ACYCLOVIR

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.

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

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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, USP in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors. General: Anaphylaxis, angioedema, fatigue, fever, headache, pain, peripheral edema. Digestive : Abdominal pain, diarrhea, gastrointestinal distress, nausea. Cardiovascular: Hypotension. Hematologic and Lymphatic: Disseminated intravascular coagulation, hemolysis, leukocytoclastic vasculitis, leukopenia, lymphadenopathy. Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice. Musculoskeletal: Myalgia. Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, dysarthria, encephalopathy, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence, tremor. These symptoms may be marked, particularly in older adults (see PRECAUTIONS ). Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria. Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues. Special Senses: Visual abnormalities. Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine (see WARNINGS ).

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 .

DESCRIPTION Acyclovir Sodium Injection is a synthetic nucleoside analogue, 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. Acyclovir Sodium Injection contains Sodium Hydroxide, NF as inactive ingredient. Further dilution of Acyclovir Sodium Injection 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, USP is a white to off-white, crystalline powder. Acyclovir sodium is the sodium salt of acyclovir, which is formed in situ , 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. figure01

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 ).

HOW SUPPLIED: Acyclovir Injection, USP is available as: Product Code Unit of Sale Strength Each PRX302510 NDC 63323-325-14 Unit of 10 500 mg per 10 mL (50 mg per mL) NDC 63323-325-41 10 mL Single Dose Plastic Vial PRX302520 NDC 63323-325-24 Unit of 10 1,000 mg per 20 mL (50 mg per mL) NDC 63323-325-43 20 mL Single Dose Plastic 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. PREMIERProRx ® is a registered trademark of Premier Healthcare Alliance, L.P., used under license. Manufactured by: Fresenius Kabi Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451376B Revised: April 2024 PREMIERProRx Logo