PRESCRIBING INFORMATION ZOVIRAX®
(acyclovir)
Capsules
ZOVIRAX®
标准像(acyclovir)
Tablets
ZOVIRAX®
(acyclovir)狐臭微创手术
Suspension
DESCRIPTION
ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against herpesviru
s. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch, lacto, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink.
Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulo, povidone, and sodium starch glycolate.
Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulo, povidone, and sodium starch glycolate.
Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as prervatives), carboxymethylcellulo sodium, flavor, glycerin, microcrystalline cellulo, and sorbitol.
Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one; it has the following structural formula:
VIROLOGY
Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly lective due to its affinity for the enzyme thymidine kina (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 kina 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 polymera, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymera. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK. Antiviral A
ctivities: The quantitative relationship between the in vitro susceptibility of herpes
virus to antivirals and the clinical respon to therapy has not been established in humans, and virus nsitivity testing has not been standardized. Sensitivity testing results, expresd as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC 50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC 50 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 IC 50 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 IC 50 of 1.35 mcg/mL.
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and
常开头的成语quantitative changes in the viral TK and/or DNA polymera. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromid patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromid patients have been found to be TK-deficient mutants, other mutants in
volving the viral TK gene (TK partial and TK altered) and DNA polymera have been isolated. TK-negative mutants may cau vere dia in infants and immunocompromid adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical respon during therapy.
CLINICAL PHARMACOLOGY
Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromid patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1.
Table 1. Acyclovir Pharmacokinetic Characteristics (Range)40岁生日
Parameter Range
Plasma protein binding 9% to 33%
Plasma elimination half-life 2.5 to 3.3 hr
Average oral bioavailability 10% to 20%*
*Bioavailability decreas with increasing do.
In one multiple-do, crossover study in healthy subjects (n = 23), it was shown that increas in plasma acyclovir concentrations were less than do proportional with increasing do, as shown in Table 2. The decrea in bioavailability is a function of the do and not the dosage form.
Table 2. Acyclovir Peak and Trough Concentrations at Steady State
Parameter 200 mg 400 mg 800 mg
max SS C 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL
trough SS C 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL
There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules, Tablets, and Suspension may be administered with or without food.
一线城市名单The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine.
Special Populations: Adults with Impaired Renal Function:The half-life and total body clearance of ac
yclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (e DOSAGE AND ADMINISTRATION).
Geriatrics:Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (e PRECAUTIONS: Geriatric U).
Pediatrics:In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral dos of 300 mg/m2 and 600 mg/m2 in pediatric patients aged
7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours).
Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increa the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.
Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decread in some patient groups.
Recurrent Genital Herpes:Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily for 4 months to 10 years prevented or reduced the frequency and/or verity of recurrences in greater than 95% of patients.
In a study of patients who received ZOVIRAX400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, cond, and third years, respectively. Serial analys of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter.
Herpes Zoster Infections:In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation.
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In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for
7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of new lesion formation; and reduced the prevalence of localized zoster-associated neur
ologic symptoms (paresthesia, dysthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash ont and was most effective if started within the first 48 hours.
Adults greater than 50 years of age showed greater benefit.
Chickenpox:Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the ont of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to
3,200 mg per day) for 5 days. In the third trial, dos of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing; reduced the maximum number of lesions; reduced the median number of vesicles; decread the median number of residual lesions on day 28; and decread the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular immune respons at 1 month or 1 year following treatment.
INDICATIONS AND USAGE
Herpes Zoster Infections:ZOVIRAX is indicated for the acute treatment of herpes zoster (shingles).
Genital Herpes:ZOVIRAX is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.
Chickenpox:ZOVIRAX is indicated for the treatment of chickenpox (varicella). CONTRAINDICATIONS
ZOVIRAX is contraindicated for patients who develop hypernsitivity to acyclovir or valacyclovir.
WARNINGS
ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cas resulting in death, has been obrved with acyclovir therapy (e ADVERSE REACTIONS: Obrved During Clinical Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromid patients receiving acyclovir therapy.
狗日女人逼PRECAUTIONS
Dosage adjustment is recommended when administering ZOVIRAX to patients with renal impairment (e DOSAGE AND ADMINISTRATION). Caution should also be exercid when administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increa the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as tho that have been reported in patients treated with intravenous acyclovir. Adequate hydration should be maintained.
Information for Patients: Patients are instructed to consult with their physician if they experience vere or troublesome adver reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions.
Patients should be advid to maintain adequate hydration.
Zoster: There are no data on treatment initiated more than 72 hours after ont of the Herpes
zoster rash. Patients should be advid to initiate treatment as soon as possible after a diagnosis of herpes zoster.
Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital herpes.
There are no data evaluating whether ZOVIRAX will prevent transmission of infection to others. Becau genital herpes is a xually transmitted dia, patients should avoid contact with lesions or intercour when lesions and/or symptoms are prent to avoid infecting partners. Genital herpes can also be transmitted in the abnce of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advid to initiate therapy at the first sign or symptom of an episode.
Chickenpox: Chickenpox in otherwi healthy children is usually a lf-limited dia of mild to moderate verity. Adolescents and adults tend to have more vere dia. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the dia cour.
Drug Interactions:See CLINICAL PHARMACOLOGY: Pharmacokinetics.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The data prented below include references to peak steady-state plasma acyclovir concentrations obrved in humans treated with
文学专业800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentr
ations in animal studies are expresd as multiples of human exposure to acyclovir at the higher and lower dosing schedules (e CLINICAL PHARMACOLOGY: Pharmacokinetics).
Acyclovir was tested in lifetime bioassays in rats and mice at single daily dos of up to
450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mou bioassay and 1 to 2 times human levels in the rat bioassay.
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the assays.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats
(25 mg/kg/day, s.c.). In the mou study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher dos (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decread. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statisticall
y significant decrea in group mean numbers of corpora lutea, total implantation sites, and live fetus.
No testicular abnormalities were en in dogs given 50 mg/kg/day, IV for 1 month (21 to
41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were obrved in rats and dogs at higher do levels. Pregnancy: Teratogenic Effects:Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mou (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and IV), or rat (50 mg/kg/day, s.c.). The exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels.
There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir u during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women expod 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 fetus. Acyclovir should be ud during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma levels. The concentrations would potentially expo the nursing infant to a do of acyclovir up to 0.3 mg/kg/day. ZOVIRAX should be administered to a nursing mother with caution and only when indicated.
Pediatric U: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.
Geriatric U: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment in immunocompetent subjects ≥50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Naua, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and req
uire do reduction. Elderly patients are also more likely to have renal or CNS adver events. With respect to CNS adver events obrved during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (e CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Obrved During Clinical Practice, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Herpes Simplex: Short-Term Administration:The most frequent adver events reported during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily every 4 hours for 10 days were naua and/or vomiting in 8 of 298 patient treatments (2.7%). Naua and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo.
Administration:The most frequent adver events reported in a clinical trial for Long-Term
the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with ZOVIRAX were naua (4.8%) and diarrhea (2.4%). The
