Indications and Usage for Valtrex
Adult Patients
Cold Sores (Herpes Labialis): Valtrex® (valacyclovir
hydrochloride) Caplets are indicated for treatment of cold sores (herpes
labialis). The efficacy of Valtrex initiated after the development of clinical
signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been
established.
Genital Herpes: Initial
Episode: Valtrex
is indicated for treatment of the initial episode of genital herpes in
immunocompetent adults. The efficacy of treatment with Valtrex when initiated
more than 72 hours after the onset of signs and symptoms has not been
established.
Recurrent Episodes: Valtrex is indicated
for treatment of recurrent episodes of genital herpes in immunocompetent
adults. The efficacy of treatment with Valtrex when initiated more than
24 hours after the onset of signs and symptoms has not been established.
Suppressive Therapy: Valtrex is indicated
for chronic suppressive therapy of recurrent episodes of genital herpes in
immunocompetent and in HIV-1─infected adults. The
efficacy and safety of Valtrex for the suppression of genital herpes beyond
1 year in immunocompetent patients and beyond 6 months in HIV-1─infected patients have not been established.
Reduction of Transmission: Valtrex is indicated
for the reduction of transmission of genital herpes in immunocompetent adults.
The efficacy of Valtrex for the reduction of transmission of genital herpes
beyond 8 months in discordant couples has not been established. The
efficacy of Valtrex for the reduction of transmission of genital herpes in
individuals with multiple partners and non─heterosexual couples has
not been established. Safer sex practices should be used with suppressive
therapy (see current Centers for Disease Control and Prevention [CDC] Sexually
Transmitted Diseases Treatment Guidelines).
Herpes Zoster: Valtrex is indicated
for the treatment of herpes zoster (shingles) in immunocompetent adults. The
efficacy of Valtrex when initiated more than 72 hours after the onset of
rash and the efficacy and safety of Valtrex for treatment of disseminated
herpes zoster have not been established.
Pediatric Patients
Cold Sores (Herpes Labialis): Valtrex is indicated
for the treatment of cold sores (herpes labialis) in pediatric patients aged
greater than or equal to 12 years. The efficacy of Valtrex initiated after
the development of clinical signs of a cold sore (e.g., papule, vesicle, or
ulcer) has not been established.
Chickenpox: Valtrex is indicated
for the treatment of chickenpox in immunocompetent pediatric patients aged 2 to
less than 18 years. Based on efficacy data from clinical trials with oral
acyclovir, treatment with Valtrex should be initiated within 24 hours
after the onset of rash [see Clinical Studies (14.4)].
Limitations of Use
The efficacy and safety of Valtrex have not been
established in:
•
Immunocompromised patients other than
for the suppression of genital herpes in HIV─1─infected patients with a CD4+ cell count greater
than or equal to 100 cells/mm3.
•
Patients aged less than 12 years
with cold sores (herpes labialis).
•
Patients aged less than 2 years
or greater than or equal to 18 years with chickenpox.
•
Patients aged less than 18 years
with genital herpes.
•
Patients aged less than 18 years
with herpes zoster.
•
Neonates and infants as suppressive
therapy following neonatal herpes simplex virus (HSV) infection.
Valtrex Dosage and Administration
•
Valtrex may be given without regard
to meals.
•
Valacyclovir oral suspension
(25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500-mg
Valtrex Caplets for use in pediatric patients for whom a solid dosage form is
not appropriate [see Dosage and Administration (2.3)].
Adult Dosing
Recommendations
Cold
Sores (Herpes Labialis): The recommended dosage of Valtrex for
treatment of cold sores is 2 grams twice daily for 1 day taken
12 hours apart. Therapy should be initiated at the earliest symptom of a
cold sore (e.g., tingling, itching, or burning).
Genital
Herpes: Initial
Episode: The
recommended dosage of Valtrex for treatment of initial genital herpes is
1 gram twice daily for 10 days. Therapy was most effective when
administered within 48 hours of the onset of signs and symptoms.
Recurrent
Episodes: The
recommended dosage of Valtrex for treatment of recurrent genital herpes is
500 mg twice daily for 3 days. Initiate treatment at the first sign or
symptom of an episode.
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.
In HIV─1─infected patients with a CD4+ cell count greater
than or equal to 100 cells/mm3, the recommended dosage of Valtrex for chronic
suppressive therapy of recurrent genital herpes is 500 mg twice daily.
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.
Herpes
Zoster: The
recommended dosage of Valtrex for treatment of herpes zoster is 1 gram
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 rash.
Pediatric Dosing
Recommendations
Cold
Sores (Herpes Labialis): The recommended dosage of Valtrex for the
treatment of cold sores in pediatric patients aged greater than or equal to
12 years is 2 grams twice daily for 1 day taken 12 hours
apart. Therapy should be initiated at the earliest symptom of a cold sore
(e.g., tingling, itching, or burning).
