DESCRIPTION:
ZOVIRAX is the brand name for acyclovir, an antiviral drug. 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, lactose, 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 cellulose,
povidone, and sodium starch glycolate.
Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive
ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium
starch glycolate.
Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 400 mg of acyclovir and
the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as
preservatives), carboxymethylcellulose sodium, flavor, glycerin,
microcrystalline cellulose, and sorbitol.
The chemical name of acyclovir is 2-amino- 1,9-dihydro-9-[(2-
hydroxyethoxy)methyl]-6H-purin- 6-one.
Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3
and a molecular weight of 225. The maximum solubility in water at 37 deg C is
2.5 mg/mL. The pka's of acyclovir are 2.27 and 9.25.
ACTIONS/CLINICAL PHARMACOLOGY:
VIROLOGY
MECHANISM OF ANTIVIRAL EFFECTS: 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). In cell
culture, acyclovir's highest antiviral activity is against HSV-1, followed in
decreasing order of potency against HSV-2 and VZV.
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
three ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation
into and termination of the growing viral DNA chain, and 3) inactivation of the
viral DNA polymerase. The greater antiviral activity of acyclovir against HSV
compared to VZV is due to its more efficient phosphorylation by the viral TK.
ANTIVIRAL ACTIVITIES: The quantitative relationship between the In Vitro
susceptibility of herpes viruses 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 VZV to antiviral nucleoside analogues can result
from qualitative or quantitative changes in the viral TK 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 to antiviral nucleoside analogues occurs by the same
mechanisms as resistance to VZV. 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 acyclovir should be considered in patients who show poor clinical
response during therapy.
CLINICAL PHARMACOLOGY
PHARMACOKINETICS: The pharmacokinetics of acyclovir after oral administration
have been evaluated in healthy volunteers and in immunocompromised patients with
herpes simplex or varicella-zoster infection. Acyclovir pharmacokinetic
parameters are summarized in Table 1.
TABLE 1: ACYCLOVIR PHARMACOKINETIC CHARACTERISTICS (RANGE)
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PARAMETER RANGE
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Plasma protein binding 9% to 33%
Plasma elimination half-life 2.5 to 3.3 hr
Average oral bioavailability 10% to 20%*
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*Bioavailability decreases with increasing dose.
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In one multiple dose, cross-over study in healthy subjects (n=23), it was shown
that increases in plasma acyclovir concentrations were less than dose
proportional with increasing dose, as shown in Table 2. The decrease in
bioavailability is a function of the dose and not the dosage form.
TABLE 2 : ACYCLOVIR PEAK AND TROUGH CONCENTRATIONS AT STEADY STATE
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Parameter 200 mg 400 mcg 800 mcg
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C SS max 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL
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C SS trough 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL
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There was no effect of food on the absorption of acyclovir (n=6); therefore
ZOVIRAX Tablets, and Suspension may be administered with or without food.
The only known urinary metabolite is 9-((caroboxymethoxy)methyl)guanine.
SPECIAL POPULATIONS: ADULTS WITH IMPAIRED RENAL FUNCTION: The half-life and
total body clearance of acyclovir are dependent on renal function. A dosage
adjustment is recommended for patients with reduced renal function (see DOSAGE
AND ADMINISTRATION).
PEDIATRICS: In general, the pharmacokinetics of acyclovir in pediatric patients
is similar to that of adults. Mean half-life after oral doses of 300
mg/m(squared) and 600 mg/m(squared) in pediatric patients ages 7 months to 7
years was 2.6 hours (range 1.59 to 3.74 hours).
DRUG INTERACTIONS: Co-administration of probenecid with intravenous acyclovir
has been shown to increase acyclovir half-life and systemic exposure. Urinary
excretion and renal clearance were correspondingly reduced.
CLINICAL STUDIES:
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 decreased in some patient groups.
RECURRENT GENITAL HERPES: Double-blind, placebo- controlled studies in patients
with frequent recurrences (six 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 severity of recurrences in greater than 95% of patients.
