n, tremors, confusion, hallucinations, agitation, seizures, or coma. acyclovir should be used with caution in those patients who have underlying neurologic abnormalities and those with serious renal, hepatic, or electrolyte abnormalities, or significant hypoxia.

d 12 years and older): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days. pediatrics (aged 3 months to 12 years): 20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days. neonatal herpes simplex virus infections: pma of at least 34 weeks : 20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 21 days. pma of less than 34 weeks : 20 mg/kg infused at a constant rate over 1 hour, every 12 hours for 21 days. in neonates with ongoing medical conditions affecting their renal function beyond the effect of prematurity, the doses recommended should be used with caution. varicella-zoster infections zoster in immunocompromised patients: adults and adolescents (aged 12 years and older): 10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days. pediatrics (younger than 12 years): 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 (older than 3 months): refer to dosage and administration section 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 >25 to 50 >10 to 25 ≤10 100% 100% 100% 50% 8 12 24 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 six-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. 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.

s 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 sodium injection 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 ).

if the potential benefit justifies the potential risk to the fetus.

te displacement are not anticipated. renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose. the only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function. the half-life and total body clearance of acyclovir are dependent on renal function as shown in table 2 . table 2: acyclovir half-life and total body clearance creatinine clearance (ml/min/1.73 m 2 ) total body clearance half-life (hr) (ml/min/1.73 m 2 ) (ml/min/kg) >80 2.5 327 5.1 50 to 80 3 248 3.9 15 to 50 3.5 190 3.4 0 (anuric) 19.5 29 0.5

t anticipated. renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose. the only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function. the half-life and total body clearance of acyclovir are dependent on renal function as shown in table 2 . table 2: acyclovir half-life and total body clearance creatinine clearance (ml/min/1.73 m 2 ) total body clearance half-life (hr) (ml/min/1.73 m 2 ) (ml/min/kg) >80 2.5 327 5.1 50 to 80 3 248 3.9 15 to 50 3.5 190 3.4 0 (anuric) 19.5 29 0.5

bioassay were lower than concentrations in humans. 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, po) or in rats (25 mg/kg/day, sc). in the mouse study, plasma levels were the same as human levels, while in the rat study, they were 1 to 2 times human levels. at higher doses (50 mg/kg/day, sc) in rats and rabbits (1 to 2 and 1 to 3 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, sc, 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 (1 to 3 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (the same as human levels). testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

yclovir (10 mg/kg every 8 hours) or vidarabine (15 mg/kg/day) for 10 days (28 were treated with acyclovir and 34 with vidarabine). overall mortality at 12 months for patients treated with acyclovir was 25% compared with 59% for patients treated with vidarabine. the proportion of patients treated with acyclovir functioning normally or with only mild sequelae (e.g., decreased attention span) was 32% compared with 12% of patients treated with vidarabine. patients younger than 30 years and those who had the least severe neurologic involvement at time of entry into study had the best outcome with treatment with acyclovir. an additional controlled study performed in europe demonstrated similar findings. neonatal herpes simplex virus infection the safety and efficacy of acyclovir was evaluated for the treatment of herpes simplex virus infection in neonates and infants. in one study (study 1), acyclovir 10 mg/kg every 8 hours (30 mg/kg/day) was compared with vidarabine. in a follow-up study, (study 2), acyclovir 20 mg/kg every 8 hours (60 mg/kg/day) was compared with acyclovir 15 mg/kg every 8 hours (45 mg/kg/day). study 2 was an open-label clinical trial with an objective of establishing the safety and efficacy of acyclovir 15 mg/kg every 8 hours (45 mg/kg/day) or 20 mg/kg every 8 hours (60 mg/kg/day) administered to neonates ≤28 days old with suspected hsv infection. neonates aged ≤28 days with suspected hsv infection were eligible for enrollment. in total, 88 neonates were enrolled in the trial and received iv acyclovir for 21 days. of the 88 subjects, 69 had confirmed systemic disease, 10 had confirmed localized disease, and 9 had suspected but unconfirmed infection. among the 79 subjects with confirmed infection, 13 subjects received 45 mg/kg/day and 66 subjects received 60 mg/kg/day. the mean gestational ages (ga) were 37.5 and 37.9 weeks for the 45-mg/kg/day and 60-mg/kg/day doses, respectively. the number of premature infants (≤37 weeks ga) receiving 45 mg/kg/day and 60 mg/kg/day were 7 (54%) and 22 (33%), respectively. among 69 patients with proven systemic (disseminated or cns) herpes infection, 57 were randomized to receive acyclovir (20 mg/kg every 8 hours) while the remaining 12 patients received a lower dose of acyclovir every 8 hours. overall, the mortality among patients treated with acyclovir 20 mg/kg every 8 hours was lower compared with patients who received a lower dose of acyclovir. varicella-zoster infections in immunocompromised patients a multicenter trial of acyclovir at a dose of 500 mg/m 2 every 8 hours for 7 days was conducted in immunocompromised patients with zoster infections (shingles). ninety-four (94) patients were evaluated (52 patients were treated with acyclovir and 42 with placebo). acyclovir was superior to placebo as measured by reductions in cutaneous dissemination and visceral dissemination.