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Acyclovir  (0105)
[ ay-sye'-kloe-veer ]
Ingredients: Acyclovir
Indications: Herpes genitalis; Herpes labialis; Herpes simplex encephalitis; Herpes zoster; Infection, herpes simplex; Infection, varicella- zoster; Varicella
Pregnancy Category: C; B
FDA Approved: 1982- 03- 01
Classes: Antivirals; Orphan Drugs
HCFA Jcodes: Q4075
Brand Names: ACERPES - Germany ; Acevir - Philippines ; Acic Creme - Germany ; Acicloftal - Italy ; Aciclor - Venezuela ; Aciclosina - Peru ; Aciclovir-BC IV - Australia ; Acihexal - Australia ; Acilax cream - Hong-kong ; Acitop - South-africa ; Acivir Cream - India, Israel ; Acivir Eye - India ; Aclova - Korea ; Aclovir - Taiwan, Thailand ; Aclovirax - Hong-kong ; Activir - France ; Acyclo-V - AUSTRALIA; Bahrain ; Acylene - Malaysia ; Acyron - Korea ; Acyrova - Korea ; Acyvir - Ecuador, Hong-kong, Italy, Korea ; Aias - Korea ; Apicol - Colombia ; Avirax - Canada ; Avorax - Hong-kong, Malaysia, Singapore ; Avorax Cream - Malaysia ; Azovir - Indonesia ; Bearax - Singapore ; Cicloferon - Mexico ; Cicloviral - Colombia ; Clinovir - Indonesia, Thailand ; Clovicin - Taiwan ; Clovir - Brazil ; Cloviran - Chile ; Colsor - Thailand ; Cusiviral - Hong-kong, Malaysia, Singapore, Spain ; Cyclivex - South-africa ; Cyclo - Korea ; Cyclomed - Israel ; Cyclorax - Hong-kong ; Cyclostad - Philippines ; Cyclovir - AFRICA(Except South-africa ); India ; Cyllanvir - Philippines ; Danovir - Singapore ; Deherp - Taiwan, Thailand ; Dravyr - Singapore ; Dumophar - Indonesia ; Duvimex - MIDDLEEAST ; Eduvir - Indonesia ; Entir - Singapore, Thailand ; Erlvirax - Singapore ; Eurovir - Paraguay ; Exavir - Brazil ; Expit - Uruguay ; Herpefug - Germany ; Herpex - Bahrain, India, Philippines ; Herpoviric - Germany ; Herpoviric Rp Creme - Germany ; Inmerax - Chile ; Innovirax - Philippines ; Isavir - Mexico ; Juviral - Germany ; Laciken - Mexico ; Leramex - Thailand ; Lermex - Thailand ; Lesaclor - Mexico ; Libravir - Ecuador ; Lisovyr - Argentina, Chile ; Lovir - AUSTRALIA; Malaysia, Singapore ; Lovire - South-africa ; Maclov - Mexico ; Marvir - Thailand ; Matrovir - Indonesia ; Maynor - Spain ; Medovir - AFRICA, MIDDLEEAST(Except Israel ); Bulgaria, Malaysia, Singapore, Taiwan ; Norum - Thailand ; Olvit - Mexico ; Oppvir - Taiwan, Thailand ; Opthavir - Mexico ; Poviral - Costa-rica, Dominican-republic, Ecuador, El-salvador, Guatemala, Honduras, Indonesia, Nicaragua, Panama ; Proviral - Argentina ; Qualiclovir - Hong-kong ; Quavir - Indonesia ; Ranvir - Thailand ; Raxclo - Philippines ; Supra-Vir - Israel ; Supraviran - Germany ; Supraviran Creme - MIDDLEEAST(Except Israel ); Germany ; Syntovir - Hong-kong ; Vacrax - Malaysia ; Vacrovir - Korea ; Vermis - Thailand ; Vicorax - Taiwan, Thailand ; Viraban - New-zealand ; Viralex - Philippines ; Viralex-DS - Philippines ; Virax - Korea ; Vircella - Indonesia ; Virest - Malaysia, Singapore ; Virex - Colombia ; Virless - China, Singapore, Taiwan ; Viroclear - Hong-kong ; Virogon - Thailand ; Virolan - Taiwan ; Viromed - Thailand ; Vironida - Peru ; Virucid - Hong-kong ; Virules - Hong-kong ; Virupos Eye Oint - Korea ; Vivir - Korea ; Warviron - Hong-kong ; Zetavir - Mexico ; Zeven Cream - Malaysia ; Zevin - Hong-kong, Thailand ; Zodiac - Korea ; Zoral - Hong-kong, Singapore ; Zoral Cream - Malaysia ; Zorax - Singapore ; Zorel - Indonesia ; Zoter - Indonesia ; Zovir - Denmark ; Zovirax - AMERICAS, ASIA, EUROPE, US ; Zovirax Topical - US ; Zoylex - Korea ; Zumasid - Indonesia ; Zyclir - Australia ; Zyvir - Kenya ;
DEA schedules: (none)
Cost of therapy: $48.60 ( Genital Herpes ; Generic Capsules (Teva) ; 200 mg ; 5 capsule(s)/day ; 10 day supply )
$87.75 ( Genital Herpes ; Zovirax ; 200 mg ; 5 capsule(s)/day ; 10 day supply )
$90.00 ( Herpes Zoster (Shingles) ; Zovirax Topical (Biovail) ; 5%; 15 g ; 6 application(s)/day ; 7 day supply )
$168.33 ( Herpes Zoster (Shingles) ; Generic Tablets (Teva) ; 800 mg ; 5 tablet(s)/day ; 10 day supply )
$331.11 ( Herpes Zoster (Shingles) ; Zovirax ; 800 mg ; 5 tablet(s)/day ; 10 day supply )
$168.33 ( Varicella Zoster (Chickenpox) ; Generic Tablets (Teva) ; 800 mg ; 5 tablets/day ; 10 day supply )
$331.11 ( Varicella Zoster (Chickenpox) ; Zovirax ; 800 mg ; 5 tablets/day ; 10 day supply )

Administration Route:IV

DESCRIPTION
  Zovirax is the brand name for acyclovir, a synthetic nucleoside analog active against herpes viruses. Acyclovir sodium for injection 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 DOSAGE AND ADMINISTRATION: Method of Preparation and Administration ).
Acyclovir sodium is a white, crystalline powder with the molecular formula C8 H10 N5 NaO3 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 un- ionized 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.
The chemical name of acyclovir sodium is 2- amino- 1, 9- dihydro- 9- [(2- hydroxyethoxy)methyl]- 6 H - purin- 6- one monosodium salt.

CLINICAL PHARMACOLOGY
 

Virology
 

Mechanism of Antiviral Action
  Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo 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. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This 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. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities
  The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque- reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 μg/ ml for HSV- 1 and from 0.01 to 9.9 μg/ ml for HSV- 2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 μg/ ml. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 μg/ ml.

