ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Herpes Simplex. Short-Term Administration. The most frequentadverse events reported during clinical trials of treatment of genital herpeswith acyclovir 200 mg administered orally times daily every hoursfor 10 days were nausea and/or vomiting in of 298 patient treatments(2.7%). Nausea and/or vomiting occurred in of 287 (0.7%) patients who receivedplacebo. Long-Term Administration. The most frequentadverse events reported in clinical trial for the prevention of recurrenceswith continuous administration of 400 mg (two 200-mg capsules) timesdaily for year in 586 patients treated with acyclovir were nausea(4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittenttreatment of recurrences with acyclovir for year reported diarrhea (2.7%),nausea (2.4%), and headache (2.2%). Herpes Zoster. The most frequent adverse event reported during clinicaltrials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir5 times daily for 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 clinicaltrials of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg4 times daily for to days or 800 mg times dailyfor days in 495 patients was diarrhea (3.2%). The 498 patientsreceiving 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 population of unknown size, estimatesof frequency cannot be made. These events have been chosen for inclusion dueto either their seriousness, frequency of reporting, potential causal connectionto acyclovir, or 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, leukocytoclasticvasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas. Elevated liver function tests, hepatitis, hyperbilirubinemia,jaundice.. Musculoskeletal. Myalgia. Skin. Alopecia, erythema multiforme,photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermalnecrolysis, urticaria. Special Senses. Visual abnormalities.. Urogenital. Renal failure, elevated blood urea nitrogen, elevated creatinine,hematuria (see WARNINGS).

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 800 mg given orally times day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally times 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). Acyclovirwas tested in lifetime bioassays in rats and mice at single daily doses ofup to 450 mg/kg administered by gavage. There was no statistically significantdifference in the incidence of tumors between treated and control animals,nor did acyclovir shorten the latency of tumors. Maximum plasma concentrationswere to times human levels in the mouse bioassay and to timeshuman levels in the rat bioassay.Acyclovir was testedin 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positivein of the assays.Acyclovir did not impair fertilityor 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 to 18 times human levels,while in the rat study, they were to 15 times human levels. At higherdoses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 timeshuman levels, respectively) implantation efficacy, but not litter size, wasdecreased. In rat peri- and post-natal study at 50 mg/kg/day, s.c.,there was statistically significant decrease in group mean numbers of corporalutea, total implantation sites, and live fetuses.Notesticular abnormalities were seen in dogs given 50 mg/kg/day, IV for1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/dayorally for year (6 to 12 times human levels). Testicular atrophyand aspermatogenesis were observed in rats and dogs at higher dose levels.

CLINICAL PHARMACOLOGY SECTION.

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)ParameterRangePlasma protein binding9% to 33%Plasma elimination half-life2.5 to 3.3 hAverage oral bioavailability10% to 20% 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 function of the dose and not the dosage form.Table 2: Acyclovir Peak and Trough Concentrations at Steady StateParameter200 mg400 mg800 mg0.83 mcg/mL1.21 mcg/mL1.61 mcg/mL0.46 mcg/mL0.63 mcg/mL0.83 mcg/mLThere 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.. ssmax. sstrough. Special Populations. Adults with Impaired Renal Function. The half-life and total body clearance of acyclovir are dependent on renal function. dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION). 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). Pediatrics. In general, thepharmacokinetics of acyclovir in pediatric patients is similar to that ofadults. Mean half-life after oral doses of 300 mg/m and 600 mg/m inpediatric patients aged months to years was 2.6 hours (range1.59 to 3.74 hours). Drug Interactions. Coadministration of probenecid with intravenous acyclovirhas been shown to increase the mean acyclovir half-life and the area underthe concentration-time curve. Urinary excretion and renal clearance were correspondinglyreduced.. Clinical Trials. Initial Genital Herpes. Double-blind, placebo-controlled studies have demonstrated that orally administered acyclovir 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 given daily for months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In study of patients who received acyclovir 400 mg twice daily for 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 double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir (800 mg 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 similar double-blind, placebo-controlled study, acyclovir (800 mg times daily for 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 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In trials, acyclovir was administered at 20 mg/kg times daily (up to 3,200 mg per day) for days. In the third trial, doses of 10, 15, or 20 mg/kg were administered times daily for to days. Treatment with acyclovir 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 did not affect varicella-zoster virus-specific humoral or cellular immune responses at month or year following treatment.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.