Chickenpox: The recommended
dosage of Valtrex for treatment of chickenpox in immunocompetent pediatric
patients aged 2 to less than 18 years is 20 mg/kg administered
3 times daily for 5 days. The total dose should not exceed
1 gram 3 times daily. Therapy should be initiated at the earliest
sign or symptom [see Use in Specific Populations
(8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)].
Extemporaneous Preparation
of Oral Suspension
Ingredients
and Preparation per USP─NF: Valtrex Caplets 500 mg, cherry flavor,
and Suspension Structured Vehicle USP─NF (SSV). Valacyclovir
oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of
100 mL.
Prepare
Suspension at Time of Dispensing as Follows:
•
Prepare SSV according to the USP-NF.
•
Using a pestle and mortar, grind the
required number of Valtrex 500 mg Caplets until a fine powder is produced
(5 Valtrex Caplets for 25 mg/mL suspension; 10 Valtrex Caplets
for 50 mg/mL suspension).
•
Gradually add approximately 5-mL
aliquots of SSV to the mortar and triturate the powder until a paste has been
produced. Ensure that the powder has been adequately wetted.
•
Continue to add approximately 5-mL
aliquots of SSV to the mortar, mixing thoroughly between additions, until a
concentrated suspension is produced, to a minimum total quantity of 20 mL
SSV and a maximum total quantity of 40 mL SSV for both the 25-mg/mL and 50─mg/mL suspensions.
•
Transfer the mixture to a suitable
100-mL measuring flask.
•
Transfer the cherry flavor* to the
mortar and dissolve in approximately 5 mL of SSV. Once dissolved, add to
the measuring flask.
•
Rinse the mortar at least
3 times with approximately 5-mL aliquots of SSV, transferring the rinsing
to the measuring flask between additions.
•
Make the suspension to volume
(100 mL) with SSV and shake thoroughly to mix.
•
Transfer the suspension to an amber
glass medicine bottle with a child─resistant closure.
•
The prepared suspension should be
labeled with the following information “Shake well before using. Store
suspension between 2° to 8°C (36° to 46°F) in a refrigerator. Discard after
28 days.”
*The amount of cherry flavor added is as instructed
by the suppliers of the cherry flavor.
Patients With Renal Impairment
Dosage recommendations for adult patients with
reduced renal function are provided in Table 1 [see
Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available
for the use of Valtrex in pediatric patients with a creatinine clearance less
than 50 mL/min/1.73 m2.
Table 1. Valtrex Dosage Recommendations for Adults With Renal
Impairment
|
|
|
Indications
|
Normal Dosage
Regimen
(Creatinine Clearance ≥50 mL/min)
|
Creatinine Clearance
(mL/min)
|
|
|
30-49
|
10-29
|
<10
|
|
|
Cold sores (Herpes labialis)
Do
not exceed 1 day of treatment.
|
Two 2 gram doses taken 12 hours apart
|
Two 1 gram doses taken 12 hours apart
|
Two 500 mg doses taken 12 hours apart
|
500 mg single dose
|
|
|
Genital herpes:
Initial episode
|
1 gram every 12 hours
|
no reduction
|
1 gram every 24 hours
|
500 mg every 24 hours
|
|
|
Genital herpes:
Recurrent episode
|
500 mg every 12 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
|
Genital herpes:
Suppressive therapy
|
|
|
|
|
|
|
Immunocompetent
patients
|
1 gram every 24 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
|
Alternate
dose for immunocompetent patients with less than or equal to 9 recurrences/year
|
500 mg every 24 hours
|
no reduction
|
500 mg every 48 hours
|
500 mg every 48 hours
|
|
|
HIV─1─infected patients
|
500 mg every 12 hours
|
no reduction
|
500 mg every 24 hours
|
500 mg every 24 hours
|
|
|
Herpes zoster
|
1 gram every 8 hours
|
1 gram every 12 hours
|
1 gram every 24 hours
|
500 mg every 24 hours
|
|
Hemodialysis: Patients requiring
hemodialysis should receive the recommended dose of Valtrex after 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.
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 end─stage renal disease (ESRD) not receiving
hemodialysis. Therefore, supplemental doses of Valtrex should not be required
following CAPD or CAVHD.
Dosage Forms and Strengths
Caplets:
•
500-mg: blue, film─coated, capsule─shaped tablets printed
with "Valtrex 500 mg."
•
1-gram: blue, film─coated, capsule─shaped tablets, with a
partial scorebar on both sides, printed with "Valtrex 1 gram."
Contraindications
Valtrex is contraindicated in
patients who have had a demonstrated clinically significant hypersensitivity
reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of
the formulation [see Adverse Reactions (6.3)].