In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%,
52%, and 63% of patients remained free of recurrences in the first, second, and
third years, respectively. Serial analyses of the 3-month recurrence rates for
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 five 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.
In a similar double-blind, placebo-controlled study, ZOVIRAX (800 gm five 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 neurologic symptoms (paresthesia,
dysesthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash onset 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 ages 2 to 18 years with chickenpox. All
patients were treated within 24 hours after the onset of rash. In two trials,
ZOVIRAX was administered at 20 mg/kg four times daily (up to 3,200 mg per day)
for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered
four 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, decreased the median number of residual lesions on day 28, and
decreased 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 responses 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 INFECTIONS: 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 hypersensitivity or
intolerance to the components of the formulations.
WARNINGS:
ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only.
PRECAUTIONS:
GENERAL: Dosage Adjustment is recommended when administering ZOVIRAX to patients
with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be
exercised when administering ZOVIRAX to patients receiving potentially
nephrotoxic agents since this may increase the risk of renal dysfunction and/or
the risk of reversible central nervous system symptoms such as those that have
been reported in patients treated with intravenous acyclovir.
INFORMATION FOR PATIENTS: Patients are instructed to consult with their
physician if they experience severe or troublesome adverse reactions, they
become pregnant or intend to become pregnant, they intend to breastfeed while
taking orally administered ZOVIRAX, or they have any other questions.
HERPES ZOSTER: There are no data on treatment initiated more than 72 hours after
onset of the zoster rash. Patients should be advised to initiate treatment as
soon as possible after a diagnosis of herpes zoster.
GENITAL HERPES 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. 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 can also be transmitted in the absence of symptoms
through asymptomatic viral shedding. 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.
CHICKENPOX: Chickenpox in otherwise healthy children is usually a self-limited
disease of mild to moderate severity.
Adolescents and adults tend to have more severe disease. 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
disease course.
DRUG INTERACTIONS: See ACTIONS/CLINICAL PHARMACOLOGY: Pharmacokinetics.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: The data presented below
include references to peak steady-state plasma acyclovir concentrations observed
in humans treated with 800 mg given orally six times a day (dosing appropriate
for treatment of herpes zoster) or 200 mg given orally six times a day (dosing
appropriate for treatment of genital herpes). Plasma drug concentrations in
animal studies are expressed as multiples of human exposure to acyclovir at the
higher and lower dosing schedules (see Pharmacokinetics).
Acyclovir was tested in lifetime bioassays in rats and mice at single daily
doses 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 three to six times human levels in the mouse bioassay and
one to two times human levels in the rat bioassay.
Acyclovir was tested in 16 genetic toxicity assays. No evidence of mutagenicity
was observed in four microbial assays. Acyclovir demonstrated mutagenic activity
in two In Vitro cytogenetic assays (one mouse lymphoma cell line and human
lymphocytes). No mutagenic activity was observed in five In Vitro cytogenetic
assays (three Chinese hamster ovary cell lines and two mouse (lymphoma cell
lines).
A positive result was demonstrated in one of two In Vitro cell transformation
assays, and morphologically transformed cells obtained in this assay formed
tumors when inoculated into immunosuppressed, syngeneic, weanling mice. No
mutagenic activity was demonstrated in another, possibly less sensitive, in
vitro cell transformation assay. Acyclovir was clastogenic in Chinese hamsters
at 380 to 760 times human dose levels. In rats, acyclovir produced a
nonsignificant increase in chromosomal damage at 62 to 125 times human levels.
No activity was observed in a dominant lethal study in mice at 36 to 73 times
human levels.
Acyclovir did not impair fertility or reproduction in mice at (450 mg/kg/day,
p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse 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 doses (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 decreased. In a rat peri-and post-natal study at 50 mg/kg/day, s.c.,
there was a statistically significant decrease in group mean number of corpea
lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg/day, i.v. for 1
month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1
year (six to 12 times human levels), Testicular atrophy and aspermatogenesis
were observed in rats and dogs at higher dose levels.
