Acyclovir

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. 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 capsules and 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 m 2 ) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours > 10 200 every 4 hours, 5x daily 0 to 10 200 every 12 hours 400 mg every 12 hours > 10 400 every 12 hours 0 to 10 200 every 12 hours 800 mg every 4 hours > 25 800 every 4 hours, 5x daily 10 to 25 800 every 8 hours 0 to 10 800 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 interval. Bioequivalence of Dosage Forms Acyclovir suspension was shown to be bioequivalent to acyclovir capsules (n = 20) and 1 acyclovir 800 mg tablet was shown to be bioequivalent to 4 acyclovir 200 mg capsules (n = 24).

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 200 mg administered orally 5 timesdaily 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 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. 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 ). To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics .

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. I n 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 with VZV is due to its more efficient phosphorylation by the viral TK.

DESCRIPTION Acyclovir, USP is a synthetic nucleoside analogue active against herpesviruses. Acyclovir Capsules, USP and Acyclovir Tablets, USP are formulations for oral administration. Each capsule contains 200 mg of acyclovir, USP and the inactive ingredients corn starch, lactose monohydrate, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 6 and titanium dioxide. Printed with edible black ink. Each 800 mg tablet of acyclovir contains 800 mg of acyclovir, USP and the inactive ingredients magnesium stearate, microcrystalline cellulose PH101, povidone K30, and sodium starch glycolate (Type A) (Starch from Non GMO potatoes). Each 400 mg tablet of acyclovir contains 400 mg of acyclovir, USP and the inactive ingredients magnesium stearate, microcrystalline cellulose PH101, povidone K30, and sodium starch glycolate (Type A) (Starch from Non GMO potatoes). Acyclovir, USP is a white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5mg/mL. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir, USP is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one; it has the following structural formula: VIROLOGY 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 with 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 50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC 50 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 50 for acyclovir 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 50 of 1.35 mcg/mL. 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 therapy. Structural formula

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 Error! Hyperlink reference not valid. ).

HOW SUPPLIED Acyclovir Tablets USP, 400 mg are white to off-white colored, round shaped, biconvex, uncoated tablets, debossed with "791" on one side and plain on the other side and are supplied as follows: NDC 68382-791-06 in bottles of 30 tablets with child-resistant closure NDC 68382-791-16 in bottles of 90 tablets with child-resistant closure NDC 68382-791-01 in bottles of 100 tablets with child-resistant closure NDC 68382-791-05 in bottles of 500 tablets NDC 68382-791-10 in bottles of 1000 tablets NDC 68382-791-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Acyclovir Tablets USP, 800 mg are white to off-white colored, oval shaped, biconvex, uncoated tablets, debossed with "792" on one side and plain on the other side and are supplied as follows: NDC 68382-792-06 in bottles of 30 tablets with child-resistant closure NDC 68382-792-16 in bottles of 90 tablets with child-resistant closure NDC 68382-792-01 in bottles of 100 tablets NDC 68382-792-05 in bottles of 500 tablets NDC 68382-792-10 in bottles of 1000 tablets NDC 68382-792-30 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] . Protect from light and moisture. Dispense in a tight, light-resistant container (USP). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Zydus Lifesciences Ltd., Baddi, India Distributed by: Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 Rev.: 11/25