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1 INDICATIONS AND USAGE Acyclovir Cream is a herpes simplex virus (HSV) deoxynucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older. Acyclovir Cream is a herpes simplex virus (HSV) deoxynucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Acyclovir Cream should be applied 5 times per day for 4 days. Therapy should be initiated as early as possible following the onset of signs or symptoms of herpes labialis, i.e. during the prodrome or when lesions appear. For adolescents 12 years of age and older, the dosage is the same as in adults. Apply 5 times a day for 4 days. ( 2 ) Administer immediately following the onset of cold sore lesions. ( 2 )

4 CONTRAINDICATIONS Acyclovir Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation. Acyclovir Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir or any component of the formulation. ( 4 )

5 WARNINGS AND PRECAUTIONS Only for topical use of recurrent HSV lesions on the external aspect of lips and the face. Acyclovir Cream should not be applied on mucous membranes including in the eye or inside the mouth or nose. ( 5.1 ) There is a potential for irritation and contact sensitization. ( 5.2 ) 5.1 General Acyclovir Cream should only be applied on the affected external aspects of the lips and face in patients with herpes labialis. Because no data are available, application to human mucous membranes is not recommended. Acyclovir Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose. 5.2 Contact Sensitization Acyclovir Cream has a potential for irritation and contact sensitization [see Adverse Reactions (6.1) ] . The effect of Acyclovir Cream has not been established in immunocompromised patients.

6 ADVERSE REACTIONS The most common adverse reactions reported were local skin reactions at the application site. ( 6.1 ) Angioedema, anaphylaxis, contact dermatitis and eczema have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in clinical practice. In five double-blind, placebo-controlled trials, 1124 patients were treated with Acyclovir Cream and 1161 with placebo (vehicle) cream. Local application site reactions were reported by 5% of patients receiving Acyclovir Cream and 4% of patients receiving placebo. The most common adverse reactions at the site of topical application were dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin; each adverse reaction occurred in less than 1% of patients receiving Acyclovir Cream and placebo. Three patients on Acyclovir Cream and one patient on placebo discontinued treatment due to an adverse event. An additional study, enrolling 22 healthy adults, was conducted to evaluate the dermal tolerance of Acyclovir Cream compared with vehicle using single occluded and semi-occluded patch testing methodology. Both Acyclovir Cream and placebo showed a high and cumulative irritation potential. Another study, enrolling 251 healthy adults, was conducted to evaluate the contact sensitization potential of Acyclovir Cream using repeat insult patch testing methodology. Of 202 evaluable subjects, possible cutaneous sensitization reactions were observed in the same 4 (2%) subjects with both Acyclovir Cream and placebo, and these reactions to both Acyclovir Cream and placebo were confirmed in 3 subjects upon rechallenge. The sensitizing ingredient(s) has not been identified. The safety profile in patients 12 to 17 years of age was similar to that observed in adults. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of acyclovir cream. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to acyclovir cream. General: Angioedema, anaphylaxis. Skin: Contact dermatitis, eczema.

7 DRUG 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 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Acyclovir is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the Acyclovir Cream [see Clinical Pharmacology (12.3) ] . Experience with topical acyclovir use in pregnant women over several decades, based on published literature including observational studies, has not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies with systemic exposure of acyclovir have been conducted. Refer to acyclovir prescribing information for additional details. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Acyclovir is minimally absorbed systemically following topical route of administration, and breastfeeding is not expected to result in exposure of the child to Acyclovir Cream [see Clinical Pharmacology (12.3) ] . There are no data on the effects of Acyclovir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Acyclovir Cream and any potential adverse effects on the breastfed child from Acyclovir Cream or from the underlying maternal condition. 8.4 Pediatric Use An open-label, uncontrolled trial with Acyclovir Cream was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults. Safety and effectiveness in pediatric patients less than 12 years of age have not been established. 8.5 Geriatric Use Clinical studies of acyclovir cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Acyclovir is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the Acyclovir Cream [see Clinical Pharmacology (12.3) ] . Experience with topical acyclovir use in pregnant women over several decades, based on published literature including observational studies, has not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies with systemic exposure of acyclovir have been conducted. Refer to acyclovir prescribing information for additional details. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.4 Pediatric Use An open-label, uncontrolled trial with Acyclovir Cream was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults. Safety and effectiveness in pediatric patients less than 12 years of age have not been established.

8.5 Geriatric Use Clinical studies of acyclovir cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal [see Clinical Pharmacology (12.3) ] .

10 OVERDOSAGE Overdosage by topical application of Acyclovir Cream is unlikely because of minimal systemic exposure [see Clinical Pharmacology (12.3) ] . There is no information available for overdose.

11 DESCRIPTION Acyclovir is a synthetic deoxynucleoside analogue active against herpes viruses. Acyclovir Cream 5% is a formulation for topical administration. 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: Acyclovir is a white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pKa’s of acyclovir are 2.27 and 9.25. Each gram of Acyclovir Cream contains 50 mg (equivalent to 5% w/w) of acyclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water and white petrolatum. chemstructure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acyclovir is an antiviral drug active against α-herpesviruses [see Microbiology (12.4) ] . 12.3 Pharmacokinetics A clinical pharmacology study was performed with Acyclovir Cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cm 2 on the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01 μM) in 5 subjects and barely detectable (0.014 μM) in 1 subject. Systemic absorption of acyclovir from Acyclovir Cream is minimal in adults. The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age. 12.4 Microbiology Mechanism of Action: Acyclovir is a synthetic purine deoxynucleoside analogue with cell culture and in vivo inhibitory activity against HSV types 1 (HSV-1) and 2 (HSV-2) DNA polymerases. It inhibits HSV-1 and HSV-2 replication in cell culture and in vivo. The inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV. This viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This inhibition 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. Antiviral Activity The quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture 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 (EC 50 value), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the EC 50 values of acyclovir against herpes simplex virus isolates range from 0.09 to 59.9 μM (0.02 to 13.5 μg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 μg/mL) for HSV-2. Resistance In Cell Culture Acyclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Acyclovir-resistant HSV resulted from mutations in the viral thymidine kinase (TK; pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 1).

negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 1). Table 1: Summary of Acyclovir (ACV) Resistance-associated Amino Acid Substitutions in Cell Culture HSV-1 TK P5A, H7Q, L50V, G56V, G59A, G61A, K62N, T63A, E83K, P84S, D116N, P131S, R163H, A167V, P173L, Q185R, R216S, R220H, T245M, R281stop, T287M, M322K HSV-2 TK L69P, C172R, T288M HSV-1 POL D368A, Y557S, E597D, V621S, L702H, N815S, V817M, G841C HSV-2 POL - In HSV-Infected Patients Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 2). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy. Table 2: Summary of ACV Resistance-associated Amino Acid Substitutions Observed in Treated Patients HSV-1 TK G6C, R32H, R41H, R51W, Y53C/D/H, Y53stop, D55N, G56D/S, P57H, H58/N/R/Y, G59R, G61A, K62N, T63I, Q67stop, S74stop, Y80N, E83K, P84L, Y87H, W88R, R89Q/W, E95stop, T103P, Q104H, Q104stop, H105P, D116N, M121L/R, S123R, Q125H, M128L, G129D, I143V, A156V, D162A/H/N, R163G/H, L170P, Y172C, P173L, A174P, A175V, R176Q/W, R176stop, L178R, S181N, V187M, A189V, V192A, G200C/D/S, T201P, V204G, A207P, L208F/H, R216C/H, R220C/H, R221H, R222C/H, L227F, T245M/P, L249P, Q250Stop, C251G, R256W, E257K, Q261R, T287M, L288Stop, L291P/R, L297S, L315S, L327R, C336Y, Q342Stop, T354P, L364P, A365T HSV-2 TK R34C, G39E, R51W, Y53N, G59P, G61W, S66P, A72S, D78N, P85S, A94V, N100H, I101S, Q105P, T131P, D137stop, F140L, L158P, S169P, R177W, S182N, M183I, V192M, G201D, R217H, R221C/H, Q222stop, R223H, Y239stop, R271V, P272S, D273R, T287M, C337Y HSV-1 POL K532T, Q570R, L583V, A605V, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, I890M, G901V, V958L H1228D HSV-2 POL E250Q, D307N, K533E, A606V, C625R, R628C, E678G, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, N820S, Y823C, Q829R, T843A, M910T, D912N/V, A915V, F923L, T934A, R964H Note: Additional substitutions to acyclovir resistance may exist. Cross-resistance Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 3].