PREGNANCY: Teratogenic Effects: Pregnancy Category B. Acyclovir was not
teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and
i.v.), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9
and 18, 16 and 106, and 11 and 22 times, respectively, human levels. In a non-
standard test, rats were given three s.c. doses of 100 mg/kg acyclovir on
gestation day 10, resulting in plasma levels 63 and 125 times human levels. In
this test, there were fetal abnormalities, such as head and tail anomalies, and
maternal toxicity.
There are no adequate and well-controlled studies in pregnant women. A
prospective epidemiologic registry of acyclovir use during pregnancy has been
ongoing since 1984. As of June 1996, outcomes of live births have been
documented in 494 women exposed to systemic acyclovir during the first trimester
of pregnancy. 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 and
definitive conclusions regarding the safety of acyclovir in pregnant women and
their developing fetuses. Acyclovir should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
PREGNANCY EXPOSURE REGISTRY: To monitor maternal- fetal outcomes of pregnant
women exposed to systemic acyclovir, Glaxo Wellcome Inc. maintains an Acyclovir
in Pregnancy Registry. Physicians are encouraged to register patients by calling
1-888-825-5249, ext. 39441.
NURSING MOTHERS: Acyclovir concentrations have been documented in breast milk in
two women following oral administration of ZOVIRAX and ranged from 0.6 to 4.1
times corresponding plasma levels. These concentrations would potentially expose
the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. ZOVIRAX should be
administered to a nursing woman with caution and only when indicated.
GERIATRIC USE: Clinical studies of ZOVIRAX did not include sufficient number of
patients aged 65 and over to determine whether they respond differently than
younger patients. Other reported clinical experience has not identified
differences in responses between elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased renal
function, and of concomitant disease or other drug therapy.
PEDIATRIC USE: Safety and effectiveness in pediatric patients less than 2 years
of age have not been adequately studied.
DRUG INTERACTIONS:
Co-administration of probenecid with intravenous acyclovir has been shown to
increase the mean half-life and the area under the concentration- time curve.
Urinary excretion and renal clearance were correspondingly reduced. (REF. 41)
The clinical effects of this combination have not been studied.
(See Also ACTIONS/CLINICAL PHARMACOLOGY and PRECAUTIONS).
ADVERSE REACTIONS:
HERPES SIMPLEX: Short-Term Administration: The most frequent adverse events
reported during clinical trials of treatment of genital herpes with ZOVIRAX 200
mg administered orally five times daily every 4 hours for 10 days were nausea
and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting
occurred in 2 of 287 (0.7%) patients who received placebo.
Long-term Administration: The most frequent adverse events reported in a
clinical trial for 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: nausea (4.8%) and diarrhea (2.4%). The 589 control patients
receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported
diarrhea (2.7%), nausea (2.4%) and headache (2.2%).
HERPES ZOSTER: The most frequent adverse event reported during three clinical
trials of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX five
times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323
placebo recipients reported malaise (11.1%).
CHICKENPOX: The most frequent adverse events reported during three clinical
trials of treatment of chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg
four times daily for 5 to 7 days or 800 mg four times daily for 5 days in 495
patients was diarrhea (3.2%). The 498 patients receiving placebo reported
diarrhea (2.2%).
OBSERVED DURING CLINICAL PRACTICE: In addition to adverse events reported from
clinical trials, the following events have been identified during post-approval
use of acyclovir (ZOVIRAX). 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 ZOVIRAX.
GENERAL: Fever, headache, pain, peripheral edema, and rarely, anaphylaxis.
NERVOUS: Confusion, dizziness, hallucinations, paresthesia, seizure, somnolence
(These symptoms may be marked, particularly in older adults.)
