See CLINICAL PHARMACOLOGY: Pharmacokinetics.
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 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 to 6 times human levels in 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.
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.
Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir 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. Acyclovir should be administered to a nursing mother with caution and only when indicated.
Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.
Of 376 subjects who received acyclovir 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 require dose 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).
Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 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.
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 acyclovir were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).
The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).
The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir 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%).
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. 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 acyclovir, or a combination of these factors.
General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.
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).
Digestive: Diarrhea, gastrointestinal distress, nausea.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.
Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Special Senses: Visual abnormalities.Urogenital: Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS).
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 is restored (see DOSAGE AND ADMINISTRATION).
Acute Treatment of Herpes Zoster:
800 mg every 4 hours orally, 5 times daily for 7 to 10 days.
Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days.
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 acyclovir.
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.
Treatment of Chickenpox:
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.
Adults and Children over 40 kg: 800 mg 4 times daily for 5 days.
Intravenous acyclovir 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 Acyclovir Tablets should be modified as shown in Table 3.
|Table 3. Dosage Modification for Renal Impairment|
|Normal Dosage Regimen||Creatinine Clearance (mL/min/1.73 m2)||Adjusted Dosage Regimen|
|Dose (mg)||Dosing Interval|
|200 mg every 4 hours||>100-10||200200||every 4 hours, 5x dailyevery 12 hours|
|400 mg every 12 hours||>100-10||400200||every 12 hoursevery 12 hours|
|800 mg every 4 hours||>2510-250-10||800800800||every 4 hours, 5x dailyevery 8 hoursevery 12 hours|
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.
No supplemental dose appears to be necessary after adjustment of the dosing interval.
Bioequivalence of Dosage Forms:
One Acyclovir 800-mg tablet was shown to be bioequivalent to four Acyclovir 200-mg capsules (n = 24).
Acyclovir Tablets, USP 400 mg is White to off white, oval, biconvex, uncoated tablets, debossed with ‘CP114’ on one side and ‘400’ on other side. It is available as follows:
Bottle of 100 (NDC 72241-026-05)
Bottle of 500 (NDC 72241-026-10)
Acyclovir Tablets, USP 800 mg is Light blue to blue, oval, biconvex, uncoated tablets, debossed with ‘CP113’ on one side and ‘800’ on the other side. It is available as follows:
Bottle of 100 (NDC 72241-027-05)
Bottle of 500 (NDC 72241-027-10)
Store at 15° to 25°C (59° to 77°F) and protect from light and moisture. Dispense in tight, light-resistant container as defined in the USP.
Made in India by:
Cadila Pharmaceuticals Limited,
1389, Dholka, District — Ahmedabad,
Gujarat State, INDIA
Modavar Pharmaceuticals LLC.
1016, 16th Street, Suite 602,
Washington, DC 20036
Toll free: 800 688 4697
Revised: June 2021
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