964H Note: Additional substitutions to acyclovir resistance may exist. Cross-resistance Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 3]. Table 3: Summary of Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS Cross-resistant to PCV/FCV HSV-1 TK G6C, R32H, R51W, Y53C/H, H58N, G61A, S74Stop, E83K, P84L, T103P, Q104Stop, D116N, M121R, I143V, R163H, L170P, Y172C, A174P, R176Q/W, Q185R, A189V, G200D, L208H, R216C, R220H, R222C/H, T245M, Q250Stop, R256W, R281Stop, T287M, L315S, M322K, C336Y Cross-resistant to PCV/FCV HSV-1 POL A657T, D672N, V715G, A719V, S724N, E798K, N815S, G841S Cross-resistant to PCV/FCV HSV-2 TK G39E, R51W, Y53N, R177W, R221H, T288M Cross-resistant to PCV/FCV HSV-2 POL K533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934A Cross-resistant to FOS HSV-1 POL D368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890M Cross-resistant to FOS HSV-2 POL K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H

12.3 Pharmacokinetics A clinical pharmacology study was performed with Acyclovir Cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cm 2 on the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01 μM) in 5 subjects and barely detectable (0.014 μM) in 1 subject. Systemic absorption of acyclovir from Acyclovir Cream is minimal in adults. The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age.

12.4 Microbiology Mechanism of Action: Acyclovir is a synthetic purine deoxynucleoside analogue with cell culture and in vivo inhibitory activity against HSV types 1 (HSV-1) and 2 (HSV-2) DNA polymerases. It inhibits HSV-1 and HSV-2 replication in cell culture and in vivo. The inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV. This viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This inhibition 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. Antiviral Activity The quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture 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 (EC 50 value), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the EC 50 values of acyclovir against herpes simplex virus isolates range from 0.09 to 59.9 μM (0.02 to 13.5 μg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 μg/mL) for HSV-2. Resistance In Cell Culture Acyclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Acyclovir-resistant HSV resulted from mutations in the viral thymidine kinase (TK; pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 1). Table 1: Summary of Acyclovir (ACV) Resistance-associated Amino Acid Substitutions in Cell Culture HSV-1 TK P5A, H7Q, L50V, G56V, G59A, G61A, K62N, T63A, E83K, P84S, D116N, P131S, R163H, A167V, P173L, Q185R, R216S, R220H, T245M, R281stop, T287M, M322K HSV-2 TK L69P, C172R, T288M HSV-1 POL D368A, Y557S, E597D, V621S, L702H, N815S, V817M, G841C HSV-2 POL - In HSV-Infected Patients Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 2). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens.

ions and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy. Table 2: Summary of ACV Resistance-associated Amino Acid Substitutions Observed in Treated Patients HSV-1 TK G6C, R32H, R41H, R51W, Y53C/D/H, Y53stop, D55N, G56D/S, P57H, H58/N/R/Y, G59R, G61A, K62N, T63I, Q67stop, S74stop, Y80N, E83K, P84L, Y87H, W88R, R89Q/W, E95stop, T103P, Q104H, Q104stop, H105P, D116N, M121L/R, S123R, Q125H, M128L, G129D, I143V, A156V, D162A/H/N, R163G/H, L170P, Y172C, P173L, A174P, A175V, R176Q/W, R176stop, L178R, S181N, V187M, A189V, V192A, G200C/D/S, T201P, V204G, A207P, L208F/H, R216C/H, R220C/H, R221H, R222C/H, L227F, T245M/P, L249P, Q250Stop, C251G, R256W, E257K, Q261R, T287M, L288Stop, L291P/R, L297S, L315S, L327R, C336Y, Q342Stop, T354P, L364P, A365T HSV-2 TK R34C, G39E, R51W, Y53N, G59P, G61W, S66P, A72S, D78N, P85S, A94V, N100H, I101S, Q105P, T131P, D137stop, F140L, L158P, S169P, R177W, S182N, M183I, V192M, G201D, R217H, R221C/H, Q222stop, R223H, Y239stop, R271V, P272S, D273R, T287M, C337Y HSV-1 POL K532T, Q570R, L583V, A605V, A657T, D672N, V715G, A719T/V, S724N, F733C, E771Q, S775N, L778M, E798K, V813M, N815S, G841S, I890M, G901V, V958L H1228D HSV-2 POL E250Q, D307N, K533E, A606V, C625R, R628C, E678G, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, N820S, Y823C, Q829R, T843A, M910T, D912N/V, A915V, F923L, T934A, R964H Note: Additional substitutions to acyclovir resistance may exist. Cross-resistance Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 3]. Table 3: Summary of Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS Cross-resistant to PCV/FCV HSV-1 TK G6C, R32H, R51W, Y53C/H, H58N, G61A, S74Stop, E83K, P84L, T103P, Q104Stop, D116N, M121R, I143V, R163H, L170P, Y172C, A174P, R176Q/W, Q185R, A189V, G200D, L208H, R216C, R220H, R222C/H, T245M, Q250Stop, R256W, R281Stop, T287M, L315S, M322K, C336Y Cross-resistant to PCV/FCV HSV-1 POL A657T, D672N, V715G, A719V, S724N, E798K, N815S, G841S Cross-resistant to PCV/FCV HSV-2 TK G39E, R51W, Y53N, R177W, R221H, T288M Cross-resistant to PCV/FCV HSV-2 POL K533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A, N820S, F923L, T934A Cross-resistant to FOS HSV-1 POL D368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890M Cross-resistant to FOS HSV-2 POL K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis and fertility are not included in the full prescribing information for Acyclovir Cream due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for Acyclovir Capsules, Tablets, and Suspension and Acyclovir for Injection.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis and fertility are not included in the full prescribing information for Acyclovir Cream due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for Acyclovir Capsules, Tablets, and Suspension and Acyclovir for Injection.

14 CLINICAL STUDIES 14.1 Adult Subjects Acyclovir Cream was evaluated in two double-blind, randomized, placebo (vehicle)-controlled trials for the treatment of recurrent herpes labialis. The average patient had five episodes of herpes labialis in the previous 12 months. In the first trial, the median age of subjects was 37 years (range 18 to 81 years), 74% were female, and 94% were Caucasian. In the second trial, median age of subjects was 38 years (range 18 to 87 years), 73% were female, and 94% were Caucasian. Subjects were instructed to initiate treatment within 1 hour of noticing signs or symptoms and continue treatment for 4 days, with application of study medication 5 times per day. In both studies, the mean duration of the recurrent herpes labialis episode was approximately one-half day shorter in the subjects treated with Acyclovir Cream (n = 682) compared with subjects treated with placebo (n = 703) for approximately 4.5 days versus 5 days, respectively. No significant difference was observed between subjects receiving Acyclovir Cream or placebo in the prevention of progression of cold sore lesions. 14.2 Pediatric Subjects An open-label, uncontrolled trial with Acyclovir Cream was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults.

16 HOW SUPPLIED/STORAGE AND HANDLING Each gram of Acyclovir Cream contains 50 mg (equivalent to 5% w/w) of acyclovir in an aqueous cream base. Acyclovir Cream is supplied as follows: 5 g tubes NDC 0093-3630-20 Store at or below 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). General Patients should be informed that Acyclovir Cream is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. Acyclovir Cream is not a cure for cold sores. Patients should be instructed that Acyclovir Cream is intended for cutaneous use only for herpes labialis of the lips and around the mouth. Patients should be advised that Acyclovir Cream should not be used in the eye, inside the mouth or nose, or on the genitals. Patients should be instructed to avoid applying other topical products to the affected area while using Acyclovir Cream. Do not use if you are allergic to Acyclovir Cream or any of the ingredients in Acyclovir Cream. Before you use Acyclovir Cream, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding. Instructions for Use Treatment should be initiated at the earliest sign or symptom of recurrence. Instruct patients to wash hands prior to application and ensure the face and/or lips are clean and dry. Advise patients to apply Acyclovir Cream topically 5 times per day for 4 days. Instruct patients to topically apply a quantity of Acyclovir Cream sufficient to cover the affected area, including the outer margin. Advise patients to avoid unnecessary rubbing of the affected area to avoid aggravating or transferring the infection. Instruct patients to wash their hands with soap and water after using Acyclovir Cream. Keep out of reach of children. Possible Side Effects Common skin-related side effects that occurred when Acyclovir Cream was applied include application site reactions. Acyclovir Cream has the potential for irritation and contact sensitization. Manufactured in Canada by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada Manufactured for: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Revised February 2021 9673501