DESCRIPTION SECTION.

DESCRIPTION. Acyclovir is synthetic nucleoside analogue active against herpes viruses. Acyclovir tablet is formulation for oral administration. Each 800 mg tablet of acyclovir contains 800 mg of acyclovir and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. Each 400 mg tablet of acyclovir contains 400 mg of acyclovir and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.Acyclovir is white, crystalline powder with the molecular formula 8H 11N 5O and molecular weight of 225.2. The maximum solubility in water at 37C is 2.5 mg/mL. The pKas of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6 H-purin-6-one; it has the following structural formula: formula1.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Acute Treatment of Herpes Zoster. 800 mg every hours orally, times dailyfor to 10 days.. Genital Herpes. Treatment of Initial Genital Herpes. 200 mg every4 hours, times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease. 400 mg timesdaily for up to 12 months, followed by re-evaluation. Alternative regimenshave included doses ranging from 200 mg times daily to 200 mg5 times daily. The frequency and severity of episodesof untreated genital herpes may change over time. After year of therapy,the frequency and severity of the patients genital herpes infectionshould be re-evaluated to assess the need for continuation of therapy withacyclovir.. Intermittent Therapy. 200 mg every4 hours, times daily for days. Therapy should be initiatedat the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox. Children (2 years of age and older). 20 mg/kg per dose orally4 times daily (80 mg/kg/day) for days. Children over 40 kgshould receive the adult dose for chickenpox. Adults and Children over 40 kg. 800 mg timesdaily for days. Intravenous acyclovir is indicatedfor the treatment of varicella-zoster infections in immunocompromised patients.Whentherapy is indicated, it should be initiated at the earliest sign or symptomof chickenpox. There is no information about the efficacy of therapy initiatedmore 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 should be modified as shown in Table 3:Table 3. Dosage Modification for Renal ImpairmentCreatinineAdjusted Dosage RegimenNormal DosageRegimenClearance(mL/min/1.73 2) Dose(mg)Dosing Interval200 mg every hours>10200every hours, 5x daily0-10200every 12 hours400 mg every 12 hours>100-10400200every 12 hoursevery12 hours800 mg every hours>25800every hours, 5x daily10-25800every hours0-10800every 12 hours. Hemodialysis. For patients who require hemodialysis, the mean plasma half-lifeof acyclovir during hemodialysis is approximately hours. This resultsin 60% decrease in plasma concentrations following 6-hour dialysis period.Therefore, the patients dosing schedule should be adjusted so thatan additional dose is administered after each dialysis.. Peritoneal Dialysis. No supplemental dose appears to be necessary after adjustmentof the dosing interval.

DRUG INTERACTIONS SECTION.

Drug Interactions. Coadministration of probenecid with intravenous acyclovirhas been shown to increase the mean acyclovir half-life and the area underthe concentration-time curve. Urinary excretion and renal clearance were correspondinglyreduced.

GERIATRIC USE SECTION.

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).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Acyclovir Tablets USP 400 mg are available for oral administration as white to off-white, oval, unscored tablets imprinted Apotex Logo 5306 on one side and plain on the other side. They are supplied as follows: Bottles of 30 (60505-5306-3) Bottles of 100 (60505-5306-1) Bottles of 500 (60505-5306-5) Bottles of 1000 (60505-5306-8) Acyclovir Tablets USP 800 mg are available for oral administration as white to off-white, oval, unscored tablets imprinted Apotex Logo 5307 on one side and plain on the other side. They are supplied as follows:Bottles of 30 (60505-5307-3) Bottles of 100 (60505-5307-1) Bottles of 500 (60505-5307-5) Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature] and protect from moisture. Manufactured by:Manufactured for:Apotex Inc.Apotex Corp.Toronto, OntarioWeston, FloridaCanada M9L 1T933326Revised: December 2005Rev.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Herpes Zoster Infections. Acyclovir tablet is indicated for the acute treatment of herpes zoster (shingles).. Genital Herpes. Acyclovir tablet is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.. Chickenpox. Acyclovir tablet is indicated for the treatment of chickenpox (varicella).

INFORMATION FOR PATIENTS SECTION.

