Valtrex Information
Valtrex (Valacyclovir) Indications And Usage
Cold Sores (Herpes Labialis):
Recurrent Episodes:
Suppressive Therapy:
Herpes Zoster:
Valtrex (Valacyclovir) Dosage And Administration
Cold Sores (Herpes Labialis):
Recurrent Episodes:
Suppressive Therapy:
In HIV-infected patients with a CD4+ cell count ≥100 cells/mm, the recommended dosage of Valtrex (Valacyclovir) for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.
Reduction of Transmission:
Herpes Zoster:
* The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor.
Dosage recommendations for adult patients with reduced renal function are provided in Table 1 . Data are not available for the use of Valtrex (Valacyclovir) in pediatric patients with a creatinine clearance <50 mL/min/1.73 m.
Hemodialysis:
Peritoneal Dialysis:
Valtrex (Valacyclovir) Dosage Forms And Strengths
Valtrex (Valacyclovir) Contraindications
Valtrex (Valacyclovir) 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 .
Valtrex (Valacyclovir) Warnings And Precautions
Cases of acute renal failure have been reported in:
In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored .
Valtrex (Valacyclovir) Adverse Reactions
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
The most common adverse reactions reported in at least 1 indication by >10% of adult patients treated with Valtrex (Valacyclovir) and observed more frequently with Valtrex (Valacyclovir) compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in >10% of pediatric patients <18 years of age was headache.
Valtrex (Valacyclovir) Drug Interactions
No clinically significant drug-drug or drug-food interactions with Valtrex (Valacyclovir) are known
Valtrex (Valacyclovir) Use In Specific Populations
Pregnancy Category B. There are no adequate and well-controlled studies of Valtrex (Valacyclovir) 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 (Valacyclovir) 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.
Valtrex (Valacyclovir) is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age
The use of Valtrex (Valacyclovir) for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores .
The use of Valtrex (Valacyclovir) for treatment of chickenpox in pediatric patients 2 to <18 years of age 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 patients with chickenpox .
The efficacy and safety of valacyclovir have not been established in pediatric patients:
The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies.
Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection
Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age 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 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (C: ↑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.
Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study 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 patients 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 patients across all age-groups (1 to <12 years of age) were lower (C: ↓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 1 to <12 years of age with recurrent genital herpes.
Valtrex (Valacyclovir) Overdosage
Caution should be exercised to prevent inadvertent overdose . 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 .
Valtrex (Valacyclovir) Description
Valtrex (Valacyclovir) (valacyclovir hydrochloride) is the hydrochloride salt of the -valyl ester of the antiviral drug acyclovir.
Valtrex (Valacyclovir) 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 -valine, 2-[(2-amino-1,6-dihydro-6-oxo-9-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 CHNO•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pks for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
Valtrex (Valacyclovir) Clinical Pharmacology
The pharmacokinetics of valacyclovir and acyclovir after oral administration of Valtrex (Valacyclovir) have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.
The absolute bioavailability of acyclovir after administration of Valtrex (Valacyclovir) is 54.5% ± 9.1% as determined following a 1 gram oral dose of Valtrex (Valacyclovir) and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valtrex (Valacyclovir) 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 (Valacyclovir) to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of Valtrex (Valacyclovir) 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.
Distribution:
Metabolism:
Elimination:
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of Valtrex (Valacyclovir) in volunteers with normal renal function.
Following administration of Valtrex (Valacyclovir) 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 m compared with 679.16 ± 162.76 mL/min/1.73 m in healthy volunteers.
Hepatic Impairment:
HIV Disease:
3
Drug Interactions:
Antacids:
Cimetidine:
max
Cimetidine Plus Probenecid:
max
Digoxin:
Probenecid:
max
Thiazide Diuretics:
Mechanism of Action:
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:
Resistance:
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.
Valtrex (Valacyclovir) Clinical Studies
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 (Valacyclovir) 2 grams twice daily on Day 1 followed by placebo on Day 2, Valtrex (Valacyclovir) 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 (Valacyclovir) or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
Initial Episode:
Recurrent Episodes:
In 1 study, patients were randomized to receive 5 days of treatment with either Valtrex (Valacyclovir) 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving Valtrex (Valacyclovir) 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 (Valacyclovir) 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving Valtrex (Valacyclovir) 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 (Valacyclovir) 500 mg twice daily for 5 days (n = 398) or Valtrex (Valacyclovir) 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:
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 5.