Patient Information PATIENT INFORMATION Acyclovir Cream Important information: Acyclovir Cream is for use on cold sores on the lips and around the mouth only. Acyclovir Cream should not be used in your eyes, mouth, nose, or on your genitals. What is Acyclovir Cream? Acyclovir Cream is a prescription medicine used to treat cold sores (herpes labialis) that are recurring in adults and children 12 years of age and older, and who have normal immune systems. Acyclovir Cream is not a cure for cold sores. It is not known if Acyclovir Cream is safe and effective in children less than 12 years of age. Do not use Acyclovir Cream if you are allergic to acyclovir, valacyclovir, or any of the ingredients in Acyclovir Cream. See the end of this leaflet for a complete list of ingredients in Acyclovir Cream. What should I tell my healthcare provider before using Acyclovir Cream? Before using Acyclovir Cream, tell your healthcare provider about all of your medical conditions, including if you: become sick very easily (have a weak immune system). are pregnant or plan to become pregnant. It is not known if Acyclovir Cream will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if Acyclovir Cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use Acyclovir Cream. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use Acyclovir Cream? Use Acyclovir Cream exactly as your healthcare provider tells you to use it. Use Acyclovir Cream as soon as you have the first symptoms of a cold sore such as itching, redness, burning or tingling, or when the cold sore appears. Wash your hands with soap and water before and after applying Acyclovir Cream. The affected area should be clean and dry before applying Acyclovir Cream. Apply Acyclovir Cream to the affected area 5 times each day for 4 days, including the outer edge. You should not apply other skin products to the affected area during treatment with Acyclovir Cream. Avoid unnecessary rubbing of the cold sore because this may cause the cold sore to spread to other areas around your mouth or make your cold sore worse. What are the possible side effects of Acyclovir Cream? The most common side effects of Acyclovir Cream are skin reactions at the treatment site and may include: dry or cracked lips, peeling, flaking or dryness of the skin, a burning or stinging feeling, and itching. These are not all the possible side effects of Acyclovir Cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Acyclovir Cream? Store Acyclovir Cream at room temperature between 68° to 77°F (20° to 25°C). Keep Acyclovir Cream and all medicines out of reach of children. General information about the safe and effective use of Acyclovir Cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Acyclovir Cream for a condition for which it was not prescribed. Do not give Acyclovir Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Acyclovir Cream that is written for health professionals. What are the ingredients in Acyclovir Cream?

on for which it was not prescribed. Do not give Acyclovir Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Acyclovir Cream that is written for health professionals. What are the ingredients in Acyclovir Cream? Active ingredient: acyclovir Inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum Manufactured in Canada by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada Manufactured for: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 For more information, call 1-800-321-4576. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 02/2021 9673501

<table width="100%"><col width="100%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content> Acyclovir Cream </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Important information: Acyclovir Cream is for use on cold sores on the lips and around the mouth only.</content>Acyclovir Cream should not be used in your eyes, mouth, nose, or on your genitals. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is Acyclovir Cream?</content></paragraph><list listType="unordered"><item>Acyclovir Cream is a prescription medicine used to treat cold sores (herpes labialis) that are recurring in adults and children 12 years of age and older, and who have normal immune systems.</item><item>Acyclovir Cream is not a cure for cold sores. <paragraph>It is not known if Acyclovir Cream is safe and effective in children less than 12 years of age.</paragraph></item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not use Acyclovir Cream if you are</content>allergic to acyclovir, valacyclovir, or any of the ingredients in Acyclovir Cream. See the end of this leaflet for a complete list of ingredients in Acyclovir Cream. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before using Acyclovir Cream?</content></paragraph><paragraph>Before using Acyclovir Cream, tell your healthcare provider about all of your medical conditions, including if you:</paragraph><list listType="unordered"><item>become sick very easily (have a weak immune system).</item><item>are pregnant or plan to become pregnant. It is not known if Acyclovir Cream will harm your unborn baby.</item><item>are breastfeeding or plan to breastfeed. It is not known if Acyclovir Cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use Acyclovir Cream.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements.

east milk. Talk to your healthcare provider about the best way to feed your baby if you use Acyclovir Cream.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I use Acyclovir Cream?</content></paragraph><list listType="unordered"><item>Use Acyclovir Cream exactly as your healthcare provider tells you to use it.</item><item>Use Acyclovir Cream as soon as you have the first symptoms of a cold sore such as itching, redness, burning or tingling, or when the cold sore appears.</item><item>Wash your hands with soap and water before and after applying Acyclovir Cream.</item><item>The affected area should be clean and dry before applying Acyclovir Cream.</item><item>Apply Acyclovir Cream to the affected area 5 times each day for 4 days, including the outer edge.</item><item>You should not apply other skin products to the affected area during treatment with Acyclovir Cream.</item><item>Avoid unnecessary rubbing of the cold sore because this may cause the cold sore to spread to other areas around your mouth or make your cold sore worse.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of Acyclovir Cream?</content></paragraph><paragraph>The most common side effects of Acyclovir Cream are skin reactions at the treatment site and may include: dry or cracked lips, peeling, flaking or dryness of the skin, a burning or stinging feeling, and itching.</paragraph><paragraph>These are not all the possible side effects of Acyclovir Cream.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store Acyclovir Cream?</content></paragraph><list listType="unordered"><item>Store Acyclovir Cream at room temperature between 68&#xB0; to 77&#xB0;F (20&#xB0; to 25&#xB0;C). <paragraph><content styleCode="bold">Keep Acyclovir Cream and all medicines out of reach of children.</content></paragraph></item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of Acyclovir Cream.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Acyclovir Cream for a condition for which it was not prescribed. Do not give Acyclovir Cream to other people, even if they have the same symptoms you have. It may harm them.

ontent></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Acyclovir Cream for a condition for which it was not prescribed. Do not give Acyclovir Cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Acyclovir Cream that is written for health professionals.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in Acyclovir Cream?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>acyclovir </paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content>cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum </paragraph><paragraph>Manufactured in Canada by:</paragraph><paragraph>Bausch Health Companies Inc.</paragraph><paragraph>Laval, Quebec H7L 4A8, Canada</paragraph><paragraph>Manufactured for:</paragraph><paragraph>Teva Pharmaceuticals USA, Inc.</paragraph><paragraph>Parsippany, NJ 07054</paragraph><paragraph>For more information, call 1-800-321-4576.</paragraph></td></tr></tbody></table>

FOR INTRAVENOUS INFUSION ONLY Rx only 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 three 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 such 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.

r 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. Special Populations Adults with Impaired Renal Function Acyclovir was administered at a dose of 2.5 mg/kg to 6 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 section 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 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours ( Table 3 ). Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively ( Table 1 ). Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours ( Table 3 ). Table 3: Acyclovir Pharmacokinetics in Pediatric Patients (Mean ± SD) Parameter Aged from Birth to 3 Months (n=12) Aged 3 Months to 12 Years (n=16) CL (mL/min/kg) 4.46 ± 1.61 8.44 ± 2.92 VDSS (L/kg) 1.08 ± 0.35 1.01 ± 0.28 Elimination half-life (hours) 3.8 ± 1.19 2.36 ± 0.97 Acyclovir pharmacokinetic samples were collected in full-term and pre-term neonates with normal renal function who received varying dosing regimens of acyclovir for the treatment of suspected neonatal HSV infection. Model-predicted pharmacokinetic parameters stratified by post-menstrual age (PMA) are summarized in Table 4 . Table 4: Acyclovir Pharmacokinetics in Neonates Aged from Birth to 3 Months a Administered over 1 hour. Post-Menstrual Age (PMA) n IV Dose a Parameter (Median [Range]) Cmin ss (mg/L) Cmax ss (mg/L) CL (L/h/kg) V (L/kg) <30 Weeks 13 500 mg/m 2 every 8 h or 10 or 20 mg/kg every 12 h 3.92 (2.38 - 39.3) 10.3 (4.59 - 110) 0.21 (0.10 - 0.31) 2.88 (0.65 - 5.30) 30 to <36 Weeks 9 500 mg/m 2 every 8 h or 10 or 20 mg/kg every 12 h or 20 mg/kg every 8 h 5.10 (2.54 - 9.62) 8.83 (5.44 - 29.8) 0.45 (0.30 - 0.81) 4.49 (1.87 - 10.85) 36 to 41 Weeks 6 500 mg/m 2 every 8 h 2.90 (2.19 - 7.46) 12.4 (10.8 - 86.1) 0.59 (0.13 - 0.77) 2.55 (0.29 - 4.09) Overall 28 – 4.15 (2.19 - 39.3) 11.1 (4.59 - 110) 0.28 (0.10 - 0.81) 3.34 (0.29 - 10.9) Geriatrics Acyclovir plasma concentrations are higher in geriatric patients compared with 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.

