and anuria, the patient may benefit from
hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).
The
safety and efficacy of VALTREX have not been established in immunocompromised
patients other than for the suppression of genital herpes in HIV-infected
patients. The safety and efficacy of VALTREX for suppression of recurrent
genital herpes in patients with advanced HIV disease (CD4 cell count <100 cells/mm3)
have not been established. The efficacy of VALTREX for the treatment of genital
herpes in HIV-infected patients has not been established. The safety and efficacy
of VALTREX have not been established for the treatment of disseminated herpes
zoster.
The efficacy of VALTREX for reducing transmission
of genital herpes has not been established in individuals with multiple partners
and non-heterosexual couples.
Precautions
Information for Patients
Patients should be advised
to maintain adequate hydration.
Herpes Zoster
There are no data on treatment initiated more than 72 hours
after onset of the zoster rash. Patients should be advised to initiate treatment
as soon as possible after a diagnosis of herpes zoster.
Genital Herpes
Patients should be informed that VALTREX is not a cure for
genital herpes. Because genital herpes is a sexually transmitted disease,
patients should avoid contact with lesions or intercourse when lesions and/or
symptoms are present to avoid infecting partners. Genital herpes is frequently
transmitted in the absence of symptoms through asymptomatic viral shedding.
Therefore, patients should be counseled to use safer sex practices in combination
with suppressive therapy with VALTREX. Sex partners of infected persons should
be advised that they might be infected even if they have no symptoms. Type-specific
serologic testing of asymptomatic partners of persons with genital herpes
can determine whether risk for HSV-2 acquisition exists.
VALTREX
has not been shown to reduce transmission of sexually transmitted infections
other than HSV-2.
If medical management of a genital
herpes recurrence is indicated, patients should be advised to initiate therapy
at the first sign or symptom of an episode.
There
are no data on the effectiveness of treatment initiated more than 72 hours
after the onset of signs and symptoms of a first episode of genital herpes
or more than 24 hours after the onset of signs and symptoms of a recurrent
episode.
There are no data on the safety or effectiveness
of chronic suppressive therapy of more than 1 year’s duration
in otherwise healthy patients. There are no data on the safety or effectiveness
of chronic suppressive therapy of more than 6 months’ duration
in HIV-infected patients.
Cold Sores (Herpes Labialis)
Patients should be advised to initiate treatment at the
earliest symptom of a cold sore (e.g., tingling, itching, or burning). There
are no data on the effectiveness of treatment initiated after the development
of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients
should be instructed that treatment for cold sores should not exceed 1 day
(2 doses) and that their doses should be taken about 12 hours apart.
Patients should be informed that VALTREX is not a cure for cold sores (herpes
labialis).
Drug Interactions
See CLINICAL PHARMACOLOGY: Pharmacokinetics.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The data presented below include references to the steady-state
acyclovir AUC observed in humans treated with 1 gram VALTREX given orally
3 times a day to treat herpes zoster. Plasma drug concentrations in animal
studies are expressed as multiples of human exposure to acyclovir (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Valacyclovir was noncarcinogenic
in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir
giving plasma acyclovir concentrations equivalent to human levels in the mouse
bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There
was no significant difference in the incidence of tumors between treated and
control animals, nor did valacyclovir shorten the latency of tumors.
Valacyclovir
was tested in 5 genetic toxicity assays. An Ames assay was negative in
the absence or presence of metabolic activation. Also negative were an in vitro
cytogenetic study with human lymphocytes and a rat cytogenetic study.
In
the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of
metabolic activation. In the presence of metabolic activation (76% to 88%
conversion to acyclovir), valacyclovir was mutagenic.
Valacyclovir
was mutagenic in a mouse micronucleus assay.
Valacyclovir
did not impair fertility or reproduction in rats at 6 times human plasma
levels.
Pregnancy
Teratogenic Effects
Pregnancy Category
B. Valacyclovir was not teratogenic in rats or rabbits at 10 and 7 times
human plasma levels, respectively, during the period of major organogenesis.