Drug Resistance
  Resistance of HSV and VZV to antiviral nucleoside analogues can result from qualitative or quantitative changes in the viral TK and/ or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir- resistant mutants isolated thus far from such patients have been found to be TK- deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK- negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Pharmacokinetics
  The pharmacokinetics of acyclovir after IV 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 CSSmax CSStrough
5 mg/ kg q8h 9.8 μg/ ml 0.7 μg/ ml
(n=8) range: 5.5- 13.8 range: 0.2- 1.0
10 mg/ kg q8h 22.9 μg/ ml 1.9 μg/ ml
(n=7) range: 14.1- 44.1 range: 0.5- 2.9

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9- 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- 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
Creatinine Clearance   Total Body Clearance
ml/ min/ 1.73 m2 Half- Life ml/ min/ 1.73 m2 ml/ min/ kg
>80 2.5 hours 327 5.1
50- 80 3.0 hours 248 3.9
15- 50 3.5 hours 190 3.4
0 (Anuric) 19.5 hours 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 μg/ ml and 0.7 μg/ ml, respectively.
Consult DOSAGE AND ADMINISTRATION 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 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, 10, and 15 mg/ kg every 8 hours ( TABLE 3 ).
TABLE 3    Acyclovir Pharmacokinetics in Pediatric Patients (Mean ±SD)
  Birth to 3 Months of Age 3 Months to 12 Years of Age
Parameter (n=12) (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

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 STUDIES
 

Herpes Simplex Infections in Immunocompromised Patients
  A multicenter trial of acyclovir for injection at a dose of 250 mg/ m2every 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 IV 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 (62) 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 (202) 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
  Treatment Group
  Acyclovir Vidarabine
HSV Disease Classification (n=107) (n=95)
SEM (n=85) 0/ 54 0/ 31
CNS (n=71) 5/ 35 5/ 36
DISS (n=46) 11/ 18 14/ 28
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.

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

Varicella-Zoster Infections in Immunocompromised Patients
  A multicenter trial of acyclovir for injection at a dose of 500 mg/ m2every 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.

INDICATIONS AND USAGE
 

Herpes Simplex Infections in Immunocompromised Patients
  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.

Initial Episodes of Herpes Genitalis
  Acyclovir for injection is indicated for the treatment of severe initial clinical episodes of herpes genitalis in immunocompetent patients.

Herpes Simplex Encephalitis
  Acyclovir for injection is indicated for the treatment of herpes simplex encephalitis.

Neonatal Herpes Simplex Virus Infection
  Acyclovir for injection is indicated for the treatment of neonatal herpes infections.

Varicella-Zoster Infections in Immunocompromised Patients
  Acyclovir for injection is indicated for the treatment of varicella- zoster (shingles) infections in immunocompromised patients.

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

WARNINGS
  Acyclovir for injection is intended for IV infusion only, and should not be administered topically, intramuscularly, orally, subcutaneously, or in the eye. IV infusions must be given over a period of at least 1 hour to reduce the risk of renal tubular damage (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).
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.

PRECAUTIONS
 

General
  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 IV infusion must be accompanied by adequate hydration.
When dosage adjustments are required, they should be based on estimated creatinine clearance (see DOSAGE AND ADMINISTRATION ).
Approximately 1% of patients receiving IV 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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
  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 CLINICAL PHARMACOLOGY, Pharmacokinetics ).
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 genetic toxicity assays. No evidence of mutagenicity was observed in 4 microbial assays. Acyclovir demonstrated mutagenic activity in 2 in vitro cytogenetic assays (1 mouse lymphoma cell line and human lymphocytes). No mutagenic activity was observed in 5 in vitro cytogenetic assays (3 Chinese hamster ovary cell lines and 2 mouse lymphoma cell lines).
A positive result was demonstrated in 1 of 2 in vitro cell transformation assays, and morphologically transformed cells obtained in this assay formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. No activity was demonstrated in another, possibly less sensitive, in vitro cell transformation assay.
Acyclovir caused chromosomal damage in Chinese hamsters at 31- 61 times human dose levels. In rats, acyclovir produced a nonsignificant increase in chromosomal damage at 5- 10 times human levels. No activity was observed in a dominant lethal study in mice at 3- 6 times human levels.
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- 2 times human levels. At higher doses (50 mg/ kg/ day, SC) in rats and rabbits (1- 2 and 1- 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- 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.

Pregnancy, Teratogenic Effects, Pregnancy Category B
  Acyclovir 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 approximates that found in the general population. However, the small size of the registry is 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.

Nursing Mothers
  Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6- 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.

Geriatric Use
  Clinical studies of acyclovir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased renal function, and of concomitant disease or other drug therapy.

Pediatric Use
  See DOSAGE AND ADMINISTRATION .

DRUG INTERACTIONS
  See CLINICAL PHARMACOLOGY, Pharmacokinetics .

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- 10% [the higher incidence occurred usually following rapid (less than 10 minutes) IV 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- 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 for 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, fever, headache, pain, peripheral edema.
Digestive: Diarrhea, gastrointestinal distress, nausea.
Cardiovascular: Hypotension.
Hematologic and Lymphatic: Disseminated intravascular coagulation, hemolysis, leukopenia, lymphadenopathy.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.
Musculoskeletal: Myalgia.
Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, delirium, dizziness, hallucinations, obtundation, paresthesia, psychosis, seizure, somnolence. 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 only in association with overdosage include agitations, coma, convulsions 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 ).

DOSAGE AND ADMINISTRATION
 
CAUTION: RAPID OR BOLUS IV 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
 

Herpes Simplex Infections
 

Mucosal and Cutaneous Herpes Simplex (HSV-1 and HSV-2) Infections in Immunocompromised Patients
 
Adults and Adolescents (12 years of age and older): 5 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 7 days.
Pediatrics (under 12 years of age): 10 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

Severe Initial Clinical Episodes of Herpes Genitalis
 
Adults and Adolescents (12 years of age and older): 5 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

Herpes Simplex Encephalitis
 
Adults and Adolescents (12 years of age and older): 10 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 10 days.
Pediatrics (3 months to 12 years of age): 20 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

Neonatal Herpes Simplex Virus Infections
 
Birth to 3 months: 10 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 10 days. In neonatal herpes simplex infections, doses of 15 or 20 mg/ kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

Varicella Zoster Infections
 

Zoster in Immunocompromised Patients
 
Adults and Adolescents (12 years of age and older): 10 mg/ kg infused at a constant rate over 1 hour, every 8 hours for 7 days.
Pediatrics (under 12 years of age): 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.

Patients With Acute or Chronic Renal Impairment
  Refer to DOSAGE AND ADMINISTRATION for recommended doses, and adjust the dosing interval as indicated in TABLE 5 .
TABLE 5    Dosage Adjustments for Patients With Renal Impairment
Creatinine Clearance Percent of Dosing Interval
(ml/ min/ 1.73 m2) Recommended Dose (hours)
>50 100% 8
25- 50 100% 12
10- 25 100% 24
0- 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.

