ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received acyclovir at approximately mg/kg (250 mg/m2) three times daily, and approximately 300 patients who received approximately 10 mg/kg (500 mg/m2) three 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 nonhospitalized 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 frequency of less than 1%: anemia, neutropenia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia. In addition, anorexia and hematuria were observed.. 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 for Injection in clinical practice. Because they are reported voluntarily from 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 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).To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 30 mg/kg/day (10 mg/kg every hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every hours, dosing appropriate for treatment of primary genital herpes or herpes simplex infections in immunocompromised patients). 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. At 450 mg/kg/day, plasma concentrations in both the mouse and rat bioassay were lower than concentrations in humans.Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 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 to times human levels. At higher doses (50 mg/kg/day, SC) in rats and rabbits (1 to and to times human levels, respectively) implantation efficacy, but not litter size, was decreased. In rat peri- and post-natal study at 50 mg/kg/day, SC., there was 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 month (1 to times human levels) or in dogs given 60 mg/kg/day orally for year (the same as human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacokinetics. The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every hours. Proportionality between dose and plasma levels is seen after single doses or at steady-state after multiple dosing. Average steady-state peak and trough concentrations from 1-hour infusions administered every hours are given in Table 1.Table 1. Acyclovir Peak and Trough Concentrations at Steady State Dosage RegimenCSS max CSS trough mg/kg 8 hr (n 8)9.8 mcg/mL range: 5.5 to 13.8 0.7 mcg/mLrange: 0.2 to 10 mg/kg 8 hr(n 7) 22.9 mcg/mL range: 14.1 to 44.11.9 mcg/mLrange: 0.5 to 2.9Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site 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 ClearanceCreatinine Clearance(mL/min/1.73 m2) Half-life(hr) Total Body Clearance (mL/min/1.73 m2)(mL/min/kg) >80 2.5 3275.1 50 80 248 3.915 50 3.5 190 3.40 (Anuric) 19.5 29 0.5. Special Populations. Adults with Impaired Renal Function. Acyclovir was administered at dose of 2.5 mg/kg to adult patients with severe renal failure. The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.Consult DOSAGE AND ADMINISTRATION for recommended adjustments in dosing based upon creatinine clearance.. Pediatrics. Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every hours (Table 3). Concentrations achieved at these regimens are similar to those in adults receiving mg/kg and 10 mg/kg every hours, respectively (Table 1). Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to months at doses of mg/kg, 10 mg/kg, and 15 mg/kg every hours (Table 3).Table 3. Acyclovir Pharmacokinetics in Pediatric Patients (Mean +- SD)Parameter Birth to Months of Age(n 12) Months to 12 Years of Age(n 16) CL (mL/min/kg)4.46 +- 1.618.44 +- 2.92VDSS (L/kg)1.08 +- 0.351.01 +- 0.28Elimination half-life (hr)3.80 +- 1.192.36 +- 0.97. 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).. Drug Interactions. Coadministration of probenecid with 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. Herpes Simplex Infections in Immunocompromised Patients. multicenter trial of acyclovir at dose of 250 mg/m2 every hours (750 mg/m2/day) for days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital, and other localized infections (52 treated with acyclovir and 46 with placebo). Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.. Initial Episodes of Herpes Genitalis. In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every hours for days. Acyclovir decreased the duration of viral excretion, new lesion formation, duration of vesicles, and promoted healing of lesions. Herpes Simplex Encephalitis. Sixty-two patients ages months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 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 to 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 to 12% of patients treated with vidarabine.Patients less than 30 years of age 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. Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every hours (n 107) or vidarabine 30 mg/kg/day (n 95) for 10 days. Outcomes are presented in Table 4.Table 4. Mortality at YearHSV Disease Classification Treatment GroupAcyclovir(n=107) Vidarabine(n=95) SEMSEM refers to localized infection with disease limited to skin, eye, and/or mouth.(n 85)0/54 0/31 CNSCNS refers to infection of the central nervous system with compatible neurologic and CSF findings.(n 71)5/35 5/36 DISSDISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.(n 46) 11/18 14/28 Rates of neurologic sequelae at year were comparable between the treatment groups.. Varicella-Zoster Infections in Immunocompromised Patients. multicenter trial of Acyclovir for Injection at dose of 500 mg/m2 every hours for 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.

