Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4191
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ZOVIRAX (Capsule)
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Acute Treatment of Herpes
Zoster: 800 mg every 4 hours orally, 5 times
daily for 7 to 10 days.<br/>Genital Herpes:<br/>Treatment of Initial Genital
Herpes: 200 mg
every 4 hours, 5 times daily for 10 days.<br/>Chronic Suppressive Therapy
for Recurrent Disease: 400 mg
2 times daily for up to 12 months, followed by re-evaluation.
Alternative regimens have included doses ranging from 200 mg
3 times daily to 200 mg 5 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 re-evaluated to assess the need for continuation of therapy with
ZOVIRAX.<br/>Intermittent Therapy: 200 mg
every 4 hours, 5 times daily for 5 days. Therapy should
be initiated at the earliest sign or symptom (prodrome) of recurrence.<br/>Treatment of Chickenpox:<br/>Children (2 years of
age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children
over 40 kg should receive the adult dose for chickenpox.<br/>Adults and Children over 40 kg: 800 mg
4 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.<br/>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:<br/>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.<br/>Peritoneal Dialysis: No supplemental dose appears to be necessary after
adjustment of the dosing interval.<br/>Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent
to ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet
was shown to be bioequivalent to 4 ZOVIRAX 200-mg capsules (n = 24).
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ZOVIRAX is the
brand name for acyclovir, a synthetic nucleoside analogue active against
herpesviruses. 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 200 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. Acyclovir is a white, crystalline powder with the molecular formula
CHNOand 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:
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Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration
have been evaluated in healthy volunteers and in immunocompromised
patients with herpes simplex or varicella-zoster virus infection.
Acyclovir pharmacokinetic parameters are summarized in Table 1. *Bioavailability decreases
with increasing dose. In one multiple-dose,
crossover 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. 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. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine.<br/>Special Populations:<br/>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).<br/>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 (see PRECAUTIONS: Geriatric Use).<br/>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/mand 600 mg/min pediatric patients aged
7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours).<br/>Drug Interactions: Coadministration of probenecid with intravenous acyclovir
has been shown to increase the mean acyclovir half-life and the area
under the concentration-time curve. Urinary excretion and renal clearance
were correspondingly reduced.<br/>Clinical Trials:<br/>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.<br/>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 severity 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, second, and third years, respectively. Serial analyses
of the 3-month recurrence rates for the patients showed that 71% to
87% were recurrence free in each quarter.<br/>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. 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 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.<br/>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 onset 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, doses 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; 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.
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ZOVIRAX is contraindicated
for patients who develop hypersensitivity to acyclovir or valacyclovir.
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ZOVIRAX Capsules (blue, opaque cap and body)
containing 200 mg acyclovir and printed with���Wellcome
ZOVIRAX 200.��� Bottle of 100 (NDC 0173-0991-55). Unit dose pack of 100 (NDC 0173-0991-56). Store at 15��to 25��C
(59��to 77��F) and protect from moisture. ZOVIRAX Tablets (light blue, oval) containing 800 mg
acyclovir and engraved with���ZOVIRAX 800.��� Bottle of 100 (NDC 0173-0945-55). Store at 15��to 25��C (59��to 77��F) and protect from moisture. ZOVIRAX Tablets (white, shield-shaped) containing 400 mg
acyclovir and engraved with "ZOVIRAX" on one side and a triangle on
the other side. Bottle of 100 (NDC 0173-0949-55). Store at 15��to 25��C
(59��to 77��F) and protect from moisture. ZOVIRAX Suspension (off-white, banana-flavored) containing
200 mg acyclovir in each teaspoonful (5 mL). Bottle of 1 pint (473 mL) (NDC 0173-0953-96). Store at 15��to 25��C
(59��to 77��F). ZOVIRAX is
a registered trademark of GlaxoSmithKline. GlaxoSmithKline Research Triangle Park, NC 27709 ��2007, GlaxoSmithKline. All rights reserved. October 2007 ZVT:1PI
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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.