Method of Preparation
  Each 10 ml vial contains acyclovir sodium equivalent to 500 mg of acyclovir. Each 20 ml vial contains acyclovir sodium equivalent to 1000 mg of acyclovir. The contents of the vial should be dissolved in sterile water for injection as described in TABLE 6 .
TABLE 6   
Contents of Vial Amount of Diluent
500 mg 10 ml
1000 mg 20 ml

The resulting solution in each case contains 50 mg acyclovir per ml (pH approximately 11). Shake the vial well to assure complete dissolution before measuring and transferring each individual dose. The reconstituted solution should be used within 12 hours. Refrigeration of reconstituted solution may result in the formation of a precipitate which will redissolve at room temperature.
DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING BENZYL ALCOHOL OR PARABENS.

Administration
  The calculated dose should then be removed and added to any appropriate IV 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 IV 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.

HOW SUPPLIED
  Zovirax is supplied in 10 ml sterile vials, each containing acyclovir sodium equivalent to 500 mg of acyclovir, and 20 ml sterile vials, each containing acyclovir sodium equivalent to 1000 mg of acyclovir.

Storage: Store at 15- 25°C (59- 77°F).

Administration Route:Oral

DESCRIPTION
  Zovirax is the brand name for acyclovir, a synthetic nucleoside analogue active against herpes viruses. Zovirax capsules, tablets, and suspension are formulations for oral administration.
Zovirax 200 mg capsule: Contains 200 mg of acyclovir and the inactive ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C blue no. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink.
Zovirax 400 mg tablet: Contains 400 mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Zovirax 800 mg tablet: Contains 800 mg of acyclovir and the inactive ingredients FD&C blue no. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Each teaspoonful (5 ml) of Zovirax suspension: Contains 200 mg of acyclovir and the inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives), carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol.

Acyclovir is a white, crystalline powder with the molecular formula C8 H11 N5 O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/ ml. The pka's of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2- amino- 1, 9- dihydro- 9- [(2- hydroxyethoxy)methyl]- 6 H - purin- 6- one.

CLINICAL PHARMACOLOGY
 

Virology
 

Mechanism of Antiviral Action
  Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo 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. In vitro, 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.

Antiviral Activities
  The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque- reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02- 13.5 μg/ ml for HSV- 1 and from 0.01- 9.9 μg/ ml for HSV- 2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12- 10.8 μg/ ml. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 μg/ ml.

Drug Resistance
  Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/ or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir- resistant mutants isolated thus far from immunocompromised patients have been found to be TK- deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK- negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Pharmacokinetics
  The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella- zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in TABLE 7 .
TABLE 7    Acyclovir Pharmacokinetic Characteristics
Parameter Range
Plasma protein binding 9- 33%
Plasma elimination half- life 2.5- 3.3 hours
Average oral bioavailability 10- 20%*
* Bioavailability decreases with increasing dose.

In one multiple- dose, crossover study in healthy subjects (n=23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in TABLE 8 . The decrease in bioavailability is a function of the dose and not the dosage form.
TABLE 8    Acyclovir Peak and Trough Concentrations at Steady State
Parameter 200 mg 400 mg 800 mg
CSSmax 0.83 μg/ ml 1.21 μg/ ml 1.61 μg/ ml
CSStrough 0.46 μg/ ml 0.63 μg/ ml 0.83 μg/ ml

There was no effect of food on the absorption of acyclovir (n=6); therefore, acyclovir capsules, tablets, and suspension may be administered with or without food.
The only known urinary metabolite is 9- [(carboxymethoxy)methyl]guanine.

Special Populations
 

Adults With Impaired Renal Function
  The half- life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION ).

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 ).

Pediatrics
  In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half- life after oral doses of 300 and 600 mg/ m2in pediatric patients ages 7 months to 7 years was 2.6 hours (range 1.59- 3.74 hours).

Drug Interactions
  Coadministration of probenecid with IV 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 STUDIES
 

Initial Genital Herpes
  Double- blind, placebo- controlled studies have demonstrated that orally administered acyclovir significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups.

Recurrent Genital Herpes
  Double- blind, placebo- controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered acyclovir given daily for 4 months to 10 years prevented or reduced the frequency and/ or severity of recurrences in greater than 95% of patients.
In a study of patients who received acyclovir 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3 month recurrence rates for the patients showed that 71- 87% were recurrence free in each quarter.

Herpes Zoster Infections
  In a double- blind, placebo- controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir (800 mg five times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation.
In a similar double- blind, placebo- controlled study, acyclovir (800 mg five times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain, reduced the duration of new lesion formation, and reduced the prevalence of localized zoster- associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours.
Adults greater than 50 years of age showed greater benefit.

Chickenpox
  Three randomized, double- blind, placebo- controlled trials were conducted in 993 pediatric patients ages 2- 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In two trials, acyclovir was administered at 20 mg/ kg four times daily (up to 3200 mg/ day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/ kg were administered 4 times daily for 5- 7 days. Treatment with acyclovir shortened the time to 50% healing, reduced the maximum number of lesions, reduced the median number of vesicles, decreased the median number of residual lesions on Day 28, and decreased the proportion of patients with fever, anorexia, and lethargy by Day 2. Treatment with acyclovir did not affect varicella- zoster virus- specific humoral or cellular immune responses at 1 month or 1 year following treatment.

INDICATIONS AND USAGE
 

Herpes Zoster Infections
  Acyclovir is indicated for the acute treatment of herpes zoster (shingles).

Genital Herpes
  Acyclovir is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.

Chickenpox
  Acyclovir is indicated for the treatment of chickenpox (varicella).

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

WARNINGS
  Acyclovir capsules, tablets, and suspension are 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.

PRECAUTIONS
  Dosage adjustment is recommended when administering acyclovir to patients with renal impairment (see DOSAGE AND ADMINISTRATION ). Caution should also be exercised when administering acyclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/ or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with IV acyclovir.

Information for the Patient
  Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered acyclovir, or they have any other questions.

Herpes Zoster
  There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

Genital Herpes Infections
  Patients should be informed that acyclovir is not a cure for genital herpes. There are no data evaluating whether acyclovir will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/ or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

Chickenpox
  Chickenpox in otherwise healthy children is usually a self- limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
  The data presented below include references to peak steady- state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY, Pharmacokinetics ).
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. Maximum plasma concentrations were 3- 6 times human levels in the mouse bioassay and 1- 2 times human levels in the rat bioassay.
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was postive 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 9- 18 times human levels, while in the rat study, they were 8- 15 times human levels. At higher doses (50 mg/ kg/ day, SC) in rats and rabbits (11- 22 and 16- 31 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 (21- 41 times human levels) or in dogs given 60 mg/ kg/ day orally for 1 year (6- 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

Pregnancy, Teratogenic Effects, Pregnancy Category B
  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 9 and 18, 16 and 106, and 11 and 22 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 approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable and 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.