There
are no adequate and well-controlled studies of VALTREX or ZOVIRAX in pregnant
women. A prospective epidemiologic registry of acyclovir use during pregnancy
was established in 1984 and completed in April 1999. There were 749 pregnancies
followed in women exposed to systemic acyclovir during the first trimester
of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects
approximates that found in the general population. However, the small size
of the registry is insufficient to evaluate the risk for less common defects
or to permit reliable or definitive conclusions regarding the safety of acyclovir
in pregnant women and their developing fetuses. VALTREX should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nursing Mothers
Following oral administration of a 500-mg dose of VALTREX
to 5 nursing mothers, peak acyclovir concentrations (Cmax) in breast
milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal
acyclovir serum concentrations. The acyclovir breast milk AUC ranged from
1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500-mg maternal dosage
of VALTREX twice daily would provide a nursing infant with an oral acyclovir
dosage of approximately 0.6 mg/kg/day. This would result in less than
2% of the exposure obtained after administration of a standard neonatal dose
of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged
valacyclovir was not detected in maternal serum, breast milk, or infant urine.
VALTREX should be administered to a nursing mother with caution and only when
indicated.
Pediatric Use
Safety and effectiveness of VALTREX in pre-pubertal pediatric
patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of VALTREX,
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. With respect
to CNS adverse events observed during clinical practice, agitation, hallucinations,
confusion, delirium, and encephalopathy were reported more frequently in elderly
patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical
Practice, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Frequently reported adverse events in clinical trials of
VALTREX in healthy patients are listed in Tables 4 and 5.
Table 4. Incidence (%) of Adverse Events in Herpes Zoster
Study Populations
|
Adverse Event
|
VALTREX
1 gram
t.i.d.
(n = 967)
|
Placebo
(n = 195)
|
|
Nausea
|
15%
|
8%
|
|
Headache
|
14%
|
12%
|
|
Vomiting
|
6%
|
3%
|
|
Dizziness
|
3%
|
2%
|
|
Abdominal pain
|
3%
|
2%
|
Table 5. Incidence (%) of Adverse Events
in Genital Herpes Study Populations
|
|
Genital Herpes Treatment
|
Genital Herpes Suppression
|
|
Adverse Event
|
VALTREX
1 gram
b.i.d.
(n = 1,194)
|
VALTREX
500 mg
b.i.d.
(n = 1,159)
|
Placebo
(n = 439)
|
VALTREX
1 gram
q.d.
(n = 269)
|
VALTREX
500 mg
q.d.
(n = 266)
|
Placebo
(n = 134)
|
|
Nausea
|
6%
|
5%
|
8%
|
11%
|
11%
|
8%
|
|
Headache
|
16%
|
15%
|
14%
|
35%
|
38%
|
34%
|
|
Vomiting
|
1%
|
<1%
|
<1%
|
3%
|
3%
|
2%
|
|
Dizziness
|
3%
|
2%
|
3%
|
4%
|
2%
|
1%
|
|
Abdominal pain
|
2%
|
1%
|
3%
|
11%
|
9%
|
6%
|
|
Dysmenorrhea
|
<1%
|
<1%
|
1%
|
8%
|
5%
|
4%
|
|
Arthralgia
|
<1%
|
<1%
|
<1%
|
6%
|
5%
|
4%
|
|
Depression
|
1%
|
0%
|
<1%
|
7%
|
5%
|
5%
|
Laboratory abnormalities reported in clinical trials of
VALTREX in otherwise healthy patientsare
listed in Table 6.
Table 6. Incidence
(%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study
Populations
|
|
Herpes Zoster
|
Genital Herpes Treatment
|
Genital Herpes Suppression
|
|
Laboratory Abnormality
|
VALTREX
1 gram
t.i.d.
|
Place-bo
|
VALTREX1 gram b.i.d.
|
VALTREX500 mg b.i.d.
|
Place-bo
|
VALTREX
1 gram
q.d.
|
VALTREX500 mg q.d.