CLINICAL STUDIES SECTION.

Clinical Trials. Herpes Simplex Infections in Immunocompromised Patients. multicenter trial of acyclovir at dose of 250 mg/m2 every hours (750 mg/m2/day) for days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital, and other localized infections (52 treated with acyclovir and 46 with placebo). Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.. Initial Episodes of Herpes Genitalis. In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every hours for days. Acyclovir decreased the duration of viral excretion, new lesion formation, duration of vesicles, and promoted healing of lesions. Herpes Simplex Encephalitis. Sixty-two patients ages months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 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 to 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 to 12% of patients treated with vidarabine.Patients less than 30 years of age 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. Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every hours (n 107) or vidarabine 30 mg/kg/day (n 95) for 10 days. Outcomes are presented in Table 4.Table 4. Mortality at YearHSV Disease Classification Treatment GroupAcyclovir(n=107) Vidarabine(n=95) SEMSEM refers to localized infection with disease limited to skin, eye, and/or mouth.(n 85)0/54 0/31 CNSCNS refers to infection of the central nervous system with compatible neurologic and CSF findings.(n 71)5/35 5/36 DISSDISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.(n 46) 11/18 14/28 Rates of neurologic sequelae at year were comparable between the treatment groups.. Varicella-Zoster Infections in Immunocompromised Patients. multicenter trial of Acyclovir for Injection at dose of 500 mg/m2 every hours for 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.

DESCRIPTION SECTION.

DESCRIPTION. Acyclovir is synthetic nucleoside analog active against herpes viruses. Acyclovir for Injection, USP is sterile lyophilized powder for intravenous administration only. Each 500 mg vial contains 500 mg of acyclovir and 49 mg of sodium, and each 1,000 mg vial contains 1,000 mg acyclovir and 98 mg of sodium. Reconstitution of the 500 mg or 1,000 mg vials with 10 mL or 20 mL, respectively, of Sterile Water for Injection, USP results in solution containing 50 mg/mL of acyclovir. The pH of the reconstituted solution is approximately 11. Further dilution in any appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION: Method of Preparation and Administration).Acyclovir sodium is white, crystalline powder with the molecular formula C8H10N5NaO3 and molecular weight of 247.19. The maximum solubility in water at 25C exceeds 100 mg/mL. At physiologic pH, acyclovir sodium exists as the un-ionized form with molecular weight of 225 and maximum solubility in water at 37C of 2.5 mg/mL. The pkas of acyclovir are 2.27 and 9.25.The chemical name of acyclovir sodium is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one monosodium salt; it has the following structural formula:. chemical structure.

DOSAGE & ADMINISTRATION SECTION.

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 hours should not be exceeded for any patient.. Dosage. Herpes Simplex Infections. Mucosal and Cutaneous HerpesSimplex (HSV-1 and HSV-2) Infections in Immunocompromised Patients. Adults and Adolescents (12 years of age and older): mg/kg infused at constant rate over hour, every hours for days.Pediatrics (Under 12 years of age): 10 mg/kg infused at constant rate over hour, every hours for days.. Severe Initial Clinical Episodesof Herpes Genitalis. Adults and Adolescents (12 years of age and older): mg/kg infused at constant rate over hour, every hours for days.. Herpes Simplex Encephalitis. Adults and Adolescents (12 years of age and older): 10 mg/kg infused at constant rate over hour, every hours for 10 days.Pediatrics (3 months to 12 years of age): 20 mg/kg infused at constant rate over hour, every hours for 10 days.. Neonatal Herpes Simplex VirusInfections (Birth to months). 10 mg/kg infused at constant rate over hour, every hours for 10 days. In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at constant rate over hour every 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 constant rate over hour, every hours for days.Pediatrics (Under 12 years of age): 20 mg/kg infused at constant rate over hour, every hours for 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 ImpairmentCreatinine Clearance(mL/min/1.73 m2) Percent ofRecommended Dose Dosing Interval(hours)>50100%825 50100%1210 25100%240 1050%24. Hemodialysis. For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately hours. This results in 60% decrease in plasma concentrations following 6-hour dialysis period. Therefore, the patients 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 Diluent500 mg10 mL1,000 mg20 mLThe 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 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 volume selected for administration during each hour infusion. Infusion concentrations of approximately 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.