Nursing Mothers
  Acyclovir concentrations have been documented in breast milk in 2 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.

Pediatric Use
  Safety and effectiveness of oral formulations of acyclovir in pediatric patients less than 2 years of age have not been established.

Geriatric Use
  Of 376 subjects who received acyclovir in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY ; ADVERSE REACTIONS, Observed During Clinical Practice ; and DOSAGE AND ADMINISTRATION ).

DRUG INTERACTIONS
  See CLINICAL PHARMACOLOGY, Pharmacokinetics .

ADVERSE REACTIONS
 

Herpes Simplex
 

Short-Term Administration
  The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/ or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/ or vomiting occurred in 2 of 287 (0.7%) patients who received placebo.

Long-Term Administration
  The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200 mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).

Herpes Zoster
  The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7- 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).

Chickenpox
  The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir at doses of 10- 20 mg/ kg four times daily for 5- 7 days or 800 mg four times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%).

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. 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, fever, headache, pain, peripheral edema.
Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS ).
Digestive: Diarrhea, gastrointestinal distress, nausea.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.
Musculoskeletal: Myalgia.
Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens- Johnson syndrome, toxic epidermal necrolysis, urticaria.
Special Senses: Visual abnormalities.
Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS ).

OVERDOSAGE
  Overdoses involving ingestion of up to 100 capsules (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 ).

DOSAGE AND ADMINISTRATION
 

Acute Treatment of Herpes Zoster
  800 mg every 4 hours orally, 5 times daily for 7- 10 days.

Genital Herpes
 

Treatment of Initial Genital Herpes
  200 mg every 4 hours, 5 times daily for 10 days.

Chronic Suppressive Therapy for Recurrent Disease
  400 mg two times daily for up to 12 months, followed by re- evaluation. Alternative regimens have included doses ranging from 200 mg three times daily to 200 mg five times daily.
The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient's genital herpes infection should be re- evaluated to assess the need for continuation of therapy with acyclovir.

Intermittent Therapy
  200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Treatment of Chickenpox
 

Children (2 years of age and older)
  20 mg/ kg per dose orally 4 times daily (80 mg/ kg/ day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox.

Adults and Children Over 40 kg
  800 mg 4 times daily for 5 days.
Intravenous acyclovir is indicated for the treatment of varicella- zoster infections in immunocompromised patients.
When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms.

Patients With Acute or Chronic Renal Impairment
  In patients with renal impairment, the dose of acyclovir capsules, tablets, or suspension should be modified as shown in TABLE 9 .
TABLE 9    Dosage Modification for Renal Impairment
  Creatinine Clearance Adjusted Dosage Regimen
Normal Dosage Regimen (ml/ min/ 1.73 m2) Dose Dosing Interval
200 mg every 4 hours >10 200 mg every 4 hours, 5× daily
200 mg every 4 hours 0- 10 200 mg every 12 hours
400 mg every 12 hours >10 400 mg every 12 hours
400 mg every 12 hours 0- 10 200 mg every 12 hours
800 mg every 4 hours >25 800 mg every 4 hours, 5× daily
800 mg every 4 hours 10- 25 800 mg every 8 hours
800 mg every 4 hours 0- 10 800 mg every 12 hours

Hemodialysis
  For patients who require hemodialysis, 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.

Bioequivalence of Dosage Forms
  Acyclovir suspension was shown to be bioequivalent to acyclovir capsules (n=20) and 1 acyclovir 800 mg tablet was shown to be bioequivalent to 4 acyclovir 200 mg capsules (n=24).

HOW SUPPLIED
 

Zovirax Capsules and Tablets
 
200 mg capsules: Blue with an opaque cap and body, containing 200 mg acyclovir and printed with “Wellcome ZOVIRAX 200”.
400 mg tablets: White, shield- shaped tablets, containing 400 mg acyclovir and engraved with “ZOVIRAX” on one side and a triangle on the other side.
800 mg tablets: Light blue, oval tablets containing 800 mg acyclovir and engraved with “ZOVIRAX 800”.


Storage: Store at 15- 25°C (59- 77°F) and protect from moisture.

Zovirax Suspension
  Zovirax suspension is an off- white, banana- flavored suspension containing 200 mg acyclovir in each teaspoonful (5 ml).

Storage: Store at 15- 25°C (59- 77°F).

Administration Route:Topical

DESCRIPTION
 
Acyclovir Cream: USE ONLY FOR COLD SORES.
Zovirax is the brand name for acyclovir, a synthetic nucleoside analogue active against herpes viruses. Zovirax cream 5% and ointment 5% are formulations for topical administration. Each gram of Zovirax cream 5% contains 50 mg of acyclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, water, and white petrolatum. Each gram of Zovirax ointment 5% contains 50 mg of acyclovir in a polyethylene glycol (PEG) base.
Acyclovir is a white, crystalline powder with the molecular formula C8 H11 N5 O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/ ml. The pka's of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2- amino- 1, 9- dihydro- 9- [(2- hydroxyethoxy)methyl]- 6 H - purin- 6- one.

CLINICAL PHARMACOLOGY
 

Acyclovir Cream and Ointment
 

Virology
 

Mechanism of Antiviral Action
  Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo 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. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This 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. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities
  The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque- reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 μg/ ml for HSV- 1 and from 0.01 to 9.9 μg/ ml for HSV- 2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 μg/ ml. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 μg/ ml.

Drug Resistance
  Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/ or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir- resistant mutants isolated thus far from immunocompromised patients have been found to be TK- deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK- negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Acyclovir Cream
 

Pharmacokinetics
 

Adults
  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 cm2on 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.

Pediatric Patients
  The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age.

Acyclovir Ointment
  Two clinical pharmacology studies were performed with acyclovir ointment 5% in immunocompromised adults at risk of developing mucocutaneous Herpes simplex virus infections or with localized varicella- zoster infections. These studies were designed to evaluate the dermal tolerance, systemic toxicity, and percutaneous absorption of acyclovir.
In 1 of these studies, which included 16 inpatients, the complete ointment or its vehicle were randomly administered in a dose of 1 cm strips (25 mg acyclovir) 4 times a day for 7 days to an intact skin surface area of 4.5 square inches. No local intolerance, systemic toxicity, or contact dermatitis were observed. In addition, no drug was detected in blood and urine by radioimmunoassay (sensitivity, 0.01 μg/ ml).
The other study included 11 patients with localized varicella- zoster infections. In this uncontrolled study, acyclovir was detected in the blood of 9 patients and in the urine of all patients tested. Acyclovir levels in plasma ranged from <0.01 to 0.28 μg/ ml in 8 patients with normal renal function, and from <0.01 to 0.78 μg/ ml in 1 patient with impaired renal function. Acyclovir excreted in the urine ranged from <0.02% to 9.4% of the daily dose. Therefore, systemic absorption of acyclovir after topical application is minimal.