DESCRIPTION Acyclovir Injection, USP is a synthetic nucleoside analog, active against herpes viruses. It is a sterile, aqueous solution for intravenous infusion, containing 50 mg acyclovir per mL in Water for Injection, USP. The concentration is equivalent to 54.9 mg of acyclovir sodium per mL in Water for Injection, USP. The sodium content is approximately 5.1 mg/mL. The pH range of the solution is 10.85 to 11.50. Further dilution of Acyclovir Injection, USP in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION, Administration ). The chemical name of acyclovir sodium is 9-[(2-Hydroxyethoxy)methyl] guanine, and has the following structural formula: Acyclovir sodium is a white, crystalline powder with the molecular formula C 8 H 10 N 5 NaO 3 and a molecular weight of 247.19. The maximum solubility in water at 25°C exceeds 100 mg/mL. At physiologic pH, acyclovir sodium exists as the unionized form with a molecular weight of 225 and a maximum solubility in water at 37°C of 2.5 mg/mL. The pka's of acyclovir are 2.27 and 9.25. Structural Formula

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 8 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 8 hours are given in Table 1 . Table 1: Acyclovir Peak and Trough Concentrations at Steady-State Dosage Regimen C SS max C SS trough 5 mg/kg q 8 h (n=8) 9.8 mcg/mL range: 5.5 to 13.8 0.7 mcg/mL range: 0.2 to 1 10 mg/kg q 8 h (n=7) 22.9 mcg/mL range: 14.1 to 44.1 1.9 mcg/mL range: 0.5 to 2.9 Concentrations 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 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 50 to 80 15 to 50 0 (Anuric) 2.5 3 3.5 19.5 327 248 190 29 5.1 3.9 3.4 0.5

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 8 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 8 hours are given in Table 1 . Table 1: Acyclovir Peak and Trough Concentrations at Steady-State Dosage Regimen C SS max C SS trough 5 mg/kg q 8 h (n=8) 9.8 mcg/mL range: 5.5 to 13.8 0.7 mcg/mL range: 0.2 to 1 10 mg/kg q 8 h (n=7) 22.9 mcg/mL range: 14.1 to 44.1 1.9 mcg/mL range: 0.5 to 2.9 Concentrations 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 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 50 to 80 15 to 50 0 (Anuric) 2.5 3 3.5 19.5 327 248 190 29 5.1 3.9 3.4 0.5

<table ID="t1" width="100%"><caption>Table 1: Acyclovir Peak and Trough Concentrations at Steady-State </caption><col width="32.667%" align="left"/><col width="35.900%" align="left"/><col width="31.433%" align="left"/><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule">Dosage Regimen </td><td align="center" valign="top" styleCode="Toprule Botrule Rrule">C^SSmax </td><td align="center" valign="top" styleCode="Toprule Botrule Rrule">C^SStrough </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">5 mg/kg q 8 h (n=8) </td><td align="center" valign="top" styleCode="Botrule Rrule">9.8 mcg/mL range: 5.5 to 13.8 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.7 mcg/mL range: 0.2 to 1 </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">10 mg/kg q 8 h (n=7) </td><td align="center" valign="top" styleCode="Botrule Rrule">22.9 mcg/mL range: 14.1 to 44.1 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.9 mcg/mL range: 0.5 to 2.9 </td></tr></tbody></table> <table ID="t2" width="100%"><caption>Table 2: Acyclovir Half-life and Total Body Clearance </caption><col width="24.975%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.025%" align="left"/><tbody><tr><td rowspan="2" align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule">Creatinine Clearance (mL/min/1.73 m²) </td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"/><td colspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule">Total Body Clearance </td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule">Half-Life (hr) </td><td align="center" valign="top" styleCode="Botrule Rrule"> (mL/min/1.73 m²) </td><td align="center" valign="top" styleCode="Botrule Rrule"> (mL/min/kg) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">&gt;80 50 to 80 15 to 50 0 (Anuric) </td><td align="center" valign="top" styleCode="Botrule Rrule">2.5 3 3.5 19.5 </td><td align="center" valign="top" styleCode="Botrule Rrule">327 248 190 29 </td><td align="center" valign="top" styleCode="Botrule Rrule">5.1 3.9 3.4 0.5 </td></tr></tbody></table>

<table ID="t3" width="100%"><caption>Table 3: Acyclovir Pharmacokinetics in Pediatric Patients (Mean &#xB1; SD) </caption><col width="29.977%" align="left"/><col width="32.311%" align="left"/><col width="37.713%" align="left"/><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule">Parameter </td><td align="center" valign="top" styleCode="Toprule Botrule Rrule">Aged from Birth to 3 Months (n=12) </td><td align="center" valign="top" styleCode="Toprule Botrule Rrule">Aged 3 Months to 12 Years (n=16) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">CL (mL/min/kg) </td><td align="center" valign="top" styleCode="Botrule Rrule">4.46 &#xB1; 1.61 </td><td align="center" valign="top" styleCode="Botrule Rrule">8.44 &#xB1; 2.92 </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">VDSS (L/kg) </td><td align="center" valign="top" styleCode="Botrule Rrule">1.08 &#xB1; 0.35 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.01 &#xB1; 0.28 </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">Elimination half-life (hours) </td><td align="center" valign="top" styleCode="Botrule Rrule">3.8 &#xB1; 1.19 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.36 &#xB1; 0.97 </td></tr></tbody></table> <table ID="t4" width="100%"><caption>Table 4: Acyclovir Pharmacokinetics in Neonates Aged from Birth to 3 Months </caption><col width="15.414%" align="left"/><col width="4.843%" align="left"/><col width="25.443%" align="left"/><col width="13.471%" align="left"/><col width="13.171%" align="left"/><col width="14.671%" align="left"/><col width="12.986%" align="left"/><tfoot><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">^a Administered over 1 hour.

4.843%" align="left"/><col width="25.443%" align="left"/><col width="13.471%" align="left"/><col width="13.171%" align="left"/><col width="14.671%" align="left"/><col width="12.986%" align="left"/><tfoot><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">^a Administered over 1 hour. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"> Post-Menstrual Age (PMA) </td><td rowspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule"> n </td><td rowspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule"> IV Dose^a</td><td colspan="4" align="center" valign="top" styleCode="Toprule Botrule Rrule">Parameter (Median [Range]) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule">Cmin_ss (mg/L) </td><td align="center" valign="top" styleCode="Botrule Rrule">Cmax_ss (mg/L) </td><td align="center" valign="top" styleCode="Botrule Rrule">CL (L/h/kg) </td><td align="center" valign="top" styleCode="Botrule Rrule">V (L/kg) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">&lt;30 Weeks </td><td align="center" valign="top" styleCode="Botrule Rrule">13 </td><td align="center" valign="top" styleCode="Botrule Rrule">500 mg/m² every 8 h or 10 or 20 mg/kg every 12 h </td><td align="center" valign="top" styleCode="Botrule Rrule">3.92 (2.38 - 39.3) </td><td align="center" valign="top" styleCode="Botrule Rrule">10.3 (4.59 - 110) </td><td align="center" valign="top" styleCode="Botrule Rrule">0.21 (0.10 - 0.31) </td><td align="center" valign="top" styleCode="Botrule Rrule">2.88 (0.65 - 5.30) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">30 to &lt;36 Weeks </td><td align="center" valign="top" styleCode="Botrule Rrule">9 </td><td align="center" valign="top" styleCode="Botrule Rrule">500 mg/m² every 8 h or 10 or 20 mg/kg every 12 h or 20 mg/kg every 8 h </td><td align="center" valign="top" styleCode="Botrule Rrule">5.10 (2.54 - 9.62) </td><td align="center" valign="top" styleCode="Botrule Rrule">8.83 (5.44 - 29.8) </td><td align="center" valign="top" styleCode="Botrule Rrule">0.45 (0.30 - 0.81) </td><td align="center" valign="top" styleCode="Botrule Rrule">4.49 (1.87 - 10.85) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">36 to 41 Weeks </td><td align="center" valign="top" styleCode="Botrule Rrule">6 </td><td align="center" valign="top" styleCode="Botrule Rrule">500 mg/m² every 8 h </td><td align="center" valign="top" styleCode="Botrule Rrule">2.90 (2.19 - 7.46) </td><td align="center" valign="top" styleCode="Botrule Rrule">12.4 (10.8 - 86.1) </td><td align="center" valign="top" styleCode="Botrule Rrule">0.59 (0.13 - 0.77) </td><td align="center" valign="top" styleCode="Botrule Rrule">2.55 (0.29 - 4.09) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">Overall </td><td align="center" valign="top" styleCode="Botrule Rrule">28 </td><td align="center" valign="top" styleCode="Botrule Rrule">&#x2013; </td><td align="center" valign="top" styleCode="Botrule Rrule">4.15 (2.19 - 39.3) </td><td align="center" valign="top" styleCode="Botrule Rrule">11.1 (4.59 - 110) </td><td align="center" valign="top" styleCode="Botrule Rrule">0.28 (0.10 - 0.81) </td><td align="center" valign="top" styleCode="Botrule Rrule">3.34 (0.29 - 10.9) </td></tr></tbody></table>

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. Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics .

CLINICAL TRIALS: Herpes Simplex Infections in Immunocompromised Patients A multicenter trial of acyclovir at a dose of 250 mg/m 2 every 8 hours (750 mg/m 2 /day) for 7 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 5 mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every 8 hours for 5 days. Acyclovir decreased the duration of viral excretion, new lesion formation, and duration of vesicles, and promoted healing of lesions. Herpes Simplex Encephalitis Sixty-two patients aged 6 months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (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.

erpes 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.

INDICATIONS AND USAGE: Herpes Simplex Infections in Immunocompromised Patients Acyclovir 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 Injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immuno-competent patients. Herpes Simplex Encephalitis Acyclovir Injection is indicated for the treatment of herpes simplex encephalitis. Neonatal Herpes Simplex Virus Infection Acyclovir Injection is indicated for the treatment of neonates and infants with herpes simplex infections. Varicella-Zoster Infections in Immunocompromised Patients Acyclovir Injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.

WARNINGS: Acyclovir Injection is intended for intravenous infusion only, and should not be administered topically, intramuscularly, orally, subcutaneously, or in the eye. Intravenous infusions must be given over a period of at least 1 hour to reduce the risk of renal tubular damage (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). 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.

PRECAUTIONS: General Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C 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 a result of acyclovir administration and depends on the state of the patient's 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 8 hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every 8 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 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.

tal 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. 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, 4 and 9, and 1 and 2 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 approximated that found in the general population. However, the small size of the registry was 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 two 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 The safety and efficacy of Acyclovir Injection has been evaluated in pediatric patients, including neonates (see CLINICAL PHARMACOLOGY , CLINICAL TRIALS , INDICATIONS AND USAGE , ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ). Geriatric Use Clinical studies of Acyclovir Injection did not include sufficient numbers of patients aged 65 and older 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.

General Precipitation of acyclovir crystals in renal tubules can occur if the maximum solubility of free acyclovir (2.5 mg/mL at 37°C 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 a result of acyclovir administration and depends on the state of the patient's 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.

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 8 hours, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg every 8 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 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.

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, 4 and 9, and 1 and 2 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 approximated that found in the general population. However, the small size of the registry was 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.

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, 4 and 9, and 1 and 2 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 approximated that found in the general population. However, the small size of the registry was 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 two 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 The safety and efficacy of Acyclovir Injection has been evaluated in pediatric patients, including neonates (see CLINICAL PHARMACOLOGY , CLINICAL TRIALS , INDICATIONS AND USAGE , ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ).

Geriatric Use Clinical studies of Acyclovir Injection did not include sufficient numbers of patients aged 65 and older 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.

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 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.

NS ). 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 ).

OVERDOSAGE: Overdoses involving ingestions of up to 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 ).

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 (Aged 12 years and older): 5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days. Pediatrics (Aged 3 months to 12 years): 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 (Aged 12 years 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 (Aged 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.

ch 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.

HOW SUPPLIED: Acyclovir Injection, USP equivalent to acyclovir is available: Product Code Unit of Sale Strength Each 622010 NDC 65219-622-10 Unit of 10 500 mg per 10 mL (50 mg per mL) NDC 65219-622-02 In a 10 mL clear, tubular glass vial 622020 NDC 65219-624-20 Unit of 10 1,000 mg per 20 mL (50 mg per mL) NDC 65219-624-04 In a 20 mL clear, tubular glass vial Store at 20°C to 25°C (68°F to 77°F)[see USP Controlled Room Temperature]. Discard unused portion. The container closure is not made with natural rubber latex. Manufactured for: Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451815 June 2024 Made in India LEIA-301.00 Fresenius Kabi Logo

<table width="100%"><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><col width="25.000%" align="left"/><tbody><tr><td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Product Code</content></td><td align="left" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Unit of Sale</content></td><td align="left" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Strength</content></td><td align="left" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Each</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">622010 </td><td align="left" valign="top" styleCode="Botrule Rrule">NDC 65219-622-10 Unit of 10 </td><td align="left" valign="top" styleCode="Botrule Rrule">500 mg per 10 mL (50 mg per mL) </td><td align="left" valign="top" styleCode="Botrule Rrule">NDC 65219-622-02 In a 10 mL clear, tubular glass vial </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">622020 </td><td align="left" valign="top" styleCode="Botrule Rrule">NDC 65219-624-20 Unit of 10 </td><td align="left" valign="top" styleCode="Botrule Rrule">1,000 mg per 20 mL (50 mg per mL) </td><td align="left" valign="top" styleCode="Botrule Rrule">NDC 65219-624-04 In a 20 mL clear, tubular glass vial </td></tr></tbody></table>

DESCRIPTION Acyclovir is a synthetic nucleoside analogue active against herpes viruses. Acyclovir capsules are a formulation for oral administration. Each capsule of acyclovir contains 200 mg of acyclovir and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shell consists of FD&C blue #1, gelatin and titanium dioxide. The capsule black imprinting ink contains the following inactive ingredients: ammonium hydroxide, black iron oxide, n-butyl, ethyl alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol and shellac. Acyclovir is a white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.2. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s 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: acyclovir-01

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.

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) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 h Average oral bioavailability 10% 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 a function of the dose and not the dosage form. Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, acyclovir capsules may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. acyclovir-02 acyclovir-03 Special Populations Adults With Impaired Renal Function The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION ). Geriatrics Acyclovir plasma concentrations are higher in geriatric patients compared with 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, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m 2 and 600 mg/m 2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. 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 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received acyclovir 400 mg twice daily for 3 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.

nts. In a study of patients who received acyclovir 400 mg twice daily for 3 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 a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir (800 mg 5 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 a similar double-blind, placebo-controlled study, acyclovir (800 mg 5 times daily for 7 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 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, acyclovir was administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 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 1 month or 1 year following treatment.

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) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 h Average oral bioavailability 10% 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 a function of the dose and not the dosage form. Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There was no effect of food on the absorption of acyclovir (n = 6); therefore, acyclovir capsules may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. acyclovir-02 acyclovir-03

<table ID="_RefID0EMIAC" width="100%"><caption>Table 1. Acyclovir Pharmacokinetic Characteristics (Range) </caption><col width="49%"/><col width="49%"/><tbody><tr><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Parameter</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Range</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Plasma protein binding</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9% to 33%</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Plasma elimination half-life</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.5 to 3.3 h</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Average oral bioavailability</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10% to 20%*</paragraph></td></tr></tbody></table>

styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2.5 to 3.3 h</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph>Average oral bioavailability</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>10% to 20%*</paragraph></td></tr></tbody></table> <table ID="_RefID0EXJAC" width="100%"><caption>Table 2. Acyclovir Peak and Trough Concentrations at Steady State</caption><col width="24%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Parameter</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>200 mg</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>400 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>800 mg</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><renderMultiMedia ID="id415" referencedObject="MM1143059448-1"/></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0.83 mcg/mL</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1.21 mcg/mL</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.61 mcg/mL</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><renderMultiMedia ID="id424" referencedObject="MM1143059456-1"/></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>0.46 mcg/mL</paragraph></td><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>0.63 mcg/mL</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0.83 mcg/mL</paragraph></td></tr></tbody></table>

Geriatrics Acyclovir plasma concentrations are higher in geriatric patients compared with 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 ). 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 ).

Pediatrics In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m 2 and 600 mg/m 2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Pediatric Use Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.

Drug Interactions Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Drug Interactions See CLINICAL PHARMACOLOGY: Pharmacokinetics .

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

CONTRAINDICATIONS Acyclovir capsules are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction [e.g., anaphylaxis, severe cutaneous adverse reactions (SCARs)] to acyclovir, valacyclovir, or any component of the formulation (see WARNINGS and ADVERSE REACTIONS ).

WARNINGS Acyclovir capsules 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. Severe cutaneous adverse reactions (SCARs), 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 (see CONTRAINDICATIONS and ADVERSE REACTIONS ). Discontinue acyclovir capsules immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. Acyclovir capsules are contraindicated in patients who have developed SCARs with the use of acyclovir or valacyclovir, or any component of the formulation (see CONTRAINDICATIONS and ADVERSE REACTIONS ).