|
Place-bo
|
|
Hemoglobin
(<0.8 x LLN)
|
0.8%
|
0%
|
0.3%
|
0.2%
|
0%
|
0%
|
0.8%
|
0.8%
|
|
White blood cells
(<0.75
x LLN)
|
1.3%
|
0.6%
|
0.7%
|
0.6%
|
0.2%
|
0.7%
|
0.8%
|
1.5%
|
|
Platelet count (<100,000/mm3)
|
1.0%
|
1.2%
|
0.3%
|
0.1%
|
0.7%
|
0.4%
|
1.1%
|
1.5%
|
|
AST (SGOT)
(>2 x ULN)
|
1.0%
|
0%
|
1.0%
|
*
|
0.5%
|
4.1%
|
3.8%
|
3.0%
|
|
Serum creatinine
(>1.5 x
ULN)
|
0.2%
|
0%
|
0.7%
|
0%
|
0%
|
0%
|
0%
|
0%
|
Suppression of Genital Herpes in HIV-Infected Patients
In HIV-infected patients,
frequently reported adverse events for VALTREX (500 mg twice daily; n = 194,
median days on therapy = 172) and placebo (n = 99, median
days on therapy = 59), respectively, included headache (13% vs.
8%), fatigue (8% vs. 5%), and rash (8% vs. 1%). Post-randomization laboratory
abnormalities that were reported more frequently in valacyclovir subjects
versus placebo included elevated alkaline phosphatase (4% vs. 2%), elevated
ALT (14% vs. 10%), elevated AST (16% vs. 11%), decreased neutrophil counts
(18% vs. 10%), and decreased platelet counts (3% vs. 0%).
Reduction of Transmission
In a clinical study for the reduction of transmission of
genital herpes, the adverse events reported by patients receiving VALTREX
500 mg once daily (n = 743) or placebo once daily (n = 741)
included headache (VALTREX 29%, placebo 26%), nasopharyngitis (VALTREX 16%,
placebo 15%), and upper respiratory tract infection (VALTREX 9%, placebo 10%).
In this 8-month study, there were no clinically significant changes from baseline
laboratory parameters in subjects receiving VALTREX compared with placebo.
Cold Sores (Herpes Labialis)
In clinical studies for the treatment of cold sores, the
adverse events reported by patients receiving VALTREX (n = 609)
or placebo (n = 609) included headache (VALTREX 14%, placebo 10%)
and dizziness (VALTREX 2%, placebo 1%). The frequencies of abnormal ALT (>2
x ULN) were 1.8% for patients receiving VALTREX compared with 0.8% for placebo.
Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase,
and serum creatinine) occurred with similar frequencies in the 2 groups.
Observed During Clinical Practice
The following events have been identified during post-approval
use of VALTREX in clinical practice. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made.
These events have been chosen for inclusion due to either their seriousness,
frequency of reporting, causal connection to VALTREX, or a combination of
these factors.
General
Facial edema, hypertension, tachycardia.
Allergic
Acute hypersensitivity
reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and
urticaria.
CNS Symptoms
Aggressive behavior; agitation; ataxia; coma; confusion;
decreased consciousness; dysarthria; encephalopathy; mania; and psychosis,
including auditory and visual hallucinations; seizures, tremors (see PRECAUTIONS).
Eye
Visual abnormalities.
Gastrointestinal
Diarrhea.
Hepatobiliary Tract and Pancreas
Liver enzyme abnormalities, hepatitis.
Renal
Elevated creatinine,
renal failure.
Hematologic
Thrombocytopenia,
aplastic anemia, leukocytoclastic vasculitis, TTP/HUS.
Skin
Erythema multiforme, rashes including photosensitivity,
alopecia.
Renal Impairment
Renal failure and CNS
symptoms have been reported in patients with renal impairment who received
VALTREX or acyclovir at greater than the recommended dose. Dose
reduction is recommended in this patient population (see DOSAGE AND ADMINISTRATION).
OVERDOSAGE
Caution should be exercised
to prevent inadvertent overdose (see PRECAUTIONS). 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).
DOSAGE AND ADMINISTRATION
VALTREX Caplets may be given without regard to meals.
Herpes Zoster
The recommended dosage of VALTREX for the treatment of herpes
zoster is 1 gram orally 3 times daily for 7 days. Therapy should
be initiated at the earliest sign or symptom of herpes zoster and is most
effective when started within 48 hours of the onset of zoster rash. No
data are available on efficacy of treatment started greater than 72 hours
after rash onset.