CLINICAL STUDIES
 

Acyclovir Cream
 

Adults
  Acyclovir cream was evaluated in 2 double- blind, randomized, placebo (vehicle)- controlled trials for the treatment of recurrent herpes labialis. The average patient had 5 episodes of herpes labialis in the previous 12 months. In the first study, median age was 37 years (range 18- 81 years), 74% were female, and 94% were Caucasian. In the second study, median age was 38 years (range 18- 87 years), 73% were female, and 94% were Caucasian. Subjects were instructed to initiate treatment within 1 hour of noticing signs or symptoms and continue treatment for 4 days, with application of study medication 5 times per day. In both studies, the mean duration of the recurrent herpes labialis episode was approximately one- half day shorter in the subjects treated with acyclovir cream (n=682) compared with subjects treated with placebo (n=703) (approximately 4.5 days vs 5 days, respectively). No significant difference was observed between subjects receiving acyclovir cream or vehicle in the prevention of progression of cold sore lesions.

Pediatric Patients
  An open- label, uncontrolled trial with acyclovir cream 5% was conducted in 113 patients aged 12- 17 years with herpes labialis. In this study, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults.

Acyclovir Ointment
  In clinical trials of initial genital herpes infections, acyclovir ointment 5% has shown a decrease in healing time and, in some cases, a decrease in duration of viral shedding and duration of pain. In studies in immunocompromised patients mainly with herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain.
In studies of recurrent genital herpes and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit; there was some decrease in duration of viral shedding.

INDICATIONS AND USAGE
 

Acyclovir Cream
  Acyclovir cream is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and adolescents (12 years of age and older).

Acyclovir Ointment
  Acyclovir ointment 5% is indicated in the management of initial genital herpes and in limited non- life- threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients.

CONTRAINDICATIONS
 

Acyclovir Cream
  Acyclovir cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation.

Acyclovir Ointment
  Acyclovir ointment 5% is contraindicated in patients who develop hypersensitivity to the components of the formulation.

WARNINGS
 

Acyclovir Ointment
  Acyclovir ointment 5% is intended for cutaneous use only and should not be used in the eye.

PRECAUTIONS
 

General
 

Acyclovir Cream
  Acyclovir cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose. Acyclovir cream should only be used on herpes labialis on the affected external aspects of the lips and face. Because no data are available, application to human mucous membranes is not recommended. Acyclovir cream has a potential for irritation and contact sensitization (see ADVERSE REACTIONS ). The effect of acyclovir cream has not been established in immunocompromised patients.

Acyclovir Ointment
  The recommended dosage, frequency of applications, and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION ). There are no data to support the use of acyclovir ointment 5% to prevent transmission of infection to other persons or prevent recurrent infections when applied in the absence of signs and symptoms. Acyclovir ointment 5% should not be used for the prevention of recurrent HSV infections. Although clinically significant viral resistance associated with the use of acyclovir ointment 5% has not been observed, this possibility exists.

Information for the Patient
 

Acyclovir Cream
  Refer to the Patient Information that is included with the prescription.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
 

Acyclovir Cream and Ointment
  Systemic exposure following topical administration of acyclovir is minimal. Dermal carcinogenicity studies were not conducted. Results from the studies of carcinogenesis, mutagenesis, and fertility are not included in the full prescribing information for acyclovir cream 5% and ointment 5% due to the minimal exposures of acyclovir that result from dermal application. Information on these studies is available in the full prescribing information for acyclovir capsules, tablets, and suspension and acyclovir for injection .

Pregnancy, Teratogenic Effects, Pregnancy Category B
 

Acyclovir Cream and Ointment
  Acyclovir was not teratogenic in the mouse, rabbit, or rat at exposures greatly in excess of human exposure. There are no adequate and well- controlled studies of systemic acyclovir 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 approximates that found in the general population. However, the small size of the registry is 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. Systemic acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers
 

Acyclovir Cream and Ointment
  It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following topical administration is minimal. After oral administration of acyclovir, acyclovir concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/ kg/ day. Nursing mothers who have active herpetic lesions near or on the breast should avoid nursing.

Geriatric Use
 

Acyclovir Cream and Ointment
  Clinical studies of acyclovir cream and ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal (see CLINICAL PHARMACOLOGY ).

Pediatric Use
 

Acyclovir Cream and Ointment
  Safety and effectiveness in pediatric patients less than 12 years of age have not been established.

DRUG INTERACTIONS
  Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with acyclovir cream 5% and ointment 5%.

ADVERSE REACTIONS
 

Acyclovir Cream
  In 5 double- blind, placebo- controlled trials, 1124 patients were treated with acyclovir cream and 1161 with placebo (vehicle) cream. Acyclovir cream was well tolerated; 5% of patients on acyclovir cream and 4% of patients on placebo reported local application site reactions.
The most common adverse reactions at the site of topical application were dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin; each event occurred in less than 1% of patients receiving acyclovir cream and vehicle. Three (3) patients on acyclovir cream and 1 patient on placebo discontinued treatment due to an adverse event.
An additional study, enrolling 22 healthy adults, was conducted to evaluate the dermal tolerance of acyclovir cream compared with vehicle using single occluded and semi- occluded patch testing methodology. Both acyclovir cream and vehicle showed a high and cumulative irritation potential. Another study, enrolling 251 healthy adults, was conducted to evaluate the contact sensitization potential of acyclovir cream using repeat insult patch testing methodology. Of 202 evaluable subjects, possible cutaneous sensitization reactions were observed in the same 4 (2%) subjects with both acyclovir cream and vehicle, and these reactions to both acyclovir cream and vehicle were confirmed in 3 subjects upon rechallenge. The sensitizing ingredient(s) has not been identified.
The safety profile in patients 12- 17 years of age was similar to that observed in adults.

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 cream. 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 a combination of their seriousness, frequency of reporting, or potential causal connection to acyclovir cream.
General: Angioedema, anaphylaxis.
Skin: Contact dermatitis, eczema, application site reactions including signs and symptoms of inflammation.

Acyclovir Ointment
  In the controlled clinical trials, mild pain (including transient burning and stinging) was reported by about 30% of patients in both the active and placebo arms; treatment was discontinued in 2 of these patients. Local pruritus occurred in 4% of these patients. In all studies, there was no significant difference between the drug and placebo group in the rate or type of reported adverse reactions nor were there any differences in abnormal clinical laboratory findings.

Observed During Clinical Practice
  Based on clinical practice experience in patients treated with acyclovir ointment in the US, spontaneously reported adverse events are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as part of the underlying disease process. Voluntary reports of adverse events that have been received since market introduction include:
General: Edema and/ or pain at the application site.
Skin: Pruritus, rash.

OVERDOSAGE
 

Acyclovir Cream
  Overdosage by topical application of acyclovir cream is unlikely because of minimal systemic exposure (see CLINICAL PHARMACOLOGY ).