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 hoursafter onset of the zoster rash. Patients should be advised to initiate treatmentas soon as possible after diagnosis of herpes zoster. Genital Herpes Infections. Patients should be informed that acyclovir is not cure forgenital herpes. There are no data evaluating whether acyclovir will preventtransmission of infection to others. Because genital herpes is sexuallytransmitted disease, patients should avoid contact with lesions or intercoursewhen lesions and/or symptoms are present to avoid infecting partners. Genitalherpes can also be transmitted in the absence of symptoms through asymptomaticviral shedding. If medical management of genital herpes recurrence is indicated,patients should be advised to initiate therapy at the first sign or symptomof an episode.. Chickenpox. Chickenpox in otherwise healthy children is usually self-limiteddisease of mild to moderate severity. Adolescents and adults tend to havemore severe disease. Treatment was initiated within 24 hours of the typicalchickenpox rash in the controlled studies, and there is no information regardingthe effects of treatment begun later in the disease course.

MECHANISM OF ACTION SECTION.

Mechanism of Antiviral Action. Acyclovir is synthetic purine nucleoside analogue within vitro and in vivo inhibitory activity against herpes simplexvirus types (HSV-1), (HSV-2), and varicella-zoster virus (VZV). Theinhibitory activity of acyclovir is highly selective due to its affinity forthe enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzymeconverts acyclovir into acyclovir monophosphate, nucleotide analogue. Themonophosphate is further converted into diphosphate by cellular guanylatekinase and into triphosphate by number of cellular enzymes. In vitro, acyclovirtriphosphate stops replication of herpes viral DNA. This is accomplished in3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporationinto and termination of the growing viral DNA chain, and 3) inactivation ofthe viral DNA polymerase. The greater antiviral activity of acyclovir againstHSV compared to VZV is due to its more efficient phosphorylation by the viralTK.

NURSING MOTHERS SECTION.

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.

OVERDOSAGE SECTION.

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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 800 mg. Acyclovir 800mg- 30 count. label.

PEDIATRIC USE SECTION.

Pediatrics. In general, thepharmacokinetics of acyclovir in pediatric patients is similar to that ofadults. Mean half-life after oral doses of 300 mg/m and 600 mg/m inpediatric patients aged months to years was 2.6 hours (range1.59 to 3.74 hours).

PHARMACOKINETICS SECTION.

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)ParameterRangePlasma protein binding9% to 33%Plasma elimination half-life2.5 to 3.3 hAverage oral bioavailability10% to 20% 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 function of the dose and not the dosage form.Table 2: Acyclovir Peak and Trough Concentrations at Steady StateParameter200 mg400 mg800 mg0.83 mcg/mL1.21 mcg/mL1.61 mcg/mL0.46 mcg/mL0.63 mcg/mL0.83 mcg/mLThere 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.. ssmax. sstrough.

PRECAUTIONS SECTION.

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. 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 hoursafter onset of the zoster rash. Patients should be advised to initiate treatmentas soon as possible after diagnosis of herpes zoster. Genital Herpes Infections. Patients should be informed that acyclovir is not cure forgenital herpes. There are no data evaluating whether acyclovir will preventtransmission of infection to others. Because genital herpes is sexuallytransmitted disease, patients should avoid contact with lesions or intercoursewhen lesions and/or symptoms are present to avoid infecting partners. Genitalherpes can also be transmitted in the absence of symptoms through asymptomaticviral shedding. If medical management of genital herpes recurrence is indicated,patients should be advised to initiate therapy at the first sign or symptomof an episode.. Chickenpox. Chickenpox in otherwise healthy children is usually self-limiteddisease of mild to moderate severity. Adolescents and adults tend to havemore severe disease. Treatment was initiated within 24 hours of the typicalchickenpox rash in the controlled studies, and there is no information regardingthe 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 times day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally times 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). Acyclovirwas tested in lifetime bioassays in rats and mice at single daily doses ofup to 450 mg/kg administered by gavage. There was no statistically significantdifference in the incidence of tumors between treated and control animals,nor did acyclovir shorten the latency of tumors. Maximum plasma concentrationswere to times human levels in the mouse bioassay and to timeshuman levels in the rat bioassay.Acyclovir was testedin 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positivein of the assays.Acyclovir did not impair fertilityor 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 to 18 times human levels,while in the rat study, they were to 15 times human levels. At higherdoses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 timeshuman levels, respectively) implantation efficacy, but not litter size, wasdecreased. In rat peri- and post-natal study at 50 mg/kg/day, s.c.,there was statistically significant decrease in group mean numbers of corporalutea, total implantation sites, and live fetuses.Notesticular abnormalities were seen in dogs given 50 mg/kg/day, IV for1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/dayorally for year (6 to 12 times human levels). Testicular atrophyand aspermatogenesis were observed in rats and dogs at higher dose levels.. Pregnancy. Teratogenic Effects. Pregnancy CategoryB. Acyclovir administered during organogenesis was not teratogenic in themouse (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 levels9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate andwell-controlled studies in pregnant women. prospective epidemiologic registryof acyclovir use during pregnancy was established in 1984 and completed inApril 1999. There were 749 pregnancies followed in women exposed to systemicacyclovir during the first trimester of pregnancy resulting in 756 outcomes.The occurrence rate of birth defects approximates that found in the generalpopulation. However, the small size of the registry is insufficient to evaluatethe risk for less common defects or to permit reliable or definitive conclusionsregarding the safety of acyclovir in pregnant women and their developing fetuses.Acyclovir should be used during pregnancy only if the potential benefit justifiesthe 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. Safety and effectiveness of oral formulations of acyclovirin pediatric patients younger than years of age have not been established.. Geriatric Use. Of 376 subjects who received acyclovir in 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).