GENERAL PRECAUTIONS SECTION.

General. Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37C in water) is exceeded or if the drug is administered by bolus injection. Ensuing renal tubular damage can produce acute renal failure.Abnormal renal function (decreased creatinine clearance) can occur as result of acyclovir administration and depends on the state of the patients hydration, other treatments, and the rate of drug administration. Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely.Administration of acyclovir by intravenous infusion must be accompanied by adequate hydration.When dosage adjustments are required, they should be based on estimated creatinine clearance (see DOSAGE AND ADMINISTRATION).Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, 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.

PHARMACOKINETICS SECTION.

Pharmacokinetics. The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every hours. Proportionality between dose and plasma levels is seen after single doses or at steady-state after multiple dosing. Average steady-state peak and trough concentrations from 1-hour infusions administered every hours are given in Table 1.Table 1. Acyclovir Peak and Trough Concentrations at Steady State Dosage RegimenCSS max CSS trough mg/kg 8 hr (n 8)9.8 mcg/mL range: 5.5 to 13.8 0.7 mcg/mLrange: 0.2 to 10 mg/kg 8 hr(n 7) 22.9 mcg/mL range: 14.1 to 44.11.9 mcg/mLrange: 0.5 to 2.9Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site 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 ClearanceCreatinine Clearance(mL/min/1.73 m2) Half-life(hr) Total Body Clearance (mL/min/1.73 m2)(mL/min/kg) >80 2.5 3275.1 50 80 248 3.915 50 3.5 190 3.40 (Anuric) 19.5 29 0.5.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37C in water) is exceeded or if the drug is administered by bolus injection. Ensuing renal tubular damage can produce acute renal failure.Abnormal renal function (decreased creatinine clearance) can occur as result of acyclovir administration and depends on the state of the patients hydration, other treatments, and the rate of drug administration. Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment with acyclovir more likely.Administration of acyclovir by intravenous infusion must be accompanied by adequate hydration.When dosage adjustments are required, they should be based on estimated creatinine clearance (see DOSAGE AND ADMINISTRATION).Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, 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.. 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 30 mg/kg/day (10 mg/kg every hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every hours, dosing appropriate for treatment of primary genital herpes or herpes simplex infections in immunocompromised patients). 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. At 450 mg/kg/day, plasma concentrations in both the mouse and rat bioassay were lower than concentrations in humans.Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 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 to times human levels. At higher doses (50 mg/kg/day, SC) in rats and rabbits (1 to and to times human levels, respectively) implantation efficacy, but not litter size, was decreased. In rat peri- and post-natal study at 50 mg/kg/day, SC., there was 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 month (1 to times human levels) or in dogs given 60 mg/kg/day orally for year (the same as human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.. Pregnancy: Teratogenic Effects. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg/day, PO), rabbit (50 mg/kg/day, SC and IV), or rat (50 mg/kg/day, SC). These exposures resulted in plasma levels the same as, and 9, and 1and times, respectively, human levels.There are no adequate and well-controlled studies in pregnant women. 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 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 dose of acyclovir up to 0.3 mg/kg/day. Acyclovir should be administered to nursing mother with caution and only when indicated.. Pediatric Use. See DOSAGE AND ADMINISTRATION.. Geriatric Use. Clinical studies of Acyclovir for Injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has identified differences in the severity of CNS adverse events between elderly and younger patients (see ADVERSE REACTIONS: Observed During Clinical Practice). In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.