Acyclovir Ointment
  Overdosage by topical application of acyclovir ointment 5% is unlikely because of limited transcutaneous absorption (see CLINICAL PHARMACOLOGY ).

DOSAGE AND ADMINISTRATION
 

Acyclovir Cream
  Acyclovir cream should be applied 5 times per day for 4 days. Therapy should be initiated as early as possible following onset of signs and symptoms ( i.e., during the prodrome or when lesions appear). For adolescents 12 years of age and older, the dosage is the same as in adults.

Acyclovir Ointment
  Apply sufficient quantity to adequately cover all lesions every 3 hours, 6 times per day for 7 days. The dose size per application will vary depending upon the total lesion area but should approximate a one- half inch ribbon of ointment per 4 square inches of surface area. A finger cot or rubber glove should be used when applying acyclovir to prevent autoinoculation of other body sites and transmission of infection to other persons. Therapy should be initiated as early as possible following onset of signs and symptoms.

HOW SUPPLIED
 

Zovirax Cream
  Each gram of Zovirax cream 5% contains 50 mg acyclovir in an aqueous cream base. It is supplied in 2 g tubes.

Storage: Store at or below 25°C (77°F); excursions permitted to 15- 30°C (59- 86°F).

Zovirax Ointment
  Each gram of Zovirax ointment 5% contains 50 mg acyclovir in a polyethylene glycol base. It is supplied in 15 and 30 g tubes.

Storage: Store at 15- 25°C (59- 77°F) in a dry place.

PRODUCT IDENTIFICATION
  Acyclovir , tablet , 400 mg [ IVAX Corporation ]
Acyclovir , tablet , 800 mg [ IVAX Corporation ]
Acyclovir , tablet , 800 mg [ Watson Pharmaceuticals ]
Acyclovir , tablet , 800 mg [ Mylan Pharmaceuticals Inc ]
Acyclovir , tablet , 800 mg [ Mylan Pharmaceuticals Inc ]
Acyclovir , tablet , 800 mg [ Par Pharmaceutical Inc ]
Acyclovir , tablet , 800 mg [ Par Pharmaceutical Inc ]
Acyclovir , capsule , 200 mg [ Teva Pharmaceuticals USA ]
Acyclovir , tablet , 400 mg [ Novopharm USA Inc ]
Acyclovir , tablet , 400 mg [ Teva Pharmaceuticals USA ]
Acyclovir , tablet , 400 mg [ UDL Laboratories Inc ]
Acyclovir , tablet , 800 mg [ Teva Pharmaceuticals USA ]
Acyclovir , tablet , 800 mg [ UDL Laboratories Inc ]
Acyclovir , capsule , 200 mg [ Watson Pharmaceuticals ]
Acyclovir , capsule , 200 mg [ IVAX Corporation ]
Acyclovir , tablet , 400 mg [ GlaxoSmithKline ]

PATIENT DRUG CONSULT HANDOUT
  Acyclovir (all)