DIGESTIVE: Diarrhea, elevated liver function tests, gastrointestinal distress,
nausea.
HEMIC AND LYMPHATIC: Leukopenia, lymphadenopathy.
MUSCULOSKELETAL: Myalgia.
SKIN: Alopecia, erythema multiforme, pruritus, rash, Stevens-Johnson syndrome,
toxic epidermal necrolysis, urticaria.
SPECIAL SENSES: Visual abnormalities.
UROGENITAL: Elevated creatinine.
OVERDOSAGE:
Patients have ingested intentional overdoses of up to 100 capsules (20 g) of
ZOVIRAX, with no unexpected adverse effects. Precipitation of acyclovir in renal
tubules may occur when the solubility (2.5 mg/mL) is exceeded in the
intratubular fluid. In the event of acute renal failure and anuria, the patient
may benefit from hemodialysis until renal function is restored (see DOSAGE AND
ADMINISTRATION).
DOSAGE AND ADMINISTRATION:
ACUTE TREATMENT OF HERPES ZOSTER: 800 mg every 4 hours orally, five times daily
for 7 to 10 days.
GENITAL HERPES: TREATMENT OF INITIAL GENITAL HERPES: 200 mg every 4 hours, five
times daily for 10 days.
CHRONIC SUPPRESSIVE THERAPY FOR RECURRENT DISEASE: 400 mg two times daily for up
to 12 months, followed by reevaluation. Alternative regimens have included doses
ranging from 200 mg three times daily to 200 mg five times daily. The frequency
and severity of episodes of untreated genital herpes may change over time. After
1 year of therapy, the frequency and severity of the patient's genital herpes
infection should be reevaluated to assess the need for continuation of therapy
with ZOVIRAX.
INTERMITTENT THERAPY: 200 mg every 4 hours, five times daily for 5 days. Therapy
should be initiated at the earliest sign or symptom (prodrome) of recurrence.
TREATMENT OF CHICKENPOX: CHILDREN (2 YEARS OF AGE AND OLDER): 20 mg/kg per dose
orally four times daily (80 mg/kg/day) for 5 days. Children over 40kg should
receive the adult dose for chickenpox.
ADULTS AND CHILDREN OVER 40 kg: 800 mg four times daily for 5 days.
Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster
infections in immunocompromised patients.
When therapy is indicated, it should be initiated at the earliest sign or
symptom of chickenpox. There is no information about the efficacy of therapy
initiated more than 24 hours after onset of signs and symptoms.
PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: In patients with renal
impairment, the dose of ZOVIRAX Capsules, Tablets, or Suspension should be
modified as shown in Table 3:
TABLE 3: DOSAGE MODIFICATION FOR RENAL IMPAIRMENT
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Adjusted Dosage Regimen
Normal Dosage Creatinine
Regimen Clearance Dose (mg) Dosing Interval
(mL/min/1.73 M(squared))
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200 mg every 4 hours >10 200 every 4 hours, 5x daily
0-10 200 every 12 hours
400 mg every 12 hours >10 400 every 12 hours
0-10 200 every 12 hours
800 mg every 4 hours >25 800 every 4 hours, 5x daily
10-25 800 every 8 hours
0-10 800 every 12 hours
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HEMODIALYSIS: For patients who require hemodialysis, the mean plasma half-life
of acyclovir during hemodialysis is approximately 5 hours. This results in a 60%
decrease in plasma concentrations following a 6-hour dialysis period. Therefore,
the patient's dosing schedule should be adjusted so that an additional dose is
administered after each dialysis.
PERITONEAL DIALYSIS: No supplemental dose appears to be necessary after
adjustment of the dosing interval.
BIOEQUIVALENCE OF DOSAGE FORMS: ZOVIRAX Suspension was shown to be bioequivalent
to ZOVIRAX Capsules (n=20) and one ZOVIRAX 800-mg tablet was shown to be
bioequivalent to four ZOVIRAX 200-mg capsules (n=24).