Genital Herpes
Initial Episodes
The recommended
dosage of VALTREX for treatment of initial genital herpes is 1 gram twice
daily for 10 days.
There are no data on the effectiveness
of treatment with VALTREX when initiated more than 72 hours after the
onset of signs and symptoms. Therapy was most effective when administered
within 48 hours of the onset of signs and symptoms.
Recurrent Episodes
The recommended dosage of VALTREX for the treatment of recurrent
genital herpes is 500 mg twice daily for 3 days.
If
medical management of a genital herpes recurrence is indicated, patients should
be advised to initiate therapy at the first sign or symptom of an episode.
There are no data on the effectiveness of treatment with VALTREX when initiated
more than 24 hours after the onset of signs or symptoms.
Suppressive Therapy
The recommended
dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes
is 1 gram once daily in patients with normal immune function. In patients
with a history of 9 or fewer recurrences per year, an alternative dose is
500 mg once daily. The safety and efficacy of therapy with VALTREX beyond
1 year have not been established.
In HIV-infected
patients with CD4 cell count =100 cells/mm3, the
recommended dosage of VALTREX for chronic suppressive therapy of recurrent
genital herpes is 500 mg twice daily. The safety and efficacy of therapy
with VALTREX beyond 6 months in patients with HIV infection have not
been established.
Reduction of Transmission
The recommended dosage
of VALTREX for reduction of transmission of genital herpes in patients with
a history of 9 or fewer recurrences per year is 500 mg once daily for
the source partner. Patients should be counseled to use safer sex practices
in combination with suppressive therapy with VALTREX. The efficacy of reducing
transmission beyond 8 months in discordant couples has not been established.
Cold Sores (Herpes Labialis)
The recommended dosage of VALTREX for the treatment of cold
sores is 2 grams twice daily for 1 day taken about 12 hours
apart. Therapy should be initiated at the earliest symptom of a cold sore
(e.g., tingling, itching, or burning). There are no data on the effectiveness
of treatment initiated after the development of clinical signs of a cold sore
(e.g., papule, vesicle, or ulcer).
Patients with Acute or Chronic Renal Impairment
In patients with reduced renal function, reduction in dosage
is recommended (see Table 7).
Table
7. Dosages for Patients with Renal Impairment
|
Indications
|
Normal Dosage
Regimen
(Creatinine
Clearance =50)
|
Creatinine Clearance
(mL/min)
|
|
30-49
|
10-29
|
<10
|
|
Herpes zoster
|
1 gram every 8 hours
|
1 gram every
12 hours
|
1 gram every
24 hours
|
500 mg every
24 hours
|
|
Genital herpes
Initial treatment
|
1 gram every 12 hours
|
no reduction
|
1 gram every 24 hours
|
500 mg every 24 hours
|
|
Genital herpes
Recurrent episodes
|
500 mg every 12 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
Genital herpes
Suppressive therapy
|
1 gram every 24 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
|
500 mg every 24 hours
|
no reduction
|
500 mg every 48 hours
|
500 mg every 48 hours
|
|
Genital herpes
Suppressive therapy in
HIV-infected patients
|
500 mg every 12 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
Herpes labialis
(cold sores)
Do
not exceed 1 day of treatment.
|
Two 2-gram doses taken about 12 hours
apart
|
Two 1-gram doses taken about 12 hours
apart
|
Two 500-mg doses taken about 12 hours
apart
|
500-mg
single
dose
|
Hemodialysis
During hemodialysis, the half-life of acyclovir after administration
of VALTREX is approximately 4 hours. About one third of acyclovir in
the body is removed by dialysis during a 4-hour hemodialysis session. Patients
requiring hemodialysis should receive the recommended dose of VALTREX after
hemodialysis.
Peritoneal Dialysis
There is no information specific to administration of VALTREX
in patients receiving peritoneal dialysis. The effect of chronic ambulatory
peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis
(CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir
after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic
parameters closely resemble those observed in patients with ESRD not receiving
hemodialysis. Therefore, supplemental doses of VALTREX should not be required
following CAPD or CAVHD.
HOW SUPPLIED
VALTREX Caplets (blue, film-coated, capsule-shaped tablets)
containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir
and printed with “VALTREX 500 mg.”