PRODUCT LISTING - RATED THERAPEUTICALLY EQUIVALENT
 
capsule - oral - 200 mg -
6.0 $12.00 Zovirax
Prescript Pharmaceuticals 		00247007506
10.0 $22.28 Zovirax
PD- RX Pharmaceuticals 		55289000610
10.0 $39.70 GENERIC
PD- RX Pharmaceuticals 		55289027310
20.0 $32.16 Zovirax
Prescript Pharmaceuticals 		00247007520
25.0 $12.03 GENERIC
PD- RX Pharmaceuticals 		55289027325
25.0 $17.48 GENERIC
Pharma Pac 		52959051725
25.0 $18.60 GENERIC
Direct Dispensing Inc 		57866695002
25.0 $37.20 Zovirax
Allscripts Healthcare Solutions 		54569009100
25.0 $39.38 Zovirax
Prescript Pharmaceuticals 		00247007525
25.0 $40.28 Zovirax
PD- RX Pharmaceuticals 		55289000625
25.0 $40.55 Zovirax
Physicians Total Care 		54868016302
25.0 $72.99 Zovirax
Pharma Pac 		52959033025
30.0 $20.10 GENERIC
Pharma Pac 		52959051730
30.0 $46.58 Zovirax
Prescript Pharmaceuticals 		00247007530
30.0 $48.42 Zovirax
Physicians Total Care 		54868016303
35.0 $14.22 GENERIC
PD- RX Pharmaceuticals 		55289027335
35.0 $21.00 GENERIC
Pharma Pac 		52959051735
35.0 $53.78 Zovirax
PD- RX Pharmaceuticals 		55289000635
35.0 $53.78 Zovirax
Prescript Pharmaceuticals 		00247007535
35.0 $55.77 Zovirax
Allscripts Healthcare Solutions 		54569009102
40.0 $60.99 Zovirax
Prescript Pharmaceuticals 		00247007540
40.0 $64.16 Zovirax
Physicians Total Care 		54868016306
42.0 $63.87 Zovirax
Prescript Pharmaceuticals 		00247007542
48.0 $72.51 Zovirax
Prescript Pharmaceuticals 		00247007548
50.0 $17.44 GENERIC
PD- RX Pharmaceuticals 		55289027350
50.0 $74.40 Zovirax
Allscripts Healthcare Solutions 		54569009101
50.0 $74.97 Zovirax
PD- RX Pharmaceuticals 		55289000650
50.0 $75.39 Zovirax
Prescript Pharmaceuticals 		00247007550
50.0 $79.90 Zovirax
Physicians Total Care 		54868016301
50.0 $82.12 GENERIC
Direct Dispensing Inc 		57866695003
50.0 $137.50 Zovirax
Pharma Pac 		52959033050
60.0 $89.80 Zovirax
Prescript Pharmaceuticals 		00247007560
100.0 $37.11 GENERIC
UDL Laboratories Inc 		51079087620
100.0 $97.20 GENERIC
Teva Pharmaceuticals USA 		00093894001
100.0 $97.70 GENERIC
Boscogen Inc 		62033020410
100.0 $97.70 GENERIC
Par Pharmaceutical Inc 		49884046001
100.0 $97.70 GENERIC
Stason Pharmaceuticals Inc 		60763204100
100.0 $106.36 GENERIC
Stada Pharmaceuticals Inc 		55370055707
100.0 $106.36 GENERIC
Ranbaxy Pharmaceuticals 		63304065201
100.0 $111.29 GENERIC
Roxane Laboratories Inc 		00054808025
100.0 $111.65 GENERIC
Stada Pharmaceuticals Inc 		67253010010
100.0 $111.67 GENERIC
Mylan Pharmaceuticals Inc 		00378220001
100.0 $111.67 GENERIC
Par Pharmaceutical Inc 		49884056501
100.0 $111.88 GENERIC
IVAX Corporation 		00182266689
100.0 $111.88 GENERIC
IVAX Corporation 		00172426660
100.0 $111.92 GENERIC
Purepac Pharmaceutical Company 		00228260511
100.0 $147.44 Zovirax
Prescript Pharmaceuticals 		00247007500
100.0 $148.79 Zovirax
GlaxoSmithKline 		00173099156
100.0 $149.85 Zovirax
Physicians Total Care 		54868016304
100.0 $159.18 Zovirax
GlaxoSmithKline 		00173099155
100.0 $260.00 Zovirax
Pharma Pac 		52959033000
120.0 $179.58 Zovirax
Physicians Total Care 		54868016305
400.0 $550.70 GENERIC
Boscogen Inc 		62033020414
400.0 $550.70 GENERIC
Stason Pharmaceuticals Inc 		60763204104
500.0 $142.47 GENERIC
Teva Pharmaceuticals USA 		00093894005
500.0 $464.08 GENERIC
ESI Lederle Generics 		59911583104
500.0 $505.20 GENERIC
Purepac Pharmaceutical Company 		00228260550
500.0 $505.25 GENERIC
Ranbaxy Pharmaceuticals 		63304065205
500.0 $530.46 GENERIC
Mylan Pharmaceuticals Inc 		00378220005
500.0 $530.68 GENERIC
IVAX Corporation 		00172426670
1000.0 $464.08 GENERIC
ESI Lederle Generics 		59911583102
1000.0 $977.00 GENERIC
Stada Pharmaceuticals Inc 		55370055709
1000.0 $1004.85 GENERIC
Stada Pharmaceuticals Inc 		67253010011
powder for injection - intravenous - 500 mg -
10.0 $100.00 GENERIC
Bedford Laboratories 		55390061210
10.0 $464.38 GENERIC
American Pharmaceutical Partners 		63323010510
10.0 $704.24 Zovirax
GlaxoSmithKline 		00173099501
powder for injection - intravenous - 1000 mg -
10.0 $200.00 GENERIC
Bedford Laboratories 		55390061320
10.0 $1202.14 Zovirax
GlaxoSmithKline 		00173095201
solution - intravenous - 50 mg/ ml -
10.0 ml $23.00 GENERIC
Bertek Pharmaceuticals Inc 		62794040131
10.0 ml x 10.0 $230.00 GENERIC
Bertek Pharmaceuticals Inc 		62794040197
20.0 ml $43.00 GENERIC
Bertek Pharmaceuticals Inc 		62794040331
20.0 ml x 10.0 $430.00 GENERIC
Bertek Pharmaceuticals Inc 		62794040397
suspension - oral - 200 mg/ 5 ml -
473.0 ml $118.55 GENERIC
Alpharma USPD 		00472008216
473.0 ml $138.49 Zovirax
GlaxoSmithKline 		00173095396
tablet - oral - 400 mg -
10.0's $8.70 GENERIC
PD- RX Pharmaceuticals 		55289046210
10.0's $20.99 GENERIC
Pharma Pac 		52959054410
12.0's $9.14 GENERIC
PD- RX Pharmaceuticals 		55289046212
12.0's $24.63 GENERIC
Pharma Pac 		52959054412
12.0's $37.53 Zovirax
PD- RX Pharmaceuticals 		55289069112
15.0's $11.43 GENERIC
PD- RX Pharmaceuticals 		55289046215
15.0's $30.15 GENERIC
Pharma Pac 		52959054415
15.0's $39.74 Zovirax
Prescript Pharmaceuticals 		00247033615
15.0's $45.91 Zovirax
Physicians Total Care 		54868302500
15.0's $57.27 Zovirax
PD- RX Pharmaceuticals 		55289069115
15.0's $245.94 Zovirax
Prescript Pharmaceuticals 		00247033600
20.0's $51.87 Zovirax
Prescript Pharmaceuticals 		00247033620
20.0's $58.84 Zovirax
Allscripts Healthcare Solutions 		54569419201
21.0's $40.90 GENERIC
Pharma Pac 		52959054421
21.0's $54.29 Zovirax
Prescript Pharmaceuticals 		00247033621
25.0's $16.50 GENERIC
PD- RX Pharmaceuticals 		55289046225
25.0's $48.14 GENERIC
Pharma Pac 		52959054425
25.0's $64.00 Zovirax
Prescript Pharmaceuticals 		00247033625
25.0's $70.97 Zovirax
PD- RX Pharmaceuticals 		55289069125
28.0's $71.28 Zovirax
Prescript Pharmaceuticals 		00247033628
30.0's $22.87 GENERIC
PD- RX Pharmaceuticals 		55289046230
30.0's $56.98 GENERIC
Pharma Pac 		52959054430
30.0's $76.13 Zovirax
Prescript Pharmaceuticals 		00247033630
30.0's $88.26 Zovirax
Allscripts Healthcare Solutions 		54569419200
50.0's $90.46 GENERIC
Pharma Pac 		52959054450
100.0's $36.88 GENERIC
Par Pharmaceutical Inc 		49884056601
100.0's $61.25 GENERIC
Teva Pharmaceuticals USA 		00093894301
100.0's $61.99 GENERIC
Watson Pharmaceuticals 		52544033501
100.0's $189.60 GENERIC
Carlsbad Technology Inc 		61442011201
100.0's $189.60 GENERIC
Mylan Pharmaceuticals Inc 		00378146401
100.0's $189.61 GENERIC
Par Pharmaceutical Inc 		49884048701
100.0's $194.40 GENERIC
UDL Laboratories Inc 		51079087720
100.0's $206.40 GENERIC
Stada Pharmaceuticals Inc 		55370055507
100.0's $216.70 GENERIC
Stada Pharmaceuticals Inc 		67253010110
100.0's $216.91 GENERIC
IVAX Corporation 		00182820089
100.0's $216.91 GENERIC
IVAX Corporation 		00172426760
100.0's $216.97 GENERIC
Ranbaxy Pharmaceuticals 		63304050401
100.0's $216.97 GENERIC
Purepac Pharmaceutical Company 		00228260611
100.0's $217.00 GENERIC
Pharma Pac 		52959054401
100.0's $217.00 GENERIC
Mylan Pharmaceuticals Inc 		00378025301
100.0's $308.90 Zovirax
GlaxoSmithKline 		00173094955
500.0's $92.38 GENERIC
IVAX Corporation 		00172426770
500.0's $895.85 GENERIC
Teva Pharmaceuticals USA 		00093894305
500.0's $900.65 GENERIC
ESI Lederle Generics 		59911316305
500.0's $915.00 GENERIC
Carlsbad Technology Inc 		61442011205
500.0's $942.65 GENERIC
Purepac Pharmaceutical Company 		00228260650
1000.0's $1895.00 GENERIC
Stada Pharmaceuticals Inc 		55370055509
1000.0's $1950.30 GENERIC
Stada Pharmaceuticals Inc 		67253010111
tablet - oral - 800 mg -
10.0's $49.99 Zovirax
Prescript Pharmaceuticals 		00247016910
15.0's $93.81 Zovirax
Physicians Total Care 		55289056415
20.0's $96.61 Zovirax
Prescript Pharmaceuticals 		00247016920
20.0's $123.03 Zovirax
Physicians Total Care 		55289056420
25.0's $147.60 Zovirax
Physicians Total Care 		54868218403
28.0's $133.92 Zovirax
Prescript Pharmaceuticals 		00247016928
30.0's $143.25 Zovirax
Prescript Pharmaceuticals 		00247016930
30.0's $167.12 Zovirax
Physicians Total Care 		54868218402
35.0's $166.55 Zovirax
Prescript Pharmaceuticals 		00247016935
48.0's $295.80 Zovirax
Physicians Total Care 		55289056448
50.0's $236.51 Zovirax
Prescript Pharmaceuticals 		00247016950
50.0's $277.75 Zovirax
Physicians Total Care 		54868218404
100.0's $72.50 GENERIC
Par Pharmaceutical Inc 		49884056701
100.0's $118.62 GENERIC
Ranbaxy Pharmaceuticals 		63304050501
100.0's $355.10 GENERIC
UDL Laboratories Inc 		51079087820
100.0's $366.65 GENERIC
Teva Pharmaceuticals USA 		00093894701
100.0's $368.65 GENERIC
Carlsbad Technology Inc 		61442011301
100.0's $368.68 GENERIC
Mylan Pharmaceuticals Inc 		00378146801
100.0's $368.70 GENERIC
Par Pharmaceutical Inc 		49884047401
100.0's $421.42 GENERIC
Stada Pharmaceuticals Inc 		67253010210
100.0's $421.42 GENERIC
Watson Pharmaceuticals 		52544033601
100.0's $421.60 GENERIC
IVAX Corporation 		00182266789
100.0's $421.60 GENERIC
IVAX Corporation 		00172426860
100.0's $421.67 GENERIC
Purepac Pharmaceutical Company 		00228260711
100.0's $421.70 GENERIC
Mylan Pharmaceuticals Inc 		00378030201
100.0's $535.88 Zovirax
Physicians Total Care 		54868218400
100.0's $630.69 Zovirax
GlaxoSmithKline 		00173094555
500.0's $1741.59 GENERIC
Teva Pharmaceuticals USA 		00093894705
500.0's $1751.33 GENERIC
ESI Lederle Generics 		59911316402
500.0's $1843.25 GENERIC
Carlsbad Technology Inc 		61442011305
500.0's $1854.25 GENERIC
Purepac Pharmaceutical Company 		00228260750
500.0's $2001.75 GENERIC
Stada Pharmaceuticals Inc 		67253010250

