Acyclovir
Acyclovir Prescribing Information
Acyclovir Injection is indicated for the treatment of initial and recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) in immunocompromised patients.
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
Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see
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.
See
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
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
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.
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.
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.
The safety and efficacy of Acyclovir Injection has been evaluated in pediatric patients, including neonates (see
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
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
Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see
A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.
Acyclovir Injection is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.
See
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.
| Dosage Regimen | CSSmax | CSStrough |
| 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.
| Creatinine Clearance (mL/min/1.73 m2) | Total Body Clearance | ||
| Half-Life (hr) | (mL/min/1.73 m2) | (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 |
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
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.
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 C8H10N5NaO3 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.