Bottle
of 30 (NDC 0173-0933-08) and unit dose pack of 100 (NDC 0173-0933-56).
VALTREX
Caplets (blue, film-coated, capsule-shaped tablets, with a partial scorebar
on both sides) containing valacyclovir hydrochloride equivalent to 1 gram
valacyclovir and printed with “VALTREX 1 gram.”
Bottle
of 30 (NDC 0173-0565-04).
Store
at 15° to 25°C (59° to 77°F).
Distributed
by
GlaxoSmithKline
Research Triangle
Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research
Triangle Park, NC 27709
or
DSM
Pharmaceuticals, Inc.
Greenville, NC 27834
©2005,
GlaxoSmithKline. All rights reserved.
October 2005 RL-2241
PHARMACIST
DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
PATIENT INFORMATION
VALTREX® (VAL-trex)
(valacyclovir hydrochloride) Caplets
Read
the Patient Information that comes with VALTREX before you start using it
and each time you get a refill. There may be new information. This information
does not take the place of talking to your healthcare provider about your
medical condition or treatment. Ask your healthcare provider or pharmacist
if you have questions.
What
is VALTREX?
VALTREX is a prescription antiviral
medicine. VALTREX lowers the ability of herpes viruses to multiply in your
body.
VALTREX is used:
- to treat cold sores (also called fever blisters or herpes labialis)
in adults
- to treat shingles (also called herpes zoster) in adults
- to treat or control genital herpes outbreaks in adults with normal immune
systems
- to control genital herpes outbreaks in adults infected with the human
immunodeficiency virus (HIV) with CD4 cell count greater than 100 cells/mm3
- with safer sex practices to lower the chances of spreading genital herpes
to others.
- Even with safer sex practices, it is still possible to spread genital
herpes.
VALTREX used daily with the following safer sex practices
can lower the chances of passing genital herpes to your partner.
- Do not have sexual contact with your partner
when you have any symptom or outbreak of genital herpes.
- Use a condom made of latex or polyurethane
whenever you have sexual contact.
VALTREX does not cure herpes infections (cold sores, shingles, or genital herpes).
VALTREX
has not been studied in children who have not reached puberty.
What are cold sores, shingles, and genital herpes?
Cold sores are
caused by a herpes virus that may be spread by kissing or other physical contact
with the infected area of the skin. They are small, painful ulcers that you
get in or around your mouth. It is not known if VALTREX can stop the spread
of cold sores to others.
Shingles is caused by the same herpes virus that causes chickenpox. It
causes small, painful blisters that happen on a certain area of your skin.
Shingles occurs in people who have already had chickenpox. Shingles can be
spread to people who have not had chickenpox or the chickenpox vaccine by
contact with the infected areas of the skin. It is not known if VALTREX can
stop the spread of shingles to others.
Genital
herpes is a sexually transmitted disease. It causes small, painful
blisters on your genital area. You can spread genital herpes to others, even
when you have no symptoms. If you are sexually active, you can still pass
herpes to your partner, even if you are taking VALTREX. VALTREX, taken every
day as prescribed and used with the following safer
sex practices, can lower the chances of passing genital herpes to
your partner.
- Do not have sexual contact with your partner
when you have any symptom or outbreak of genital herpes.
- Use a condom made of latex or polyurethane
whenever you have sexual contact.
Ask your healthcare provider for more information about
safer sex practices.
Who
should not take VALTREX?
Do
not take VALTREX if you are allergic to any of its ingredients or
to acyclovir. The active ingredient is valacyclovir. See the end of this leaflet
for a complete list of ingredients in VALTREX.
Before taking VALTREX, tell your healthcare provider:
About all your medical conditions, including:
- if you have had a bone marrow transplant or
kidney transplant, or if you have advanced HIV disease or "AIDS". Patients
with these conditions may have a higher chance for getting a blood disorder
called thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).
TTP/HUS can result in death.
- if you have kidney problems. Patients
with kidney problems may have a higher chance for getting side effects or
more kidney problems with VALTREX. Your healthcare provider may give you a
lower dose of VALTREX.
- if you are 65 years of age or older. Elderly patients have a higher chance of certain side effects.