Warnings and Precautions
Thrombotic
Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)
TTP/HUS, in some cases resulting in
death, has occurred in patients with advanced HIV─1
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. Treatment with Valtrex should be stopped immediately if clinical
signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
Acute Renal Failure
Cases of acute renal failure have
been reported in:
•
Elderly patients with or without
reduced renal function. Caution should be exercised when administering Valtrex
to geriatric patients, and dosage reduction is recommended for those with
impaired renal function [see Dosage and Administration (2.4),
Use in Specific Populations (8.5)].
•
Patients with underlying renal
disease who received higher-than-recommended doses of Valtrex for their level
of renal function. Dosage reduction is recommended when administering Valtrex
to patients with renal impairment [see
Dosage and Administration (2.4), Use in Specific Populations (8.6)].
•
Patients receiving other nephrotoxic
drugs. Caution should be exercised when administering Valtrex to patients
receiving potentially nephrotoxic drugs.
•
Patients without adequate hydration.
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 for all patients.
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), Adverse
Reactions (6.3)].
Central Nervous System
Effects
Central nervous system adverse
reactions, including agitation, hallucinations, confusion, delirium, seizures,
and encephalopathy, have been reported in both adult and pediatric patients
with or without reduced renal function and in patients with underlying renal
disease who received higher-than-recommended doses of Valtrex for their level
of renal function. Elderly patients are more likely to have central nervous
system adverse reactions. Valtrex should be discontinued if central nervous
system adverse reactions occur [see
Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].
Adverse Reactions
The following serious adverse
reactions are discussed in greater detail in other sections of the labeling:
•
Thrombotic Thrombocytopenic
Purpura/Hemolytic Uremic Syndrome [see
Warnings and Precautions (5.1)].
•
Acute Renal Failure [see
Warnings and Precautions (5.2)].
•
Central Nervous System Effects [see
Warnings and Precautions (5.3)].
The most common adverse reactions
reported in at least 1 indication by greater than 10% of adult subjects
treated with Valtrex and observed more frequently with Valtrex compared to
placebo are headache, nausea, and abdominal pain. The only adverse reaction
reported in greater than 10% of pediatric subjects aged less than 18 years
was headache.
Clinical Trials Experience
in Adult Subjects
Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Cold
Sores (Herpes Labialis): In clinical trials for the treatment of cold
sores, the adverse reactions reported by subjects receiving Valtrex
2 grams twice daily (n = 609) or placebo (n = 609) for
1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%).
The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for subjects
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.
Genital
Herpes: Initial
Episode: In
a clinical trial for the treatment of initial episodes of genital herpes, the
adverse reactions reported by greater than or equal to 5% of subjects receiving
Valtrex 1 gram twice daily for 10 days (n = 318) or oral
acyclovir 200 mg 5 times daily for 10 days (n = 318),
respectively, included headache (13%, 10%) and nausea (6%, 6%). For the
incidence of laboratory abnormalities see Table 2.
Recurrent
Episodes: In
3 clinical trials for the episodic treatment of recurrent genital herpes, the
adverse reactions reported by greater than or equal to 5% of subjects receiving
Valtrex 500 mg twice daily for 3 days (n = 402), Valtrex 500 mg
twice daily for 5 days (n = 1,136) or placebo
(n = 259), respectively, included headache (16%, 11%, 14%) and nausea
(5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2.
Suppressive Therapy: Suppression of
Recurrent Genital Herpes in Immunocompetent Adults: In a clinical trial for the
suppression of recurrent genital herpes infections, the adverse reactions
reported by subjects receiving Valtrex 1 gram once daily
(n = 269), Valtrex 500 mg once daily (n = 266), or
placebo (n = 134), respectively, included headache (35%, 38%, 34%),
nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%),
depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and
dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see
Table 2.
Suppression of Recurrent Genital
Herpes in HIV─1-Infected Subjects: In HIV─1-infected subjects, frequently reported adverse
reactions 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%, 8%), fatigue
(8%, 5%), and rash (8%, 1%). Post─randomization laboratory
abnormalities that were reported more frequently in valacyclovir subjects
versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT
(14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%),
and decreased platelet counts (3%, 0%), respectively.
Reduction of Transmission: In a clinical trial
for the reduction of transmission of genital herpes, the adverse reactions
reported by subjects receiving Valtrex 500 mg once daily
(n = 743) or placebo once daily (n = 741), respectively,
included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory
tract infection (9%, 10%).
Herpes Zoster: In 2 clinical
trials for the treatment of herpes zoster, the adverse reactions reported by
subjects receiving Valtrex 1 gram 3 times daily for 7 to 14 days
(n = 967) or placebo (n = 195), respectively, included
nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%),
and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see
Table 2.
Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster
and Genital Herpes Trial Populations
|
|
|
Laboratory Abnormality
|
Herpes Zoster
|
Genital Herpes
Treatment
|
Genital Herpes
Suppression
|
|
|
Valtrex
1 gram
3 Times Daily
(n = 967)
|
Placebo
(n = 195)
|
Valtrex
1 gram Twice Daily
(n = 1,194)
|
Valtrex
500 mg Twice Daily
(n = 1,159)
|
Placebo
(n = 439)
|
Valtrex
1 gram Once Daily
(n = 269)
|
Valtrex
500 mg Once Daily
(n = 266)
|
Placebo
(n = 134)
|
|
|
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%
|
a
|
0.5%
|
4.1%
|
3.8%
|
3.0%
|
|
|
Serum
creatinine
(>1.5 x ULN)
|
0.2%
|
0%
|
0.7%
|
0%
|
0%
|
0%
|
0%
|
0%
|
|
|
a Data were not collected prospectively.
|
|
|
LLN
= Lower limit of normal.
|
|
|
ULN
= Upper limit of normal.
|
|
Clinical Trials Experience in
Pediatric Subjects
The safety profile of Valtrex has been studied in
177 pediatric subjects aged 1 month to less than 18 years. Sixty-five
of these pediatric subjects, aged 12 to less than 18 years, received oral
caplets for 1 to 2 days for treatment of cold sores. The remaining
112 pediatric subjects, aged 1 month to less than 12 years,
participated in 3 pharmacokinetic and safety trials and received valacyclovir
oral suspension. Fifty-one of these 112 pediatric subjects received oral
suspension for 3 to 6 days. The frequency, intensity, and nature of
clinical adverse reactions and laboratory abnormalities were similar to those
seen in adults.
Pediatric Subjects Aged 12 to Less
Than 18 Years (Cold Sores): In clinical trials for the treatment of cold
sores, the adverse reactions reported by adolescent subjects receiving Valtrex
2 grams twice daily for 1 day, or Valtrex 2 grams twice daily
for 1 day followed by 1 gram twice daily for 1 day
(n = 65, across both dosing groups), or placebo (n = 30),
respectively, included headache (17%, 3%) and nausea (8%, 0%).
Pediatric Subjects Aged 1 Month to
Less Than 12 Years: Adverse events reported in more than
1 subject across the 3 pharmacokinetic and safety trials in children
aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%),
dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically
meaningful changes in laboratory values were observed.
Postmarketing Experience
In addition to adverse events reported from
clinical trials, the following events have been identified during postmarketing
use of Valtrex. 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 a combination of their seriousness, frequency of
reporting, or potential causal connection to Valtrex
General: Facial edema, hypertension,
tachycardia.
Allergic: Acute hypersensitivity
reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and
urticaria [see Contraindications (4)].
CNS Symptoms: Aggressive behavior;
agitation; ataxia; coma; confusion; decreased consciousness; dysarthria;
encephalopathy; mania; and psychosis, including auditory and visual
hallucinations, seizures, tremors [see
Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6)].
Eye: Visual abnormalities.
Gastrointestinal: Diarrhea.
Hepatobiliary Tract and Pancreas: Liver enzyme
abnormalities, hepatitis.
Renal: Renal failure, renal pain (may
be associated with renal failure) [see
Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6)].
Hematologic: Thrombocytopenia,
aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see
Warnings and Precautions (5.1)].
Skin: Erythema multiforme, rashes
including photosensitivity, alopecia.
Drug Interactions
No clinically significant drug-drug or drug-food
interactions with Valtrex are known [see
Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B. There are no adequate and
well─controlled trials of Valtrex or
acyclovir in pregnant women. Based on prospective pregnancy registry data on
749 pregnancies, the overall rate of birth defects in infants exposed to
acyclovir in-utero appears similar to the rate for infants in the general
population. Valtrex should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
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.
Animal reproduction studies performed at oral doses
that provided up to 10 and 7 times the human plasma levels during the
period of major organogenesis in rats and rabbits, respectively, revealed no
evidence of teratogenicity.
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.
Caution should be exercised when Valtrex is administered to a nursing woman.
Pediatric Use
Valtrex is indicated for treatment of cold sores in
pediatric patients aged greater than or equal to 12 years and for
treatment of chickenpox in pediatric patients aged 2 to less than
18 years [see Indications and Usage (1.2),
Dosage and Administration (2.2)].
The use of Valtrex for treatment of cold sores is
based on 2 double-blind, placebo-controlled clinical trials in healthy
adults and adolescents (aged greater than or equal to 12 years) with a
history of recurrent cold sores [see
Clinical Studies (14.1)].
The use of Valtrex for treatment of chickenpox in
pediatric patients aged 2 to less than 18 years is based on single─dose pharmacokinetic and multiple─dose safety data from an open─label trial with valacyclovir and supported by
efficacy and safety data from 3 randomized, double─blind, placebo─controlled trials
evaluating oral acyclovir in pediatric subjects with chickenpox [see
Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology
(12.3), Clinical Studies (14.4)].
