Acyclovir Information
Acyclovir () Description
Acyclovir () is a synthetic nucleoside analog active against herpes viruses. Acyclovir () for Injection USP is a sterile lyophilized powder for intravenous administration only. Each 500 mg vial contains 500 mg of Acyclovir () and 49 mg of sodium, and each 1000 mg vial contains 1000 mg Acyclovir () and 98 mg of sodium. Reconstitution of the 500 mg or 1000 mg vials with 10 mL or 20 mL, respectively, of Sterile Water for Injection, results in a solution containing 50 mg/mL of Acyclovir () . The pH of the reconstituted solution is approximately 11. Further dilution in any appropriate intravenous solution must be performed before infusion (see :).
Acyclovir () sodium is a white, crystalline powder with a molecular weight of 247.19, and a maximum solubility in water at 25°C exceeds 100 mg/mL. Each 500 mg or 1000 mg vial of Acyclovir () for injection USP when reconstituted with 10 mL or 20 mL, respectively, sterile diluent yields 50 mg/mL Acyclovir () (pH approximately 11). At physiologic pH, Acyclovir () exists as the un-ionized form with a molecular weight of 225.21 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.
The chemical name of Acyclovir () sodium is 9-[(2-Hydroxyethoxy)methyl]guanine sodium salt; it has the following structural formula:
Molecular Formula: CHNONa
Acyclovir () Virology
Acyclovir () is a synthetic purine nucleoside analogue with and 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. , 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 to VZV is due to its more efficient phosphorylation by the viral TK.
Acyclovir () Clinical Pharmacology
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.
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 () is dependent on renal function as shown in Table 2.
Acyclovir () Indications And Usage
Acyclovir () for injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.
Acyclovir () for injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immunocompetent patients.
Acyclovir () for injection is indicated for the treatment of herpes simplex encephalitis.
Acyclovir () for injection is indicated for the treatment of neonatal herpes infections.
Acyclovir () for injection is indicated for the treatment of varicella-zoster (shingles) infections in immunocompromised patients.
Acyclovir () Contraindications
Acyclovir () for injection is contraindicated for patients who develop hypersensitivity to Acyclovir () or valAcyclovir () .
Acyclovir () Warnings
Acyclovir () for 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 and ).
Renal failure, in some cases resulting in death, has been observed with Acyclovir () therapy (see : and ).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving Acyclovir () therapy.
Acyclovir () Precautions
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 ).
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.
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 hr, dosing appropriate for treatment of herpes zoster or herpes encephalitis), or 15 mg/kg/day (5 mg/kg/every 8 hr, 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 : ).
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 and 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 per 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.
Acyclovir () Adverse Reactions
The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received Acyclovir () at ~ 5 mg/kg (250 mg/m) three times daily, and approximately 300 patients who received ~ 10 mg/kg (500 mg/m) three times daily.
The most frequent adverse reactions reported during administration of Acyclovir () were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10% (the higher incidence occurred usually following rapid [less than 10 minutes] intravenous infusion). Nausea and/or vomiting occurred in approximately 7% of the patients (the majority occurring in nonhospitalized patients who received 10 mg/kg). Itching, rash or hives occurred in approximately 2% of patients. Elevation of transaminases occurred in 1% to 2% of patients.
The following hematologic abnormalities occurred at a frequency of less than 1%: anemia, neutropenia, thrombocytopenia, thrombocytosis, leukocytosis, and neutrophilia. In addition, anorexia and hematuria were observed.
Acyclovir () 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 ).
Acyclovir () Dosage And Administration
A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.
Acyclovir () How Supplied
Acyclovir () for Injection USP is available as:
Store between 15° to 25° C (59° to 77° F).
Manufactured by: Ben Venue Laboratories, Inc., Bedford, OH 44146.
Manufactured for: Bedford Laboratories™, Bedford, OH 44146.
June 2005 Div-ACYP05
Acyclovir () Vial Label Mg
Acyclovir () Vial Label Mg
Acyclovir () Carton Mg
Acyclovir () Carton Mg