Also, elderly patients are more likely to have kidney problems. Your healthcare
provider may give you a lower dose of VALTREX.
- if you are pregnant or planning to become
pregnant. Talk with your healthcare provider about the risks and
benefits of taking prescription drugs (including VALTREX) during pregnancy.
- if you are breastfeeding. VALTREX
may pass into your milk and it may harm your baby. Talk with your healthcare
provider about the best way to feed your baby if you are taking VALTREX.
- about all the medicines you take,
including prescription and non-prescription medicines, vitamins, and herbal
supplements. VALTREX may affect other medicines, and other medicines may affect
VALTREX. This may happen if you have certain medical conditions such as kidney
problems. It is a good idea to keep a complete list of all the medicines you
take. Show this list to your healthcare provider and pharmacist any time you
get a new medicine.
How should I take VALTREX?
Take VALTREX exactly as prescribed by your
healthcare provider. Your dose of VALTREX and length of treatment will depend
on the type of herpes infection that you have and any other medical problems
that you have.
- Do not stop VALTREX or change your treatment without talking to your
healthcare provider.
- VALTREX can be taken with or without food.
- If you are taking VALTREX to treat cold sores, shingles, or genital
herpes, you should start treatment as soon as possible after your symptoms
start. VALTREX may not help you if you start treatment too late.
- If you miss a dose of VALTREX, take it as soon as you remember and then
take your next dose at its regular time. However, if it is almost time for
your next dose, do not take the missed dose. Wait and take the next dose at
the regular time.
- Do not take more than the prescribed number of VALTREX Caplets each
day. Call your healthcare provider right away if you take too much VALTREX.
What are the possible
side effects of VALTREX?
Kidney
failure and nervous system problems are not common, but can be serious in
some patients taking VALTREX. Nervous system problemsincludeaggressive behavior,
unsteady movement, shaky movements, confusion, speech problems, hallucinations
(seeing or hearing things that are really not there), seizures, and coma.
Kidney failure and nervous system problems have happened in patients who already
have kidney disease and in elderly patients whose kidneys do not work well
due to age. Always tell your healthcare provider
if you have kidney problems before taking VALTREX. Call your doctor right
away if you get a nervous system problem while you are taking VALTREX.
Common
side effects of VALTREX include headache, nausea, stomach pain, vomiting,
and dizziness. Side effects in HIV-infected adults include headache, tiredness,
and rash. These side effects are usually mild and usually do not cause patients
to stop taking VALTREX.
Other less common side effects
include painful periods in women, joint pain, depression, low blood cell counts,
and changes in tests that measure how well the liver and kidneys work.
Talk to your healthcare provider if you develop any side
effects that concern you.
These are not all
the side effects of VALTREX. For more information ask your healthcare provider
or pharmacist.
How
should I store VALTREX?
- Store VALTREX at room temperature, 59° to 77°F (15° to
25°C).
- Keep VALTREX in a tightly closed container.
- Do not keep medicine that is out of date or that you no longer need.
- Keep VALTREX and all medicines out of the
reach of children.
General information
about VALTREX
Medicines are sometimes prescribed
for conditions that are not mentioned in patient information leaflets. Do
not use VALTREX for a condition for which it was not prescribed. Do not give
VALTREX to other people, even if they have the same symptoms you have. It
may harm them.
This leaflet summarizes the most important
information about VALTREX. If you would like more information, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about VALTREX that is written for health professionals. More information
is available at www.VALTREX.com.
What
are the ingredients in VALTREX?
Active
Ingredient: valacyclovir hydrochloride
Inactive Ingredients: carnauba wax, colloidal silicon
dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone,
and titanium dioxide.
Rx Only
Distributed by
GlaxoSmithKline
Research
Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research
Triangle Park, NC 27709
or
DSM
Pharmaceuticals, Inc.
Greenville, NC 27834
©2005,
GlaxoSmithKline. All rights reserved.
October 2005 RL-2241
| Valtrex (valacyclovir hydrochloride) |
|
|
|
|
|
|
|
|
| Valtrex (valacyclovir hydrochloride) |
|
|
|
|
|
|
|
|
Revised: 08/2006GlaxoSmithKline