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects. Pregnancy CategoryB. Acyclovir administered during organogenesis was not teratogenic in themouse (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 levels9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate andwell-controlled studies in pregnant women. prospective epidemiologic registryof acyclovir use during pregnancy was established in 1984 and completed inApril 1999. There were 749 pregnancies followed in women exposed to systemicacyclovir during the first trimester of pregnancy resulting in 756 outcomes.The occurrence rate of birth defects approximates that found in the generalpopulation. However, the small size of the registry is insufficient to evaluatethe risk for less common defects or to permit reliable or definitive conclusionsregarding the safety of acyclovir in pregnant women and their developing fetuses.Acyclovir should be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.

SPL UNCLASSIFIED SECTION.

VIROLOGY. Mechanism of Antiviral Action. Acyclovir is synthetic purine nucleoside analogue within vitro and in vivo inhibitory activity against herpes simplexvirus types (HSV-1), (HSV-2), and varicella-zoster virus (VZV). Theinhibitory activity of acyclovir is highly selective due to its affinity forthe enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzymeconverts acyclovir into acyclovir monophosphate, nucleotide analogue. Themonophosphate is further converted into diphosphate by cellular guanylatekinase and into triphosphate by number of cellular enzymes. In vitro, acyclovirtriphosphate stops replication of herpes viral DNA. This is accomplished in3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporationinto and termination of the growing viral DNA chain, and 3) inactivation ofthe viral DNA polymerase. The greater antiviral activity of acyclovir againstHSV compared to VZV is due to its more efficient phosphorylation by the viralTK.. 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 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 mean IC 50 of1.35 mcg/mL. Drug Resistance. Resistance of HSV and VZV to acyclovir can result from qualitativeand quantitative changes in the viral TK and/or DNA polymerase. Clinical isolatesof HSV and VZV with reduced susceptibility to acyclovir have been recoveredfrom immunocompromised patients, especially with advanced HIV infection. Whilemost of the acyclovir-resistant mutants isolated thus far from immunocompromisedpatients have been found to be TK-deficient mutants, other mutants involvingthe viral TK gene (TK partial and TK altered) and DNA polymerase have beenisolated. TK-negative mutants may cause severe disease in infants and immunocompromisedadults. The possibility of viral resistance to acyclovir should be consideredin patients who show poor clinical response during therapy.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy CategoryB. Acyclovir administered during organogenesis was not teratogenic in themouse (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 levels9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels. There are no adequate andwell-controlled studies in pregnant women. prospective epidemiologic registryof acyclovir use during pregnancy was established in 1984 and completed inApril 1999. There were 749 pregnancies followed in women exposed to systemicacyclovir during the first trimester of pregnancy resulting in 756 outcomes.The occurrence rate of birth defects approximates that found in the generalpopulation. However, the small size of the registry is insufficient to evaluatethe risk for less common defects or to permit reliable or definitive conclusionsregarding the safety of acyclovir in pregnant women and their developing fetuses.Acyclovir should be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. Acyclovir tablet is 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.