CONTRAINDICATIONS
Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or
valacyclovir.
Acyclovir ointment 5% is contraindicated for patients who develop hypersensitivity or
chemical intolerance to the components of the formulation.
WARNINGS
Acyclovir capsules, tablets, and suspension are intended for oral ingestion only. Renal
failure, in some cases resulting in death, has been observed with acyclovir therapy
PRECAUTIONS
Dosage adjustment is recommended when administering acyclovir to patients with renal
impairment (see DOSAGE AND ADMINISTRATION). Caution should also be
exercised when administering acyclovir 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 the Patient
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 acyclovir, 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 acyclovir is not a cure for
genital herpes. There are no data evaluating whether acyclovir 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.
Carcinogenesis, Mutagenesis, and 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 6 times a day
(dosing appropriate for treatment of herpes zoster) or 200 mg given orally 6 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 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 3–6 times human levels in the
mouse bioassay and 1–2 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 1 of 2 in vitro cell transformation assays, and
morphologically transformed cells obtained in this assay formed tumors when inoculated
into immunosuppressed, syngeneic, weanling mice. No activity was demonstrated in
another, possibly less sensitive, in vitro cell transformation assay.
Acyclovir caused chromosomal damage in Chinese hamsters at 380-760 times human
dose levels. In rats, acyclovir produced a nonsignificant increase in chromosomal damage
at 62-125 times human levels. No activity was observed in a dominant lethal study in
mice at 36-73 times human levels.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, po) or in rats
(25 mg/kg/day, SC). In the mouse study, plasma levels were 9-18 times human levels,
while in the rat study, they were 8-15 times human levels. At higher doses (50 mg/kg/day,
SC) in rats and rabbits (11–22 and 16-31 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, SC, 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
(21-41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (6–12 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, po), rabbit (50 mg/kg/day,
SC and IV), or rat (50 mg/kg/day, SC). 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 756 pregnancies followed in 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.
Nursing Mothers
Acyclovir concentrations have been documented in breast milk in 2 women following oral
administration of acyclovir and ranged from 0.6-4.1 times corresponding plasma levels.
These concentrations would potentially expose the nursing infant to a dose of acyclovir up
to 0.3 mg/kg/day. Acyclovir should be administered to a nursing mother with caution and
only when indicated.
Geriatric Use
Clinical studies of acyclovir did not include sufficient numbers 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.
General
The recommended dosage, frequency of applications, and length of treatment should not
be exceeded (see DOSAGE AND ADMINISTRATION). There exist no data which
demonstrate that the use of acyclovir ointment 5% will either prevent transmission of
infection to other persons or prevent recurrent infections when applied in the absence of
signs and symptoms. Acyclovir ointment 5% should not be used for the prevention of
recurrent HSV infections. Although clinically significant viral resistance associated with the
use of acyclovir ointment 5% has not been observed, this possibility exists.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of 50,
150, and 450 mg/kg/day given by gavage. These studies showed no statistically
significant difference in the incidence of benign and malignant tumors produced in
drug-treated as compared to control animals, nor did acyclovir induce the occurrence of
tumors earlier in drug-treated animals as compared to controls. In two in vitro cell
transformation assays, used to provide preliminary assessment of potential oncogenicity in
advance of these more definitive lifetime bioassays in rodents, conflicting results were
obtained. Acyclovir was positive at the highest dose used in 1 system and the resulting
morphologically transformed cells formed tumors when inoculated into
immunosuppressed, syngeneic, weanling mice. Acyclovir was negative in another
transformation system.
No chromosome damage was observed at maximum tolerated parenteral doses of 100
mg/kg acyclovir in rats or Chinese hamsters; higher doses of 500 and 1000 mg/kg were
clastogenic in Chinese hamsters. In addition, no activity was found in a dominant lethal
study in mice. In 9 of 11 microbial and mammalian cell assays, no evidence of
mutagenicity was observed. In two mammalian cell assays (human lymphocytes and
L5178Y mouse lymphoma cells in vitro), positive response for mutagenicity and
chromosomal damage occurred, but only at concentrations at least 1000 times the plasma
levels achieved in humans following topical application.
Acyclovir does not impair fertility or reproduction in mice at oral doses of up to 450
mg/kg/day or in rats at subcutaneous doses of up to 25 mg/kg/day. In rabbits given a high
dose of acyclovir (50 mg/kg/day, SC), there was a statistically significant decrease in
implantation efficiency.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Acyclovir was not teratogenic in the mouse (450 mg/kg/day, PO), rabbit (50 mg/kg/day,
SC and IV), or in standard tests in the rat (50 mg/kg/day, SC). In a non-standard test in
rats, fetal abnormalities, such as head and tail anomalies, were observed following
subcutaneous administration of acyclovir at very high doses associated with toxicity to the
maternal rat. The clinical relevance of these findings is uncertain.8 There are no adequate
and well-controlled studies in pregnant women. Acyclovir should not be used during
pregnancy unless the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether topically applied acyclovir is excreted in breast milk. After oral
administration of acyclovir, acyclovir concentrations have been documented in breast milk
in 2 women and ranged from 0.6-4.1 times the corresponding plasma levels.9,10 Caution
should be exercised when acyclovir ointment is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.