The efficacy and safety of valacyclovir have not
been established in pediatric patients:
•
aged less than 12 years with
cold sores
•
aged less than 18 years with
genital herpes
•
aged less than 18 years with
herpes zoster
•
aged less than 2 years with
chickenpox
•
for suppressive therapy following
neonatal HSV infection
The pharmacokinetic profile and safety of
valacyclovir oral suspension in children aged less than 12 years were
studied in 3 open‑label trials. No efficacy evaluations were conducted in any
of the 3 trials.
Trial 1 was a single‑dose pharmacokinetic, multiple‑dose
safety trial in 27 pediatric subjects aged 1 to less than 12 years
with clinically suspected varicella─zoster virus (VZV)
infection [see Dosage and Administration (2.2), Adverse
Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].
Trial 2 was a single‑dose pharmacokinetic and
safety trial in pediatric subjects aged 1 month to less than 6 years
who had an active herpes virus infection or who were at risk for herpes virus
infection. Fifty─seven subjects were enrolled and
received a single dose of 25 mg/kg valacyclovir oral suspension. In
infants and children aged 3 months to less than 6 years, this dose
provided comparable systemic acyclovir exposures to that from a 1─gram dose of valacyclovir in adults (historical
data). In infants aged 1 month to less than 3 months, mean acyclovir
exposures resulting from a 25─mg/kg dose were higher (Cmax: ↑30%, AUC: ↑60%) than
acyclovir exposures following a 1─gram dose of valacyclovir
in adults. Acyclovir is not approved for suppressive therapy in infants and
children following neonatal HSV infections; therefore valacyclovir is not
recommended for this indication because efficacy cannot be extrapolated from acyclovir.
Trial 3 was a single‑dose pharmacokinetic, multiple‑dose
safety trial in 28 pediatric subjects aged 1 to less than 12 years
with clinically suspected HSV infection. None of the subjects enrolled in this
trial had genital herpes. Each subject was dosed with valacyclovir oral
suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic
exposures in pediatric subjects following valacyclovir oral suspension were
compared with historical acyclovir systemic exposures in immunocompetent adults
receiving the solid oral dosage form of valacyclovir or acyclovir for the
treatment of recurrent genital herpes. The mean projected daily acyclovir
systemic exposures in pediatric subjects across all age‑groups (1 to less than
12 years) were lower (Cmax: ↓20%, AUC: ↓33%) compared with the
acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice
daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults
receiving acyclovir 200 mg 5 times daily. Insufficient data are
available to support valacyclovir for the treatment of recurrent genital herpes
in this age‑group because clinical information on recurrent genital herpes in
young children is limited; therefore, extrapolating efficacy data from adults
to this population is not possible. Moreover, valacyclovir has not been studied
in children aged 1 to less than 12 years with recurrent genital herpes.
Geriatric Use
[Of the total number of subjects in clinical trials
of Valtrex, 906 were 65 and over, and 352 were 75 and over. In a clinical trial
of herpes zoster, the duration of pain after healing (post-herpetic neuralgia)
was longer in subjects 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)].
Renal Impairment
Dosage reduction is recommended when administering
Valtrex to patients with renal impairment [see
Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].
Overdosage
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)].
Valtrex Description
Valtrex (valacyclovir hydrochloride) is the
hydrochloride salt of the L─valyl ester of the antiviral drug acyclovir.
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─white powder 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 pkas for valacyclovir hydrochloride are 1.90, 7.47,
and 9.43.
Valtrex - Clinical Pharmacology
Mechanism of Action
Valacyclovir is an antiviral drug [see
Clinical Pharmacology (12.4)].
Pharmacokinetics
The pharmacokinetics of valacyclovir and acyclovir
after oral administration of Valtrex have been investigated in
14 volunteer trials involving 283 adults and in 3 trials
involving 112 pediatric subjects aged 1 month to less than
12 years.
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 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).
Acyclovir pharmacokinetic parameter estimates
following administration of Valtrex to healthy adult volunteers are presented
in Table 3. There was a less than dose─proportional increase in
acyclovir maximum concentration (Cmax) and area under the
acyclovir concentration─time curve (AUC) after
single─dose and multiple─dose administration (4 times daily) of Valtrex
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 Valtrex to
Healthy Adult Volunteers
|
|
|
Dose
|
Single─Dose Administration
(N = 8)
|
Multiple─Dose Administrationa
(N = 24,
8 per treatment arm)
|
|
|
Cmax (±SD)
(mcg/mL)
|
AUC (±SD) (h•mcg/mL)
|
Cmax (±SD)
(mcg/mL)
|
AUC (±SD) (h•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
Valtrex, average plasma valacyclovir concentrations observed were 0.5, 0.4, and
0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and
in healthy subjects 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 Valtrex to 12 healthy subjects
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 trials of Valtrex in subjects
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 Valtrex to subjects
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
subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m2compared with
679.16 ± 162.76 mL/min/1.73 m2 in healthy subjects.
