Precipitation of acyclovir crystals in renal tubules can occur if the maximum
solubility of free acyclovir (2.5 mg/mL at 37°C in water) is exceeded or
if the drug is administered by bolus injection. Ensuing renal tubular damage
can produce acute renal failure.
Abnormal renal function (decreased creatinine clearance) can occur as a result
of acyclovir administration and depends on the state of the patient's hydration,
other treatments, and the rate of drug administration. Concomitant use of other
nephrotoxic drugs, pre-existing renal disease, and dehydration make further
renal impairment with acyclovir more likely.
Administration of ZOVIRAX by intravenous infusion must be accompanied by adequate
When dosage adjustments are required, they should be based on estimated creatinine
clearance (see DOSAGE AND ADMINISTRATION).
Approximately 1% of patients receiving intravenous acyclovir have manifested
encephalopathic changes characterized by either lethargy, obtundation, tremors,
confusion, hallucinations, agitation, seizures, or coma. ZOVIRAX should be used
with caution in those patients who have underlying neurologic abnormalities
and those with serious renal, hepatic, or electrolyte abnormalities, or significant
Carcinogenesis, Mutagenesis, Impairment of Fertility
The data presented below include references to peak steady-state plasma acyclovir
concentrations observed in humans treated with 30 mg/kg/day (10 mg/kg every
8 hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis),
or 15 mg/kg/day (5 mg/kg every 8 hours, dosing appropriate for treatment of
primary genital herpes or herpes simplex infections in immunocompromised patients).
Plasma drug concentrations in animal studies are expressed as multiples of human
exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL
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. At 450 mg/kg/day,
plasma concentrations in both the mouse and rat bioassay were lower than concentrations
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
the same as human levels, while in the rat study, they were 1 to 2 times human
levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (1 to 2 and
1 to 3 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 (1 to 3 times human levels) or in dogs given 60 mg/kg/day orally for 1
year (the same as human levels). Testicular atrophy and aspermatogenesis were
observed in rats and dogs at higher dose levels.
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 the same as,
4 and 9, and 1 and 2 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.
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.
See DOSAGE AND ADMINISTRATION.
Clinical studies of ZOVIRAX for Injection did not include sufficient numbers
of patients aged 65 and over to determine whether they respond differently from
younger patients. Other reported clinical experience has identified differences
in the severity of CNS adverse events between elderly and younger patients (see
ADVERSE REACTIONS: Observed During Clinical Practice). In general, dose
selection for an elderly patient should be cautious, reflecting the greater
frequency of decreased renal function, and of concomitant disease or other drug
therapy. This drug is known to be substantially excreted by the kidney, and
the risk of toxic reactions to this drug may be greater in patients with impaired
renal function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to monitor