PRECAUTIONS Dosage adjustment is recommended when administering acyclovir capsules to patients with renal impairment (see DOSAGE AND ADMINISTRATION ). Caution should also be exercised when administering acyclovir capsules 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 capsules, 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 capsules are not a cure for genital herpes. There are no data evaluating whether acyclovir capsules 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 capsules and seek medical attention if a painful rash with mucosal involvement develops (see CONTRAINDICATIONS and WARNINGS ). 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.

s). 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 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 capsules 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 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.

all 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 ).

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 capsules, 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 capsules are not a cure for genital herpes. There are no data evaluating whether acyclovir capsules 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.

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.

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

ADVERSE REACTIONS Herpes Simplex Short-Term Administration The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors. General Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS ). Digestive Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal Myalgia. Skin and Subcutaneous Tissue Disorders Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM), rashes including photosensitivity, alopecia, pruritus, urticaria (see CONTRAINDICATIONS and WARNINGS ). Special Senses Visual abnormalities. Urogenital Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS ).

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 ).

DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes Treatment of Initial Genital Herpes 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be reevaluated to assess the need for continuation of therapy with acyclovir capsules. Intermittent Therapy 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox Children (2 years of age and older) 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg 800 mg 4 times daily for 5 days. Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment In patients with renal impairment, the dose of acyclovir capsules should be modified as shown in Table 3: Table 3. Dosage Modification for Renal Impairment Creatinine Adjusted Dosage Regimen Normal Dosage Regimen Clearance (mL/min/1.73 m 2 ) Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0-10 200 every 12 hours 400 mg every 12 hours >10 0-10 400 200 every 12 hours every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10-25 800 every 8 hours 0-10 800 every 12 hours Hemodialysis For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis No supplemental dose appears to be necessary after adjustment of the dosing interval.

HOW SUPPLIED Acyclovir Capsules USP 200 mg are available for oral administration as hard gelatin capsules with a white opaque body and an aqua blue opaque cap. “APO 042” is imprinted on each capsule in black ink. They are supplied as follows: Cartons of 100 capsules (10 capsules each blister pack x 10), NDC 0904-5789-61 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from moisture. Manufactured by: Manufactured for: Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326 Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised: November 2025 Rev. 5

DESCRIPTION Acyclovir is a synthetic nucleoside analogue active against herpesviruses. Acyclovir tablets, USP is a formulation for oral administration. Each acyclovir tablet contains 400 mg or 800 mg of acyclovir. In addition, each tablet contains the inactive ingredients colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. The 400 mg and 800 mg tablet also contains ferric oxide and FD&C blue lake # 2 Indigo carmine AL, respectively. Acyclovir USP is a white to off white crystalline powder, slightly hygroscopic with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.20. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka's of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-. It has the following structural formula: acyclovirchemicalstructure

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.

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) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% 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 a function of the dose and not the dosage form. Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg C SS max 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL C SS trough 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There 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. Special Populations: Adults With Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION ). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared with 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, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m 2 and 600 mg/m 2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered acyclovir tablets 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 tablets given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received acyclovir tablets 400 mg twice daily for 3 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.

a study of patients who received acyclovir tablets 400 mg twice daily for 3 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 a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir tablets (800 mg 5 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 a similar double-blind, placebo-controlled study, acyclovir tablets (800 mg 5 times daily for 7 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 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, acyclovir tablets were administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with acyclovir tablets 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 tablets did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment.

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

CONTRAINDICATIONS Acyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction [e.g., anaphylaxis, severe cutaneous adverse reactions (SCARs)] to acyclovir, valacyclovir, or any component of the formulation (see WARNINGS and ADVERSE REACTIONS ).

WARNINGS 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. Severe cutaneous adverse reactions (SCARs), 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 (see CONTRAINDICATIONS and ADVERSE REACTIONS ). Discontinue acyclovir tablets immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. Acyclovir tablets are contraindicated in patients who have developed SCARs with the use of acyclovir or valacyclovir, or any component of the formulation (see CONTRAINDICATIONS and ADVERSE REACTIONS ).

PRECAUTIONS 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. 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 tablets and seek medical attention if a painful rash with mucosal involvement develops (see CONTRAINDICATIONS and WARNINGS) . Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 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 ).

riate 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.

lets 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 ).

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. 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 tablets and seek medical attention if a painful rash with mucosal involvement develops (see CONTRAINDICATIONS and WARNINGS) . Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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.

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 ).

ADVERSE REACTIONS Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir tablets 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200 mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir tablets were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir tablets for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir tablets 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir tablets at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir tablets. 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 tablets or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS ). Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM), rashes including photosensitivity, alopecia, pruritus, urticaria (see CONTRAINDICATIONS and WARNINGS ). Special Senses: Visual abnormalities. Urogenital: Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS ).

DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with acyclovir tablets. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of acyclovir tablets should be modified as shown in Table 3. Table 3. Dosage Modification for Renal Impairment Normal Dosage Regimen Creatinine Clearance (mL/min/1.73 m 2) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours > 10 0 to 10 200 200 every 4 hours, 5x daily every 12 hours 400 mg every 12 hours > 10 0 to 10 400 200 every 12 hours every 12 hours 800 mg every 4 hours > 25 10 to 25 0 to 10 800 800 800 every 4 hours, 5x daily every 8 hours every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval.

HOW SUPPLIED Acyclovir tablets USP, 400 mg containing 400 mg of acyclovir USP are pink, shield shaped, flat tablets debossed with 'J' on one side and '49' in triangle on the other. They are supplied as follows: NDC: 70518-2117-00 NDC: 70518-2117-01 NDC: 70518-2117-02 PACKAGING: 30 in 1 BOTTLE PLASTIC PACKAGING: 14 in 1 BLISTER PACK PACKAGING: 30 in 1 BLISTER PACK Store between 15º and 25ºC. Protect from light and moisture. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

DESCRIPTION Acyclovir is a synthetic nucleoside analogue active against herpes viruses. Acyclovir ointment USP, 5% is a formulation for topical administration. Each gram of acyclovir ointment USP, 5% contains 50 mg of acyclovir, USP in a polyethylene glycol (PEG) base. Acyclovir, USP is a white to off-white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.2 g/mol. The maximum solubility in water at 37°C is 2.5 mg/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]-6 H purin-6-one; it has the following structural formula: acyclovir-structura-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 to 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.

r 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. CLINICAL TRIALS In clinical trials of initial genital herpes infections, acyclovir ointment 5% has shown a decrease in healing time and, in some cases, a decrease in duration of viral shedding and duration of pain. In studies in immunocompromised patients mainly with herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain. In studies of recurrent genital herpes and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit; there was some decrease in duration of viral shedding.

CLINICAL PHARMACOLOGY Two clinical pharmacology studies were performed with acyclovir ointment 5% in immunocompromised adults at risk of developing mucocutaneous Herpes simplex virus infections or with localized varicella-zoster infections. These studies were designed to evaluate the dermal tolerance, systemic toxicity, and percutaneous absorption of acyclovir. In 1 of these studies, which included 16 inpatients, the complete ointment or its vehicle were randomly administered in a dose of 1-cm strips (25 mg acyclovir) 4 times a day for 7 days to an intact skin surface area of 4.5 square inches. No local intolerance, systemic toxicity, or contact dermatitis were observed. In addition, no drug was detected in blood and urine by radioimmunoassay (sensitivity, 0.01 mcg/mL). The other study included 11 patients with localized varicella-zoster infections. In this uncontrolled study, acyclovir was detected in the blood of 9 patients and in the urine of all patients tested. Acyclovir levels in plasma ranged from <0.01 to 0.28 mcg/mL in 8 patients with normal renal function, and from <0.01 to 0.78 mcg/mL in 1 patient with impaired renal function. Acyclovir excreted in the urine ranged from <0.02% to 9.4% of the daily dose. Therefore, systemic absorption of acyclovir after topical application is minimal.

INDICATIONS AND USAGE Acyclovir ointment USP 5% is indicated in the management of initial genital herpes and in limited non-life-threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients.

PRECAUTIONS General The recommended dosage, frequency of applications, and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION ). There are no data to support the use of acyclovir ointment 5% to prevent transmission of infection to other persons or prevent recurrent infections when applied in the absence of signs and symptoms. Acyclovir ointment 5% should not be used for the prevention of recurrent HSV infections. Although clinically significant viral resistance associated with the use of acyclovir ointment 5% has not been observed, this possibility exists. Drug Interactions Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir ointment 5%. Carcinogenesis, Mutagenesis, Impairment of Fertility Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis, and fertility are not included in the full prescribing information for acyclovir ointment 5% due to the minimal exposures of acyclovir that result from dermal application. Pregnancy Teratogenic Effects: Pregnancy Category B. Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure. There are no adequate and well-controlled studies of systemic acyclovir 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. Systemic acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of acyclovir, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing. Geriatric Use Clinical studies of acyclovir ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY ). Pediatric Use Safety and effectiveness in pediatric patients have not been established.