Hepatic Impairment: Administration of
Valtrex to subjects 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-1 Disease: In 9 subjects
with HIV-1 disease and CD4+ cell counts less than 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 subjects.
Geriatrics: After single-dose
administration of 1 gram of Valtrex in healthy geriatric subjects, the
half‑life of acyclovir was 3.11 ± 0.51 hours, compared with
2.91 ± 0.63 hours in healthy younger adult subjects. The
pharmacokinetics of acyclovir following single- and multiple‑dose oral
administration of Valtrex in geriatric subjects 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 subjects
(aged 1 month to less than 12 years) 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
Subjects vs. 1─Gram Single Dose of Valtrex to Adults
|
|
a Historical estimates using pediatric pharmacokinetic
sampling schedule.
|
|
Parameter
|
Pediatric Subjects
(20 mg/kg Oral Suspension)
|
Adults
1─gram Solid Dose of Valtrexa
(N = 15)
|
|
|
|
|
|
|
1 -<2 yr
(N = 6)
|
2 -<6 yr
(N = 12)
|
6 -<12 yr
(N = 8)
|
|
|
|
|
|
|
AUC (mcg•h/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)
|
|
|
|
|
|
Drug Interactions: When Valtrex 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 Valtrex
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 Valtrex (1 gram) were unchanged by
coadministration of a single dose of antacids (Al3+ or Mg++).
Cimetidine: 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).
Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a
single dose of Valtrex (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 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).
Probenecid: Acyclovir Cmax and AUC following a
single dose of Valtrex (1 gram) increased by 22% and 49%, respectively,
after probenecid (1 gram).
Thiazide Diuretics: The pharmacokinetics
of acyclovir after a single dose of Valtrex (1 gram) were unchanged by
coadministration of multiple doses of thiazide diuretics.
Microbiology
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 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 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 (EC50), vary greatly depending
upon a number of factors. Using plaque-reduction assays, the EC50 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 EC50 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 theOkavaccine strain of VZV with a
mean EC50 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.
Nonclinical Toxicology
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 (12.3)].
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. AnAmesassay 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.
Clinical Studies
Cold Sores (Herpes Labialis)
Two double‑blind, placebo‑controlled clinical
trials were conducted in 1,856 healthy adults and adolescents (aged
greater than or equal to 12 years) with a history of recurrent cold sores.
Subjects self‑initiated therapy at the earliest symptoms and prior to any signs
of a cold sore. The majority of subjects initiated treatment within
2 hours of onset of symptoms. Subjects 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.
Genital Herpes Infections
Initial Episode: Six hundred 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 oral acyclovir 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, and 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. Subjects self─initiated therapy within 24 hours of the first
sign or symptom of a recurrent genital herpes episode.
In 1 trial, subjects 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 subjects with at least 1 positive culture (42% of the overall
trial 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 trial, subjects 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 trials
were conducted, one in immunocompetent adults and one in HIV-1─infected adults.
A double‑blind, 12‑month, placebo‑ and active‑controlled
trial enrolled immunocompetent adults with a history of 6 or more
recurrences per year. Outcomes for the overall trial population are shown in
Table 5
Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months
|
|
a Includes lost to follow-up, discontinuations due
to adverse events, and consent withdrawn.
|
|
Outcome
|
6 Months
|
12 Months
|
|
Valtrex
1 gram
Once Daily
(n = 269)
|
Oral Acyclovir
400 mg
Twice Daily
(n = 267)
|
Placebo
(n = 134)
|
Valtrex
1 gram Once Daily
(n = 269)
|
Oral Acyclovir
400 mg
Twice Daily
(n = 267)
|
Placebo
(n = 134)
|
|
Recurrence
free
|
55%
|
54%
|
7%
|
34%
|
34%
|
4%
|
|
Recurrences
|
35%
|
36%
|
83%
|
46%
|
46%
|
85%
|
|
Unknowna
|
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 trial, 293 HIV‑1-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 pretrial HIV‑1 RNA was
2.6 log10 copies/mL. Among subjects who received
Valtrex, the pretrial median CD4+ cell count was 336 cells/mm3; 11% had less than
100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to
499 cells/mm3, and 31% had greater than or equal to
500 cells/mm3. Outcomes for the overall trial population are
shown in Table 6.
Table 6. Recurrence Rates in HIV─1-Infected Adults at 6 Months
|
|
a Includes lost to follow-up, discontinuations due
to adverse events, and consent withdrawn.
|
|
Outcome
|
Valtrex
500 mg Twice Daily
(n = 194)
|
Placebo
(n = 99)
|
|
|
|
|
|
|
|
|
Recurrence
free
|
65%
|
26%
|
|
|
|
|
|
|
|
|
Recurrences
|
17%
|
57%
|
|
|
|
|
|
|
|
|
Unknowna
|
18%
|
17%
|
|
|
|
|
|
|
|
Reduction of Transmission of Genital
Herpes: A
double─blind, placebo─controlled trial 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 trial 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 7.
