Acyclovir IV Infusion

Name: Acyclovir IV Infusion

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 CSS max CSS trough
5 mg/kg q 8 hr
(n = 8)
9.8 mcg/ml
range: 5.5 to 13.8
0.7 mcg/ml
range: 0.2 to 1.0
10 mg/kg q 8 hr
(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
Creatine Clearance
(mL/min/1.73 m2)
Half-Life (h) Total Body Clearance
(mL/min/1.73 m2) (mL/min/mg)
>80 2.5 327 5.1
50 - 80 3.0 248 3.9
15 - 50 3.5 190 3.4
0 (Anuric) 19.5 29 0.5

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 Birth to 3 Months of Age
(n = 12)
3 Months to 12 Months of Age
(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 (h) 3.80 ± 1.19 2.36 ± 0.97

Geriatrics

Acyclovir plasma concentrations are higher in geriatric patients compared to 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.

Clinical Trials

Herpes Simplex Infections in Immunocompromised Patients

A multicenter trial of acyclovir injection at a dose of 250 mg/m2 every 8 hours (750 mg/m2/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 ages 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 to 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 to 12% of patients treated with vidarabine.

Patients less than 30 years of age 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

Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every 8 hours (n = 107) or vidarabine 30 mg/kg/day (n = 95) for 10 days. Outcomes are presented in Table 4.

Table 4: Mortality at 1 Year
HSV Disease Classification Treatment Group
*SEM refers to localized infection with disease limited to skin, eye, and/or mouth.
+CNS refers to infection of the central nervous system with compatible neurologic and CSF findings.
++DISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.
Acyclovir
(n = 107)
Vidarabine
(n = 95)
SEM* (n = 85) 0/54 0/31
CNS+ (n = 71) 5/35 5/36
DISS++ (n = 46) 11/18 14/28

Rates of neurologic sequelae at 1 year were comparable between the treatment groups.

Varicella-Zoster Infections in Immunocompromised Patients

A multicenter trial of acyclovir injection at a dose of 500 mg/m2 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.

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/m2) 3 times daily, and approximately 300 patients who received ~10 mg/kg (500 mg/m2) 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 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.

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 and 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).

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 was 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 is supplied as sterile vials, each containing acyclovir sodium equivalent to 500 mg of acyclovir for intravenous administration in 20 mL of water for injection, tray of 10 (NDC 61703-311-21). Each mL contains acyclovir 25 mg/mL.

Acyclovir Injection is supplied as sterile vials, each containing acyclovir sodium equivalent to 1000 mg of acyclovir for intravenous administration in 40 mL of water for injection, tray of 10 (NDC 61703-311-43). Each mL contains acyclovir 25 mg/mL.

Store between 15° to 25°C (59° and 77°F).

Manufactured for:

Mayne Pharma ( USA) Inc.

Paramus, NJ  07652

By: Mayne Pharma Pty Ltd

Mulgrave VIC 3170

Australia

Rev. February 2004

480162

ACYCLOVIR 
acyclovir solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61703-311
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
acyclovir sodium (acyclovir ) acyclovir 500 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
sodium hydroxide  
hydrochloric acid  
Packaging
# Item Code Package Description
1 NDC:61703-311-21 10 VIAL (10 VIAL) in 1 TRAY
1 20 mL (20 MILLILITER) in 1 VIAL
2 NDC:61703-311-43 10 VIAL (10 VIAL) in 1 TRAY
2 40 mL (40 MILLILITER) in 1 VIAL
Labeler - Mayne Pharma (USA) Inc.
Revised: 01/2006   Mayne Pharma (USA) Inc.
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