Buy Valtrex online
Valacyclovir for the treatment of herpes virus infections
Valtrex is an antiviral drug. It slows the growth and spread of the herpes virus so that the body can fight off the infection. Valtrex will not cure herpes, but it can lessen the symptoms of the infection.
Valtrex is used to treat infections caused by herpes viruses in adults and children. Illnesses caused by herpes viruses include genital herpes, cold sores, shingles, and chickenpox.
Valtrex is used to treat cold sores in children who are at least 12 years old, and to treat chickenpox in children who are at least 2 years old.
Valtrex may also be used for other purposes not listed in this medication guide.
Prescribing Information Valtrex
Valtrex Description
Valtrex (valacyclovir hydrochloride) is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir (ZOVIRAX® Brand, GlaxoSmithKline).
Valtrex Caplets are for oral administration. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.
The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride.
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 pka’s for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.
MICROBIOLOGY
Mechanism of Antiviral Action
Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in vitro and in vivo.
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate,a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities
The quantitative relationship between the in vitro susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Drug Resistance
Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.
Valtrex - Clinical Pharmacology
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
Pharmacokinetics
The pharmacokinetics of valacyclovir and acyclovir after oral administration of Valtrex have been investigated in 14 volunteer studies involving 283 adults.
Absorption and BioavailabilityThe absolute bioavailability of acyclovir after administration of Valtrex is 54.5% ± 9.1% as determined following a 1-gram oral dose of Valtrex and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valtrex is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
There was a lack of dose proportionality in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of Valtrex to 8 healthy volunteers. The mean Cmax (± SD) was 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) mcg/mL, respectively; and the mean AUC (± SD) was 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr•mcg/mL, respectively.
There was also a lack of dose proportionality in acyclovir Cmax and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 gram of Valtrex administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers. The mean Cmax (± SD) was 2.11 (± 0.33), 3.69 (± 0.87), and 4.96 (± 0.64) mcg/mL, respectively, and the mean AUC (± SD) was 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr•mcg/mL, respectively.
There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in healthy volunteers with normal renal function.
DistributionThe binding of valacyclovir to human plasma proteins ranged from 13.5% to 17.9%.
MetabolismAfter oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of Valtrex, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.
EliminationThe pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1-gram dose of radiolabeled valacyclovir to 4 healthy subjects, 45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively. Acyclovir accounted for 88.60% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of Valtrex to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 41.9% of total acyclovir apparent plasma clearance.
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of Valtrex in volunteers with normal renal function.
End-Stage Renal Disease (ESRD)Following administration of Valtrex to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2, compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Reduction in dosage is recommended in patients with renal impairment (see DOSAGE AND ADMINISTRATION).
GeriatricsAfter single-dose administration of 1 gram of Valtrex in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of Valtrex in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
PediatricsValacyclovir pharmacokinetics have not been evaluated in pediatric patients.
Liver DiseaseAdministration of Valtrex to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate butnot the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.
HIV DiseaseIn 9 patients with HIV disease and CD4 cell counts <150 cells/mm3 who received Valtrex at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers (see WARNINGS).
Drug InteractionsThe pharmacokinetics of digoxin was not affected by coadministration of Valtrex 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of Valtrex (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg), single doses of antacids (Al3+ or Mg++), or multiple doses of thiazide diuretics. Acyclovir Cmax and AUC following a single dose of Valtrex (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after probenecid (1 gram), or by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. These effects are not considered to be of clinical significance insubjects with normal renal function. Therefore, no dosage adjustment is recommended when Valtrex is coadministered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function.
Clinical Trials
Herpes Zoster
Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valtrex was compared with placebo in patients less than 50 years of age, and to ZOVIRAX in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with Valtrex compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either Valtrex or ZOVIRAX. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of Valtrex and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day Valtrex, 14-day Valtrex, and 7-day ZOVIRAX, respectively.
Genital Herpes Infections
Initial EpisodeSix hundred and forty-three immunocompetent adults with first episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of Valtrex 1 gram twice daily (n = 323) or ZOVIRAX 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.
Recurrent EpisodesThree double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
In 1 study, patients were randomized to receive 5 days of treatment with either Valtrex 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving Valtrex 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving Valtrex 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving Valtrex 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
In a third study, patients were randomized to receive Valtrex 500 mg twice daily for 5 days (n = 398) or Valtrex 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402).The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
Suppressive TherapyTwo clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.