Table 7. Percentage of Susceptible Partners Who Acquired HSV─2 Defined by the Primary and Selected Secondary
Endpoints
|
|
a 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.
|
|
Endpoint
|
Valtrexa
(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%)
|
|
|
|
|
|
|
|
|
|
|
Herpes Zoster
Two randomized double‑blind clinical trials in
immunocompetent adults with localized herpes zoster were conducted. Valtrex was
compared with placebo in subjects aged less than 50 years, and with oral
acyclovir in subjects aged greater than 50 years. All subjects were
treated within 72 hours of appearance of zoster rash. In subjects aged
less than 50 years, 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 subjects aged greater than 50 years, the
median time to cessation of new lesions was 3 days in subjects treated
with either Valtrex or oral acyclovir. In subjects aged less than 50 years,
no difference was found with respect to the duration of pain after healing
(post‑herpetic neuralgia) between the recipients of Valtrex and placebo. In
subjects aged greater than 50 years, 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 oral acyclovir, respectively
Chickenpox
The use of Valtrex for treatment of chickenpox in
pediatric subjects aged 2 to less than 18 years is based on single‑dose
pharmacokinetic and multiple‑dose safety data from an open‑label trial with
valacyclovir and supported by safety and extrapolated efficacy data from
3 randomized, double‑blind, placebo‑controlled trials evaluating oral
acyclovir in pediatric subjects.
The single‑dose pharmacokinetic and multiple‑dose
safety trial enrolled 27 pediatric subjects aged 1 to less than
12 years with clinically suspected VZV infection. Each subject was dosed
with valacyclovir oral suspension, 20 mg/kg 3 times daily for
5 days. Acyclovir systemic exposures in pediatric subjects following
valacyclovir oral suspension were compared with historical acyclovir systemic
exposures in immunocompetent adults receiving the solid oral dosage form of
valacyclovir or acyclovir for the treatment of herpes zoster. The mean
projected daily acyclovir exposures in pediatric subjects across all age‑groups
(1 to less than 12 years) were lower (Cmax: ↓13%, AUC: ↓30%) than
the mean daily historical exposures in adults receiving valacyclovir
1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean
daily historical exposures in adults receiving acyclovir 800 mg
5 times daily. The projected daily exposures in pediatric subjects were
greater (daily AUC approximately 100% greater) than the exposures seen in
immunocompetent pediatric subjects receiving acyclovir 20 mg/kg
4 times daily for the treatment of chickenpox. Based on the
pharmacokinetic and safety data from this trial and the safety and extrapolated
efficacy data from the acyclovir trials, oral valacyclovir 20 mg/kg
3 times a day for 5 days (not to exceed 1 gram 3 times
daily) is recommended for the treatment of chickenpox in pediatric patients
aged 2 to less than 18 years. Because the efficacy and safety of acyclovir
for the treatment of chickenpox in children aged less than 2 years have
not been established, efficacy data cannot be extrapolated to support
valacyclovir treatment in children aged less than 2 years with chickenpox.
Valacyclovir is also not recommended for the treatment of herpes zoster in
children because safety data up to 7 days’ duration are not
available [see Use in Specific Populations (8.4)].
How Supplied/Storage and Handling
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).
Bottle of 90 (NDC 0173-0933-10).
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).
Bottle of 90 (NDC 0173-0565-10).
Storage:
Store at 15° to 25°C (59° to 77°F). Dispense in a
well-closed container as defined in the USP.
Patient Counseling Information
Advise the patient to read the FDA‑Approved
Patient Labeling (Patient Information).
Importance of Adequate Hydration: Patients should be
advised to maintain adequate hydration.
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.
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‑1-infected
patients
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.
Chickenpox:
Patients should be advised to initiate treatment at the earliest sign or
symptom of chickenpox.
Valtrex
is a registered trademark of the GlaxoSmithKline group of companies.
Distributed
by:
GlaxoSmithKline
Research Triangle Park,NC27709
©2013,
GlaxoSmithKline group of companies. All rights reserved.
VTX:6PI
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 in adults:
•
to treat cold sores (also called
fever blisters or herpes labialis)
•
to treat shingles (also called herpes
zoster)
•
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-1) 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 is used in children:
•
to treat cold sores (for children
aged greater than or equal to 12 years)
•
to treat chickenpox (for children
aged 2 to less than 18 years).
Valtrex
does not cure herpes infections (cold sores, chickenpox, shingles, or genital
herpes).
The efficacy of Valtrex has not been
studied in children who have not reached puberty.
What
are cold sores, chickenpox, 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.
