ACYCLOVIR- acyclovir capsule
A-S Medication Solutions
Acyclovir Capsules USP
Acyclovir is a synthetic nucleoside analogue active against herpesviruses. Acyclovir capsules are
formulations for oral administration.
Each capsule contains 200 mg of acyclovir and the inactive ingredients: lactose monohydrate, sodium
lauryl sulfate, sodium starch glycolate, and magnesium stearate. The capsule shell consists of FD&C
Blue #1, gelatin, and titanium dioxide. The imprinting ink contains, alcohol, FD&C Blue #2, FD&C Red
#40, FD&C Yellow #10, iron oxide black, shellac Glaze.
Acyclovir is a white, crystalline powder with the molecular formula C H N O and 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
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:
Mechanism of Antiviral Action: 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). 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 3 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 (IC
), vary greatly depending upon a
number of factors. Using plaque-reduction assays, the IC
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 IC
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 IC
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative
changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced
susceptibility to acyclovir have been recovered from immunocompromised patients, especially with
advanced HIV infection. 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 been isolated. TK-negative
mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral
resistance to acyclovir should be considered in patients who show poor clinical response during
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.
Table 1. Acyclovir Pharmacokinetic Characteristics (Range)
* Bioavailability decreases with increasing dose.
Plasma protein binding
9% to 33%
Plasma elimination half-life
2.5 to 3.3 h
Average oral bioavailability
10% to 20%*
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.
Table 2: Acyclovir Peak and Trough Concentrations at Steady State
There was no effect of food on the absorption of acyclovir (n = 6); therefore, acyclovir capsules may
be administered with or without food.
The only known urinary metabolite is 9-[(carboxymethoxy) 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
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).
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 and 600 mg/m in pediatric patients aged 7 months to 7
years was 2.6 hours (range 1.59 to 3.74 hours).
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.
Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally
administered acyclovir 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 (6 or more episodes per year) have shown that orally administered acyclovir 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 acyclovir 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 the patients showed that 71% to 87% were recurrence free in each
Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with
localized cutaneous zoster infection, acyclovir (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, acyclovir (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
Adults greater than 50 years of age showed greater benefit.
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, acyclovir 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 acyclovir 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 acyclovir 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: acyclovir is indicated for the acute treatment of herpes zoster (shingles).
Genital Herpes: acyclovir is indicated for the treatment of initial episodes and the management of
recurrent episodes of genital herpes.
Chickenpox: acyclovir is indicated for the treatment of chickenpox (varicella).
Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.
Acyclovir capsules 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
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. Adequate hydration should be maintained.
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 breast feed while taking orally administered acyclovir, or they have any other questions.
Patients should be advised to maintain adequate hydration.
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.
Drug Interactions: See 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 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
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the
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.
Pregnancy: 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.
Nursing Mothers: 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
Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger
than 2 years of age have not been established.
Geriatric Use: 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).
Herpes Simplex: 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%).
Herpes Zoster: 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%).
Chickenpox: 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
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
Digestive: Diarrhea, gastrointestinal distress, nausea.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy,
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, elevated blood urea nitrogen, elevated creatinine, hematuria (see
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).
DOSAGE AND ADMINISTRATION
Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.
Genital Herpes: 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 reevaluation. 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
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
Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of
acyclovir capsules should be modified as shown in Table 3:
Table 3. Dosage Modification for Renal Impairment
Adjusted Dosage Regimen
mL/min/1.73 m )
200 mg every
every 4 hours,
every 12 hours
400 mg every
every 12 hours
every 12 hours
800 mg every
every 4 hours,
every 8 hours
every 12 hours
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
Bioequivalence of Dosage Forms: acyclovir Suspension was shown to be bioequivalent to acyclovir
Capsules (n = 20) and 1 acyclovir 800-mg capsule was shown to be bioequivalent to 4 acyclovir 200-
mg capsules (n = 24).
NDC: 50090-0596-0 25 CAPSULE in a BOTTLE
NDC: 50090-0596-1 50 CAPSULE in a BOTTLE
NDC: 50090-0596-7 30 CAPSULE in a BOTTLE
Product T ype
HUMAN PRESCRIPTION DRUG
Ite m Code (Source )
NDC:50 0 9 0 -0 59 6 (NDC:6 1442-111)
Route of Administration
Active Ingredient/Active Moiety
Basis of Strength
Stre ng th
ACYCLO VIR (UNII: X4HES1O11F) (ACYCLOVIR - UNII:X4HES1O11F)
20 0 mg
Stre ng th
LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)
19 5.5 mg
SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)
SO DIUM LAURETH-3 SULFATE (UNII: BPV39 0 UAP0 )
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
blue (light blue o paque cap, white o paque bo dy)
no sco re
S hap e
S iz e
20 0 ;CTI;111
Marketing Start Date
Marketing End Date
NDC:50 0 9 0 -0 59 6 -0
25 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct
11/28 /20 14
NDC:50 0 9 0 -0 59 6 -1
50 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct
11/28 /20 14
NDC:50 0 9 0 -0 59 6 -7
30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct
11/28 /20 14
A-S Medication Solutions
Marke ting Cate gory
Application Numbe r or Monograph Citation
Marke ting Start Date
Marke ting End Date
ANDA0 750 9 0
10 /22/20 0 9
A-S Medication Solutions (830016429)
Ad d re s s
Busine ss Ope rations
A-S Medicatio n So lutio ns
8 30 0 16 429
RELABEL(50 0 9 0 -0 59 6 ) , REPACK(50 0 9 0 -0 59 6 )