Professional Information — Acyclovir N 947 800 00093 8947 01

Indications and Usage

Herpes Zoster Infections:Acyclovir tablets, USP are indicated for the acute treatment of herpes zoster (shingles).
Genital Herpes:Acyclovir tablets, USP are indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.
Chickenpox:Acyclovir tablets, USP are indicated for the treatment of chickenpox (varicella).

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 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 tablets.
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 doseorally 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 

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 interval.

Contraindications

Acyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction [e.g., anaphylaxis, severe cutaneous adverse reactions (SCARs)] to acyclovir, valacyclovir, or any component of the formulation (see    WARNINGS  and    ADVERSE REACTIONS ).

Adverse Reactions

Herpes Simplex:

Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir tablets 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 tablets were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir tablets 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 tablets 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 tablets 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 tablets. 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 tablets 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.
Musculoskeletal: Myalgia.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM), rashes including photosensitivity, alopecia, pruritus, urticaria (see CONTRAINDICATIONS   and WARNINGS ).
Special Senses: Visual abnormalities.
Urogenital: Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS ).

Drug Interactions

See CLINICAL PHARMACOLOGY : Pharmacokinetics .

Overdosage

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 ).

Description

Acyclovir is a synthetic nucleoside analogue active against herpesviruses. Acyclovir tablets, USP is a formulation for oral administration.
Each acyclovir tablet contains 400 mg or 800 mg of acyclovir. In addition, each tablet contains the inactive ingredients colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. The 400 mg and 800 mg tablet also contains ferric oxide and FD&C blue lake # 2 Indigo carmine AL, respectively.
Acyclovir USP is a white to off white crystalline powder, slightly hygroscopic with the molecular formula C ₈H ₁₁N ₅O ₃and a molecular weight of 225.20. 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 6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-. It has the following structural formula:

Clinical Pharmacology

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.
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 tablets 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 ADMINISTRATION ).
Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared with 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 ²and 600 mg/m ²in 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.

Clinical Trials:

Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered acyclovir tablets 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 tablets 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 tablets 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 quarter.
Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir tablets (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 tablets (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.
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 tablets were 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 tablets 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 tablets did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment.

How Supplied / Storage and Handling

Acyclovir tablets USP, 800 mg containing 800 mg of acyclovir USP are blue, oval, biconvex tablets debossed with 'J' on one side and '50' on the other side. They are supplied as follows:

NDC 43063-589-10 Bottle of 10

NDC 43063-589-30 Bottle of 30

NDC 43063-589-35 Bottle of 35

NDC 43063-589-50 Bottle of 50

Store between 15º and 25ºC. Protect from light and moisture.

Patient Counseling Information

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 tablets 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 tablets is not a cure for genital herpes. There are no data evaluating whether acyclovir tablets 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.

Severe Cutaneous Adverse Reactions:Inform patients that severe skin reactions including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme (EM) have been reported with acyclovir. Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking acyclovir tablets and seek medical attention if a painful rash with mucosal involvement develops (see CONTRAINDICATIONS and WARNINGS) .