Chickenpox is caused by a
herpes virus. It causes an itchy rash of multiple small, red bumps that look
like pimples or insect bites usually appearing first on the abdomen or back and
face. It can spread to almost everywhere else on the body and may be
accompanied by flu-like symptoms.
Shingles is caused by the
same herpes virus that causes chickenpox. It causes small, painful blisters
that happen on 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 of your medical conditions, including:
•
if
you have had a bone marrow transplant or kidney transplant, or if you have
advanced HIV-1 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 aged 65 years 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. 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, chickenpox, 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 problems include aggressive
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 in
adults include headache, nausea, stomach pain, vomiting, and dizziness. Side
effects in HIV-1-infected adults include headache, tiredness, and rash. These
side effects usually are mild and do not cause patients to stop taking Valtrex.
Other less common side effects in
adults 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.
The most common side effect seen in
children aged less than 18 years was headache.
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 Caplets at room
temperature, 59° to 77°F (15° to 25°C).
•
Store Valtrex suspension between 2°
to 8°C (36° to 46°F) in a refrigerator. Discard after 28 days.
•
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.
Valtrex is a registered trademark of the
GlaxoSmithKline group of companies.
Distributed by:
GlaxoSmithKline
Research Triangle Park,NC27709
©2013, GlaxoSmithKline group of companies. All
rights reserved.
November 2013
VTX:5PIL
PRINCIPAL DISPLAY PANEL
NDC 0173-0933-08
Valtrex®
(valacyclovir HCl) CAPLETS
500 mg
30 Caplets
Rx only
Equivalent to 500 mg valacyclovir per caplet.
See prescribing information for dosage information.
Store at 15o to 25oC (59o to 77oF).
Do not use if printed safety seal
under cap is broken or missing.
Distributed by:
GlaxoSmithKline
Research Triangle Park,NC27709
Made inIndia
Rev. 1/17
A143761
PRINCIPAL DISPLAY PANEL
NDC 0173-0565-04
Valtrex®
(valacyclovir HCl) CAPLETS
1 gram
30 Caplets
Rx only
Equivalent to 1 gram valacyclovir per caplet.
See prescribing information for dosage information
Store at 15o to 25oC (59o to 77oF).
Do not use if printed safety seal
under cap is broken or missing.
Distributed by:
GlaxoSmithKline
Research Triangle Park,NC27709
Made inIndia
Rev. 5/17
10000000146410
|
Valtrex valacyclovir
hydrochloride tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0173-0933
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
VALACYCLOVIR HYDROCHLORIDE (ACYCLOVIR)
|
VALACYCLOVIR
|
500 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
CARNAUBA WAX
|
|
|
SILICON DIOXIDE
|
|
|
CROSPOVIDONE (15 MPA.S AT 5%)
|
|
|
FD&C BLUE NO. 2
|
|
|
HYPROMELLOSES
|
|
|
MAGNESIUM STEARATE
|
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
POVIDONES
|
|
|
TITANIUM DIOXIDE
|
|
|
|
Product Characteristics
|
|
Color
|
BLUE
|
Score
|
no score
|
|
Shape
|
OVAL (capsule-shaped)
|
Size
|
18mm
|
|
Flavor
|
|
Imprint Code
|
Valtrex;500;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0173-0933-08
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
2
|
NDC:0173-0933-10
|
90 TABLET, FILM COATED in 1 BOTTLE
|
|
|
3
|
NDC:0173-0933-56
|
100 TABLET, FILM COATED in 1 BOX, UNIT-DOSE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020487
|
08/01/1995
|
|
|
|
Valtrex valacyclovir
hydrochloride tablet, film coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0173-0565
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
VALACYCLOVIR HYDROCHLORIDE (ACYCLOVIR)
|
VALACYCLOVIR
|
1 g
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
CARNAUBA WAX
|
|
|
SILICON DIOXIDE
|
|
|
CROSPOVIDONE (15 MPA.S AT 5%)
|
|
|
FD&C BLUE NO. 2
|
|
|
HYPROMELLOSES
|
|
|
MAGNESIUM STEARATE
|
|
|
CELLULOSE, MICROCRYSTALLINE
|
|
|
POLYETHYLENE GLYCOLS
|
|
|
POLYSORBATE 80
|
|
|
POVIDONES
|
|
|
TITANIUM DIOXIDE
|
|
|
|
Product Characteristics
|
|
Color
|
BLUE
|
Score
|
2 pieces
|
|
Shape
|
OVAL (capsule-shaped)
|
Size
|
23mm
|
|
Flavor
|
|
Imprint Code
|
Valtrex;1;gram
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0173-0565-04
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
2
|
NDC:0173-0565-10
|
90 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA020487
|
08/12/2002
|
|
|
|
Labeler - GlaxoSmithKline LLC (167380711)
|
Revised:
12/2013
GlaxoSmithKline LLC
