acyclovir 50 MG Buccal Tablet

INDICATIONS AND USAGE Herpes Simplex Infections in Immunocompromised Patients Acyclovir Sodium Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients. Initial Episodes of Herpes Genitalis Acyclovir Sodium Injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immunocompetent patients. Herpes Simplex Encephalitis Acyclovir Sodium Injection is indicated for the treatment of herpes simplex encephalitis. Neonatal Herpes Simplex Virus Infection Acyclovir Sodium Injection is indicated for the treatment of neonates and infants with herpes simplex infections. Varicella-Zoster Infections in Immunocompromised Patients Acyclovir Sodium Injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.

DOSAGE AND ADMINISTRATION CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS). INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED ( see WARNINGS). Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient. Dosage 1. 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. 2. 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. 3. 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 . 4. 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. 5. 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. 6. 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 6. Table 6 Dosage Adjustments for Patients with Renal Impairment Creatinine Clearance (mL/min/1.73 m 2 ) Percent of Recommended Dose Dosing Interval (hours) > 50 100% 8 >25 to 50 100% 12 >10 to 25 100% 24 ≤ 10 50% 24 Hemodialysis For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient's dosing schedule should be adjusted so that an additional dose is administered after each dialysis. Peritoneal Dialysis No supplemental dose appears to be necessary after adjustment of the dosing interval. Administration The calculated dose should then be removed and added to any appropriate intravenous solution at a volume selected for administration during each 1 hour infusion. Infusion concentrations of approximately 7 mg/mL or lower are recommended. In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose. Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation. Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended. Once diluted for administration, each dose should be used within 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

WARNINGS Acyclovir Oral Suspension is intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS : Observed During Clinical Practice and OVERDOSAGE ). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy. 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 oral suspension immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. Acyclovir oral suspension is 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 ).

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

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acyclovir is an antiviral drug active against α-herpes viruses [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 mcg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 mcg/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. 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