General The recommended dosage, frequency of applications, and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION ). There are no data to support the use of acyclovir ointment 5% to prevent transmission of infection to other persons or prevent recurrent infections when applied in the absence of signs and symptoms. Acyclovir ointment 5% should not be used for the prevention of recurrent HSV infections. Although clinically significant viral resistance associated with the use of acyclovir ointment 5% has not been observed, this possibility exists.

Carcinogenesis, Mutagenesis, Impairment of Fertility Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis, and fertility are not included in the full prescribing information for acyclovir ointment 5% due to the minimal exposures of acyclovir that result from dermal application.

Pregnancy Teratogenic Effects: Pregnancy Category B. Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure. There are no adequate and well-controlled studies of systemic acyclovir 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. Systemic acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of acyclovir, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.

Geriatric Use Clinical studies of acyclovir ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY ).

ADVERSE REACTIONS In the controlled clinical trials, mild pain (including transient burning and stinging) was reported by about 30% of patients in both the active and placebo arms; treatment was discontinued in 2 of these patients. Local pruritus occurred in 4% of these patients. In all studies, there was no significant difference between the drug and placebo group in the rate or type of reported adverse reactions nor were there any differences in abnormal clinical laboratory findings. Observed During Clinical Practice Based on clinical practice experience in patients treated with acyclovir ointment in the US, spontaneously reported adverse events are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as part of the underlying disease process. Voluntary reports of adverse events that have been received since market introduction include: General: Edema and/or pain at the application site. Skin: Pruritus, rash.

DOSAGE AND ADMINISTRATION Apply sufficient quantity to adequately cover all lesions every 3 hours, 6 times per day for 7 days. The dose size per application will vary depending upon the total lesion area but should approximate a one-half inch ribbon of ointment per 4 square inches of surface area. A finger cot or rubber glove should be used when applying acyclovir ointment to prevent autoinoculation of other body sites and transmission of infection to other persons. Therapy should be initiated as early as possible following onset of signs and symptoms.

HOW SUPPLIED Each gram of acyclovir ointment USP, 5% contains 50 mg acyclovir, USP in a polyethylene glycol base. Acyclovir ointment USP, 5% is a white to off-white translucent ointment. It is supplied as follows: NDC 16714-885-01 15 gram tubes (1 tube per carton) NDC 16714-885-02 30 gram tubes (1 tube per carton) Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Glenmark Pharmaceuticals Limited Colvale-Bardez, Goa 403513, India To report SUSPECT ADVERSE REACTIONS, Contact NorthStar Rx LLC 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fdagov/medwatch December 2021

DESCRIPTION Acyclovir is a synthetic nucleoside analogue active against herpesviruses. Acyclovir tablets are formulations for oral administration. Acyclovir is a white or almost white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.20. It is soluble in diluted hydrochloric acid; slightly soluble in water and insoluble in alcohol. The pka’s of acyclovir are 2.27 and 9.25. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]- 6H- purin-6-one; it has the following structural formula: Each acyclovir tablet intended for oral administration contains 400 mg and 800 mg of acyclovir. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate. structure

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) * Bioavailability decreases with increasing dose. Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% to 20% * 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 a function of the dose and not the dosage form. Table 2. Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg C S S m a x 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL C S S t r o u g h 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL There 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. Special Populations: Adults With Impaired Renal Function: The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function ( see DOSAGE AND ADMINISTRATION ). Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared with 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, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m 2 and 600 mg/m 2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours). Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced. 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 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients. In a study of patients who received acyclovir 400 mg twice daily for 3 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.

nts. In a study of patients who received acyclovir 400 mg twice daily for 3 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 a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir (800 mg 5 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 a similar double-blind, placebo-controlled study, acyclovir (800 mg 5 times daily for 7 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 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, acyclovir was administered at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 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 1 month or 1 year following treatment.

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

WARNINGS 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. Severe cutaneous adverse reactions (SCARs), 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 (see CONTRAINDICATIONS and ADVERSE REACTIONS ). Discontinue Acyclovir immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. Acyclovir Tablets contraindicated in patients who have developed SCARs with the use of acyclovir or valacyclovir, or any component of the formulation (see CONTRAINDICATIONS and ADVERSE REACTIONS ).

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

). 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 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: 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 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.

all 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 ).

ADVERSE REACTIONS Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo. Long-Term Administration: The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%). Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%). Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%). Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors. General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment ( see PRECAUTIONS ). Digestive: Diarrhea, gastrointestinal distress, nausea. Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Skin and Subcutaneous Tissue Disorders : Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM), rashes including photosensitivity, alopecia, pruritus, urticaria (see CONTRAINDICATIONS and WARNINGS ). Special Senses: Visual abnormalities. Urogenital: Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria ( see WARNINGS ).

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 ).

DOSAGE AND ADMINISTRATION Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily. The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with acyclovir. Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence. Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox. Adults and Children over 40 kg: 800 mg 4 times daily for 5 days. Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients. When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms. Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of Acyclovir Tablets should be modified as shown in Table 3. Table 3. Dosage Modification for Renal Impairment Normal Dosage Regimen Creatinine Clearance (mL/min/1.73 m 2 ) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0 to 10 200 every 12 hours 400 mg every 12 hours >10 400 every 12 hours 0 to 10 200 every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10 to 25 800 every 8 hours 0 to 10 800 every 12 hours Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval.

HOW SUPPLIED Acyclovir Tablets USP, 800 mg are white to off-white colored, oval shaped, biconvex, uncoated tablets, debossed with "792" on one side and plain on the other side and are supplied as follows: NDC 82868-107-35 in bottles of 35 tablets with child-resistant closure Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] . Protect from light and moisture. Dispense in a tight, light-resistant container (USP). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Zydus Lifesciences Ltd., Baddi, India Distributed by: Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 Rev.: 11/25

1 INDICATIONS AND USAGE AVACLYR is a sterile topical antiviral indicated for the treatment of acute herpetic keratitis (dendritic ulcers) in patients with herpes simplex (HSV-1 and HSV-2) virus. AVACLYR (acyclovir ophthalmic ointment) 3%, a herpes simplex virus nucleoside analog DNA polymerase inhibitor, is indicated in the treatment of acute herpetic keratitis (dendritic ulcers) in patients with herpes simplex (HSV-1 and HSV-2) virus.

2 DOSAGE AND ADMINISTRATION The recommended dosing regimen is to apply a 1 cm ribbon of ointment in the lower cul-de-sac of the affected eye 5 times per day (approximately every 3 hours while awake) until the corneal ulcer heals and then a 1 cm ribbon 3 times per day for 7 days. Apply a 1 cm ribbon in the lower cul-de-sac of the affected eye 5 times per day until healed then 3 times per day for 7 days. ( 2 )

4 CONTRAINDICATIONS AVACLYR is contraindicated for patients who develop sensitivity to acyclovir or valacyclovir. AVACLYR is contraindicated in patients with a known hypersensitivity to acyclovir or valacyclovir.

5 WARNINGS AND PRECAUTIONS AVACLYR is indicated for topical ophthalmic use. ( 5.1 ) Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with AVACLYR. ( 5.2 ) 5.1 Topical Ophthalmic Use AVACLYR is indicated for topical ophthalmic use. 5.2 Avoidance of Contact Lenses Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with AVACLYR. 5.3 Risk of Contamination This product is sterile when packaged. Patients should be advised to not allow the tip of the container to touch any surface, as this may contaminate the ointment. If pain develops, or if redness, itching, or inflammation becomes aggravated, the patient should be advised to consult a physician.