Subjects with 9 or fewer recurrences per year showed comparable results with Valtrex (Valacyclovir) 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 (Valacyclovir) 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log copies/mL. Among patients who received Valtrex (Valacyclovir) , the prestudy median CD4+ cell count was 336 cells/mm; 11% had <100 cells/mm, 16% had 100 to 199 cells/mm, 42% had 200 to 499 cells/mm, and 31% had ≥500 cells/mm. Outcomes for the overall study population are shown in Table 6.
Reduction of Transmission of Genital Herpes:
The use of Valtrex (Valacyclovir) for treatment of chickenpox in pediatric patients 2 to <18 years of age 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 patients.
The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age 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 patients 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 patients across all age-groups (1 to <12 years of age) were lower (C: ↓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 patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, 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 2 to <18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children <2 years of age 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
Valtrex (Valacyclovir) How Supplied/storage And Handling
Valtrex (Valacyclovir) Caplets (blue, film-coated, capsule-shaped tablets) containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir and printed with "Valtrex (Valacyclovir) 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 (Valacyclovir) 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 (Valacyclovir) 1 gram."
Bottle of 30 (NDC 0173-0565-04).
Bottle of 90 (NDC 0173-0565-10).
Store at 15° to 25°C (59° to 77°F). Dispense in a well-closed container as defined in the USP.
Valtrex (Valacyclovir) Patient Counseling Information
See FDA-Approved Patient Labeling (17.6).
Patients should be informed that Valtrex (Valacyclovir) 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 (Valacyclovir) . 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 (Valacyclovir) 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.
Patients should be advised to initiate treatment at the earliest sign or symptom of
chickenpox.
Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.
Distributed byGlaxoSmithKlineResearch Triangle Park, NC 27709
Manufactured by:GlaxoSmithKlineResearch Triangle Park, NC 27709orDSM Pharmaceuticals, Inc.Greenville, NC 27834
©2008, GlaxoSmithKline. All rights reserved.
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
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Valtrex (Valacyclovir) Patient Information
Read the Patient Information that comes with Valtrex (Valacyclovir) 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.
Valtrex (Valacyclovir) is a prescription antiviral medicine. Valtrex (Valacyclovir) lowers the ability of herpes viruses to multiply in your body.
Valtrex (Valacyclovir) is used in adults:
Valtrex (Valacyclovir) used daily with the following safer sex practices can lower the chances of passing genital herpes to your partner.
Valtrex (Valacyclovir) is used in children:
The efficacy of Valtrex (Valacyclovir) has not been studied in children who have not reached puberty.
Ask your healthcare provider for more information about safer sex practices.
Take Valtrex (Valacyclovir) exactly as prescribed by your healthcare provider. Your dose of Valtrex (Valacyclovir) and length of treatment will depend on the type of herpes infection that you have and any other medical problems that you have.
Common side effects of Valtrex (Valacyclovir) in adults include headache, nausea, stomach pain, vomiting, and dizziness. Side effects in HIV-infected adults include headache, tiredness, and rash. These side effects usually are mild and do not cause patients to stop taking Valtrex (Valacyclovir) .
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 <18 years of age was headache.
These are not all the side effects of Valtrex (Valacyclovir) . For more information ask your healthcare provider or pharmacist.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Valtrex (Valacyclovir) for a condition for which it was not prescribed. Do not give Valtrex (Valacyclovir) 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 (Valacyclovir) . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Valtrex (Valacyclovir) that is written for health professionals. More information is available at www.Valtrex (Valacyclovir) .com.
Distributed byGlaxoSmithKlineResearch Triangle Park, NC 27709
Manufactured by:GlaxoSmithKlineResearch Triangle Park, NC 27709orDSM Pharmaceuticals, Inc.Greenville, NC 27834
©2008, GlaxoSmithKline. All rights reserved.
September 2008VTX:2PIL
Valtrex (Valacyclovir) Principal Display Panel
Valtrex (Valacyclovir)
(valacyclovir HCl)
500 mg
1260 Caplets
Valtrex (Valacyclovir) Principal Display Panel
Valtrex (Valacyclovir)
(valacyclovir HCl)
500 mg
3780 Caplets