Adequate hydration should be maintained.<br/>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. Patients should be advised to maintain adequate hydration.<br/>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.<br/>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 symptomsthrough 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.<br/>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.<br/>Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics.<br/>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 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 concentrations in animal studies areexpressed as multiples of
human exposure to acyclovir at the higher and lower dosing schedules
(see CLINICAL PHARMACOLOGY: 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 3 to
6 times human levelsin the mouse 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 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
numbers of corpora lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen 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 observed in rats and dogs at higher dose levels.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy
Category B. Acyclovir administered during organogenesis was not teratogenic
in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day,
s.c. and IV), 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. There are no adequate and well-controlled studies in pregnant
women. 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. Acyclovir should be used during
pregnancy only if the potential benefit justifies the potential risk
to the fetus.<br/>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.
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 mother with caution and only when indicated.<br/>Pediatric Use: Safety and effectiveness of oral formulations of
acyclovir in pediatric patients younger than 2 years of age have
not been established.<br/>Geriatric Use: 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. Nausea, vomiting, and dizziness were reported more frequently
in elderly subjects. Elderly patients are more likely to have reduced
renal function and requiredose reduction. Elderly patients are also
more likely to have renal or CNS adverse events. With respect to CNS
adverse events observed during clinical practice, somnolence, hallucinations,
confusion, and coma were reported more frequently in elderly patients
(see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical
Practice, and DOSAGE AND ADMINISTRATION).
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Overdoses involving ingestion of up to 100 capsules
(20 g) have been reported. Adverse events that have been reported
in association with overdosage include agitation, coma, seizures,
and lethargy. Precipitation of acyclovir in renal tubules may occur
when the solubility (2.5 mg/mL) is exceeded in the intratubular
fluid. Overdosage has been reported following bolus injections or
inappropriately high doses and in patients whose fluid and electrolyte
balance were not properly monitored. This has resulted in elevated
BUN and serum creatinine and subsequent renal failure. In the event
of acute renal failure and anuria, the patient may benefit from hemodialysis
until renal function isrestored (see DOSAGE AND ADMINISTRATION).
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acyclovir
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ZOVIRAX (Capsule)
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Herpes Simplex:<br/>Short-Term Administration: The most
frequent adverse 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 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.<br/>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%).<br/>Herpes Zoster: The most frequent adverse event reported during
3 clinical trials of treatment of herpes zoster (shingles) with
800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days
in 323 patients was malaise (11.5%). The 323 placebo recipients
reported malaise (11.1%).<br/>Chickenpox: The most frequent adverse event reported during
3 clinical trials of treatment of chickenpox with oral ZOVIRAX
at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days
or 800 mg 4 times daily for 5 days in 495 patients
was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea
(2.2%).<br/>Observed During Clinical Practice: In addition to adverse events reported from clinical
trials, the following events have been identified during post-approval
use of 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 either their seriousness, frequency
of reporting, potential causal connection to ZOVIRAX, or a combination
of these factors.<br/>General: Anaphylaxis,
angioedema, fever, headache, pain, peripheral edema.<br/>Nervous: Aggressive behavior,
agitation, ataxia, coma,confusion,
decreased consciousness, delirium, dizziness, dysarthria, encephalopathy,
hallucinations, paresthesia, psychosis, seizure, somnolence, tremors.
These symptoms may be marked, particularly in older adults or in patients
with renal impairment (see PRECAUTIONS).<br/>Digestive: Diarrhea, gastrointestinal distress, nausea.<br/>Hematologic and Lymphatic: Anemia, leukocytoclastic
vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.<br/>Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia,
jaundice.<br/>Musculoskeletal: Myalgia.<br/>Skin: Alopecia, erythema
multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome,
toxic epidermal necrolysis, urticaria.<br/>Special Senses: Visual abnormalities.<br/>Urogenital: Renal failure, renal pain (may be associated with
renal failure), elevated blood urea nitrogen, elevated creatinine,
hematuria (see WARNINGS).
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ZOVIRAX Capsules,
Tablets, and Suspension are intended for oral ingestion only. Renal
failure, in some cases resulting in death, has been observed with
acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical
Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic
uremic syndrome (TTP/HUS), which has resulted in death, has occurred
in immunocompromised patients receiving acyclovir therapy.
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Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes
zoster (shingles).<br/>Genital Herpes: ZOVIRAX is indicated for the treatment of initial
episodes and the management of recurrent episodes of genital herpes.<br/>Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox
(varicella).
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ZOVIRAX
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