6 ADVERSE REACTIONS The most common adverse reactions (2-10%) reported in patients were eye pain (stinging), punctate keratitis and follicular conjunctivitis. Rare reports of blepharitis and very rare reports of immediate hypersensitivity reactions including angioedema and urticaria have been observed post-marketing in patients taking AVACLYR. The most common adverse reactions (2 to 10%) reported in patients were eye pain (stinging), punctate keratitis and follicular conjunctivitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fera Pharmaceuticals, LLC at (414) 434-6604 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary A prospective epidemiologic registry of acyclovir use from 1984 to 1999 indicated that the occurrence rate of birth defects in women exposed to systemically administered acyclovir during the first trimester of pregnancy (period of organogenesis) approximated that found in the general population. Likewise, oral and subcutaneous administration of acyclovir to pregnant mice, rats, and rabbits during organogenesis did not produce teratogenicity at clinically relevant doses (see Animal Data ) . Data Human Data 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 systemically administered 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. The human maternal plasma level of acyclovir following ocular administration is unknown. Animal Data In published animal reproduction studies, acyclovir was not maternally toxic and did not produce teratogenicity in the mouse at oral doses up to 450 mg/kg/day (1100 times the maximum recommended human ophthalmic dose [RHOD] on a mg/m 2 basis, assuming 100% absorption), or in the rat and rabbit at subcutaneous doses up to 50 mg/kg/day (approximately 250 and 500 times the RHOD, respectively) when administered throughout the period of organogenesis. Administration of acyclovir from postnatal days 3 to 21 did not produce adverse effects in neonatal rats at subcutaneous doses less than or equal to 20 mg/kg/day (100 times the RHOD). 8.2 Lactation Risk Summary Acyclovir concentrations have been documented in breast milk following oral administration of acyclovir. There is no information regarding the presence of acyclovir in human milk following ocular administration, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for acyclovir, and any potential adverse effects on the breast-fed child from acyclovir or from the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of Acyclovir ophthalmic ointment in pediatric patients below the age of two years has not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

8.1 Pregnancy Risk Summary A prospective epidemiologic registry of acyclovir use from 1984 to 1999 indicated that the occurrence rate of birth defects in women exposed to systemically administered acyclovir during the first trimester of pregnancy (period of organogenesis) approximated that found in the general population. Likewise, oral and subcutaneous administration of acyclovir to pregnant mice, rats, and rabbits during organogenesis did not produce teratogenicity at clinically relevant doses (see Animal Data ) . Data Human Data 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 systemically administered 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. The human maternal plasma level of acyclovir following ocular administration is unknown. Animal Data In published animal reproduction studies, acyclovir was not maternally toxic and did not produce teratogenicity in the mouse at oral doses up to 450 mg/kg/day (1100 times the maximum recommended human ophthalmic dose [RHOD] on a mg/m 2 basis, assuming 100% absorption), or in the rat and rabbit at subcutaneous doses up to 50 mg/kg/day (approximately 250 and 500 times the RHOD, respectively) when administered throughout the period of organogenesis. Administration of acyclovir from postnatal days 3 to 21 did not produce adverse effects in neonatal rats at subcutaneous doses less than or equal to 20 mg/kg/day (100 times the RHOD).

11 DESCRIPTION Acyclovir is a synthetic herpes simplex virus nucleoside analog DNA polymerase inhibitor. The drug substance is a white crystalline powder with the molecular formula of C 8 H 11 N 5 O 3 and a molecular weight of 225.2. The maximum solubility in water at 25°C is 1.41 mg/mL. The pka's of acyclovir are 2.52 and 9.35. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]6H-purin-6-one, it has the following chemical structure: AVACLYR is a sterile ointment for topical administration in eyes. Each gram of ointment contains 30 mg of acyclovir in a white petrolatum base. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acyclovir is an antiviral drug [see Microbiology ( 12.4 )] . 12.3 Pharmacokinetics It has not been possible to detect acyclovir concentrations in the blood by existing bioanalytical methods after topical application to the eye. Trace quantities are detectable in the urine but are not therapeutically relevant. 12.4 Microbiology Acyclovir is a synthetic purine nucleoside analogue that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK) of HSV 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 a biochemical reaction, acyclovir triphosphate inhibits replication of herpes viral DNA by competing with nucleotides for binding to the viral DNA polymerase and by incorporation into and termination of the growing viral DNA chain. The cellular thymidine kinase of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low. Antiviral Activities : The quantitative relationship between the cell culture susceptibility of herpes virus 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 (EC 50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, on Vero cells, the median EC 50 value of acyclovir against clinical herpes simplex virus isolates (subjects receiving placebo) was 1.3 μM (range: < 0.56 to 3.3 μM). Drug Resistance : Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir resistant mutant isolates thus far from such patients have been found to be TK deficient, other mutant isolates involving the viral TK gene (TK partial and TK altered) or DNA polymerase have been identified. TK negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in immunocompromised patients who show poor clinical response during therapy.

12.3 Pharmacokinetics It has not been possible to detect acyclovir concentrations in the blood by existing bioanalytical methods after topical application to the eye. Trace quantities are detectable in the urine but are not therapeutically relevant.

12.4 Microbiology Acyclovir is a synthetic purine nucleoside analogue that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK) of HSV 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 a biochemical reaction, acyclovir triphosphate inhibits replication of herpes viral DNA by competing with nucleotides for binding to the viral DNA polymerase and by incorporation into and termination of the growing viral DNA chain. The cellular thymidine kinase of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low. Antiviral Activities : The quantitative relationship between the cell culture susceptibility of herpes virus 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 (EC 50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, on Vero cells, the median EC 50 value of acyclovir against clinical herpes simplex virus isolates (subjects receiving placebo) was 1.3 μM (range: < 0.56 to 3.3 μM). Drug Resistance : Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir resistant mutant isolates thus far from such patients have been found to be TK deficient, other mutant isolates involving the viral TK gene (TK partial and TK altered) or DNA polymerase have been identified. TK negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in immunocompromised patients who show poor clinical response during therapy.

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Acyclovir was not shown to be carcinogenic in mouse and rat bioassays at oral doses up to 450 mg/kg (approximately 1100 – 2200 times the maximum RHOD, on a mg/m 2 basis, assuming 100% absorption). Mutagenesis Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was found to be negative in the Ames test, positive in the in vitro mouse lymphoma assay (TK locus), and positive in the in vitro and in vivo assays for chromosomal effects. Impairment of Fertility In reproduction studies, acyclovir did not impair fertility or reproduction at oral doses up to 450 mg/kg/day in mice (1100 times the RHOD), or at subcutaneous doses of 25 mg/kg/day in rats (125 times the RHOD). At a dose of 50 mg/kg/day in rats and rabbits (250 and 500 times the RHOD, respectively), implantation efficiency was decreased.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Acyclovir was not shown to be carcinogenic in mouse and rat bioassays at oral doses up to 450 mg/kg (approximately 1100 – 2200 times the maximum RHOD, on a mg/m 2 basis, assuming 100% absorption). Mutagenesis Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was found to be negative in the Ames test, positive in the in vitro mouse lymphoma assay (TK locus), and positive in the in vitro and in vivo assays for chromosomal effects. Impairment of Fertility In reproduction studies, acyclovir did not impair fertility or reproduction at oral doses up to 450 mg/kg/day in mice (1100 times the RHOD), or at subcutaneous doses of 25 mg/kg/day in rats (125 times the RHOD). At a dose of 50 mg/kg/day in rats and rabbits (250 and 500 times the RHOD, respectively), implantation efficiency was decreased.

14 CLINICAL STUDIES In five randomized, double masked studies which enrolled a total of 238 subjects with dendritic herpetic keratitis, acyclovir ophthalmic ointment, 3% was either superior or as effective as idoxuridine ophthalmic ointment 0.5% or 1% in subjects with dendritic ulcers. Clinical resolution (healed ulcers) at Day 7 averaged 83% for acyclovir and 50% for idoxuridine.

16 HOW SUPPLIED/STORAGE AND HANDLING AVACLYR is available in a 3.5 g aluminum tube with a white high density polyethylene cap as a clear, colorless, sterile ophthalmic ointment for topical use containing 3% acyclovir active drug. Each tube is packaged in an individual carton. 3.5 g tube (NDC 48102-028-35) Store at 15°C to 25°C (59°F to 77°F).

17 PATIENT COUNSELING INFORMATION Administration Advise patients to wash hands well and pull down lower lid of the affected eye to form a pocket. Instruct the patient to apply a 1 cm (1/2 inch) ribbon of ointment in the pocket formed by the lower lid 5 times per day (approximately every 3 hours while awake). After application of the ointment, the patient should be advised to close their eye for 1-2 minutes. Excess ointment can be wiped away. Continue this dosing 5 times per day until the patient is advised by their physician that the corneal ulcer is healed. Once healed, instruct the patient to continue use of a 1 cm (1/2 inch) ribbon of ointment 3 times per day for 7 more days. [see Dosage and Administration ( 2 )]. Risk of Contamination This product is sterile when packaged. Advise patients to not allow the tip of the container to touch any surface, as this may contaminate the ointment. When to Consult a Physician Advise patients to consult a physician if pain develops, or if redness, itching, or inflammation becomes aggravated. Avoidance of Contact Lenses Advise patients to not wear contact lenses when using AVACLYR. Manufactured in Canada for: Fera Pharmaceuticals, LLC Locust Valley, N.Y. 11560 PF028 P-622V1