PRODUCT LISTING - RATED NOT THERAPEUTICALLY EQUIVALENT
 
tablet - oral - 400 mg -
35.0's $88.26 Zovirax
Prescript Pharmaceuticals 		00247033635

PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
 
capsule - oral - 200 mg -
15.0 $16.78 GENERIC
Allscripts Healthcare Solutions 		54569448202
25.0 $7.32 GENERIC
Physicians Total Care 		54868399600
25.0 $27.99 GENERIC
Allscripts Healthcare Solutions 		54569448200
30.0 $8.47 GENERIC
Physicians Total Care 		54868399602
35.0 $36.58 GENERIC
Allscripts Healthcare Solutions 		54569448203
40.0 $10.72 GENERIC
Physicians Total Care 		54868399601
50.0 $10.32 GENERIC
Physicians Total Care 		54868399603
50.0 $55.93 GENERIC
Allscripts Healthcare Solutions 		54569448201
100.0 $97.70 GENERIC
Watson Pharmaceuticals 		00364269201
cream - topical - 5% -
2.0 gm $35.28 Zovirax Topical
Biovail Pharmaceuticals Inc 		64455099442
5.0 gm $82.03 Zovirax Topical
Biovail Pharmaceuticals Inc 		64455099445
ointment - topical - 5% -
3.0 gm $26.51 Zovirax Topical
Biovail Pharmaceuticals Inc 		64455099341
3.0 gm $26.51 Zovirax Topical
Allscripts Healthcare Solutions 		54569204700
3.0 gm $27.56 Zovirax Topical
Physicians Total Care 		54868016502
15.0 gm $58.19 Zovirax Topical
Physicians Total Care 		54868016501
15.0 gm $68.91 Zovirax Topical
Prescript Pharmaceuticals 		00247003915
15.0 gm $81.91 Zovirax Topical
Allscripts Healthcare Solutions 		54569079200
15.0 gm $85.71 Zovirax Topical
Biovail Pharmaceuticals Inc 		64455099394
15.0 gm $85.71 Zovirax Topical
Biovail Pharmaceuticals Inc 		00173099394
powder for injection - intravenous - 500 mg -
10.0 $553.99 GENERIC
Allscripts Healthcare Solutions 		54569517300
solution - intravenous - 25 mg/ ml -
20.0 ml x 10.0 $490.04 GENERIC
Mayne Pharma Inc 		61703031121
40.0 ml x 10.0 $954.00 GENERIC
Mayne Pharma Inc 		61703031143
solution - intravenous - 50 mg/ ml -
10.0 ml x 10.0 $187.50 GENERIC
American Pharmaceutical Partners 		63323032510
20.0 ml x 10.0 $350.00 GENERIC
Astellas Pharma US, Inc 		63323032520
tablet - oral - 400 mg -
2.0's $4.34 GENERIC
Allscripts Healthcare Solutions 		54569476500
14.0's $30.37 GENERIC
Allscripts Healthcare Solutions 		54569476501
15.0's $30.58 GENERIC
Allscripts Healthcare Solutions 		54569476504
25.0's $54.22 GENERIC
Allscripts Healthcare Solutions 		54569476502
30.0's $14.97 GENERIC
Physicians Total Care 		54868699700
45.0's $61.16 GENERIC
Allscripts Healthcare Solutions 		54569476505
50.0's $108.45 GENERIC
Allscripts Healthcare Solutions 		54569476503
60.0's $130.03 GENERIC
Southwood Pharmaceuticals Inc 		58016011260
100.0's $216.72 GENERIC
Watson Pharmaceuticals 		00364268901
tablet - oral - 800 mg -
20.0's $80.27 GENERIC
Southwood Pharmaceuticals Inc 		58016062720
30.0's $30.71 GENERIC
Physicians Total Care 		54686399800
30.0's $120.41 GENERIC
Southwood Pharmaceuticals Inc 		58016062730
35.0's $147.58 GENERIC
Allscripts Healthcare Solutions 		54569472400
50.0's $28.97 GENERIC
Physicians Total Care 		54686399801
60.0's $240.82 GENERIC
Southwood Pharmaceuticals Inc 		58016062760
90.0's $361.23 GENERIC
Southwood Pharmaceuticals Inc 		58016062790
100.0's $368.65 GENERIC
Watson Pharmaceuticals 		00364269001
100.0's $401.37 GENERIC
Southwood Pharmaceuticals Inc 		58016062700
100.0's $421.42 GENERIC
Watson Pharmaceuticals 		00591033601

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