ACYCLOVIR: 14,197 Adverse Event Reports & Safety Profile

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℃ 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

INDICATIONS AND USAGE Herpes Simplex Infections in Immunocompromised Patients Acyclovir Sodium Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.

Initial

Episodes of Herpes Genitalis Acyclovir Sodium Injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immunocompetent patients.

Herpes Simplex Encephalitis Acyclovir Sodium

Injection is indicated for the treatment of herpes simplex encephalitis.

Neonatal Herpes Simplex Virus Infection

Acyclovir Sodium Injection is indicated for the treatment of neonates and infants with herpes simplex infections. Varicella-Zoster Infections in Immunocompromised Patients Acyclovir Sodium Injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.

DOSAGE AND ADMINISTRATION CAUTION—RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS ). INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (see WARNINGS ). Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

Dosage Herpes Simplex Infections

Mucosal and Cutaneous Herpes Simplex (HSV-1 and HSV-2) Infections in Immunocompromised Patients Adults and Adolescents (12 years of age and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days. Pediatrics (Under 12 years of age): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Severe Initial Clinical

Episodes of Herpes Genitalis Adults and Adolescents (12 years of age and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

Herpes Simplex Encephalitis

Adults and Adolescents (12 years of age and older) : 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days. Pediatrics (3 months to 12 years of age): 20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days .

Neonatal Herpes Simplex Virus

Infections (Birth to 3 months) 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days. In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

Varicella Zoster Infections

Zoster in Immunocompromised Patients Adults and Adolescents (12 years of age and older): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days. Pediatrics (Under 12 years of age): 20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Obese

Patients: Obese patients should be dosed at the recommended adult dose using Ideal Body Weight. Patients with Acute or Chronic Renal Impairment Refer to DOSAGE AND ADMINISTRATION for recommended doses, and adjust the dosing interval as indicated in Table 5.

Table

5.

Dosage

Adjustments for Patients with Renal Impairment Creatinine Clearance (mL/min/1.73 m 2 ) Percent of Recommended Dose Dosing Interval (hours) >50 100% 8 25 - 50 100% 12 10 - 25 100% 24 0 - 10 50% 24 Hemodialysis For patients who require dialysis, 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. Method of Preparation Each 10 mL vial contains acyclovir sodium equivalent to 500 mg of acyclovir.

Each

20 mL vial contains acyclovir sodium equivalent to 1,000 mg of acyclovir. The contents of the vial should be dissolved in Sterile Water for Injection as follows: Contents of Vial Amount of Diluent 500 mg 10 mL 1,000 mg 20 mL The resulting solution in each case contains 50 mg acyclovir per mL (pH approximately 11). Shake the vial well to assure complete dissolution before measuring and transferring each individual dose. The reconstituted solution should be used within 12 hours. Refrigeration of reconstituted solution may result in the formation of a precipitate which will redissolve at room temperature. DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING BENZYL ALCOHOL OR PARABENS.

Administration

The calculated dose should then be removed and added to any appropriate intravenous solution at a volume selected for administration during each 1 hour infusion. Infusion concentrations of approximately 7 mg/mL or lower are recommended. In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose. Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation. Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended. Once diluted for administration, each dose should be used within 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS Acyclovir Oral Suspension, USP is 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 To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adult and Pediatric Clinical Trials The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received acyclovir at approximately 5 mg/kg (250 mg/m 2 ) 3 times daily, and approximately 300 patients who received approximately 10 mg/kg (500 mg/m 2 ) 3 times daily. The most frequent adverse reactions reported during administration of acyclovir were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10% (the higher incidence occurred usually following rapid [less than 10 minutes] intravenous infusion). Nausea and/or vomiting occurred in approximately 7% of the patients (the majority occurring in non-hospitalized patients who received 10 mg/kg). Itching, rash, or hives occurred in approximately 2% of patients. Elevation of transaminases occurred in 1% to 2% of patients. The following hematologic abnormalities occurred at a frequency of less than 1%: anemia, neutropenia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia. In addition, anorexia and hematuria were observed.

Neonatal Clinical Trial In Study

2, 72 of the 88 enrolled neonates received 60 mg/kg/day. Among subjects with recorded normal baseline values, the following laboratory abnormalities were reported: 6% (4/64) with Grade 3 or 4 increase in creatinine; 4% (2/52) with total bilirubin Grade 3 or 4 toxicity; 13% (8/64) with hemoglobin <8 gram%; 16% (10/64) and 3% (2/64) with absolute neutrophil count 500 to 1,000 cells/mm 3 and <500 cells/mm 3 , respectively; 10% (6/63) and 5% (3/63) with platelet count 50,000 to 100,000 and <50,000, respectively.

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 Injection, USP in clinical practice. 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, fatigue, fever, headache, pain, peripheral edema. Digestive : Abdominal pain, diarrhea, gastrointestinal distress, nausea. Cardiovascular: Hypotension. Hematologic and Lymphatic: Disseminated intravascular coagulation, hemolysis, leukocytoclastic vasculitis, leukopenia, lymphadenopathy.

Hepatobiliary

Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, dysarthria, encephalopathy, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence, tremor. These symptoms may be marked, particularly in older adults (see PRECAUTIONS ). Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues.

Special

Senses: Visual abnormalities. Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine (see WARNINGS ).

Warnings and Precautions Acyclovir tablets 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 acyclovir therapy. Dosage adjustment is recommended when administering acyclovir tablets to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering acyclovir tablets 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 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.

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 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.

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 tablets 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 tablets should be administered to a nursing mother with caution and only when indicated.

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 tablets 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).

PRECAUTIONS GENERAL PRECAUTIONS 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

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 breastfeed 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.

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 oral suspension and seek medical attention if a painful rash with mucosal involvement develops (see CONTRAINDICATIONS and WARNINGS ).

Drug Interactions

Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics. CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY 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 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.

Pregnancy

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

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 indicated.

Pediatric Use

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

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 ).

INTERACTIONS Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream. Due to minimal systemic absorption of acyclovir cream, systemic drug interactions are unlikely.

• Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream. Due to minimal systemic absorption of acyclovir cream, systemic drug interactions are unlikely. ( 7 )