August 24, 2016
Recommended Topic Related To:

Zovirax

"The Food and Drug Administration (FDA) has approved the approval of Qutenza (capsaicin) 8% patch, a medicated skin patch that relieves the pain of post-herpetic neuralgia (PHN), a serious complication that can occur after a bout with shingles.

"...
A A A

Zovirax




CLINICAL PHARMACOLOGY

Action And Clinical Pharmacology

Mechanism Of Action

ZOVIRAX® (acyclovir), a synthetic acyclic purine nucleoside analog, is a substrate with a high degree of specificity for herpes simplex and varicella-zoster specified thymidine kinase. Acyclovir is a poor substrate for host cell-specified thymidine kinase. Herpes simplex and varicella-zoster specified thymidine kinase transform acyclovir to its monophosphate which is then transformed by a number of cellular enzymes to acyclovir diphosphate and acyclovir triphosphate. Acyclovir triphosphate is both an inhibitor of, and a substrate for, herpesvirus-specified DNA polymerase. Although the cellular α-DNA polymerase in infected cells may also be inhibited by acyclovir triphosphate, this occurs only at concentrations of acyclovir triphosphate which are higher than those which inhibit the herpesvirus-specified DNA polymerase. Acyclovir is selectively converted to its active form in herpesvirus-infected cells and is thus preferentially taken up by these cells. Acyclovir has demonstrated a very much lower toxic potential in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form; and 3) cellular α-DNA polymerase has a lower sensitivity to the action of the active form of the drug. A combination of the thymidine kinase specificity, inhibition of DNA polymerase and premature termination of DNA synthesis results in inhibition of herpes virus replication. No effect on latent non-replicating virus has been demonstrated. Inhibition of the virus reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing. During suppression there is no evidence that acyclovir prevents neural migration of the virus. It aborts episodes of recurrent herpes due to inhibition of viral replication following reactivation.

Pharmacokinetics

The pharmacokinetics of acyclovir after oral administration have been evaluated in 6 clinical studies involving 110 adult patients.

Absorption

In one study of 35 immunocompromised patients with herpes simplex or varicella-zoster infection given ZOVIRAX® Capsules in doses of 200 to 1,000 mg every 4 hours, 6 times daily for 5 days, the bioavailability was estimated to be 15 to 20%. In this study, steady-state plasma levels were reached by the second day of dosing. Mean steady-state peak and trough concentrations following the last 200 mg dose were 0.49 μg/mL (0.47 to 0.54 μg/mL) and 0.31 μg/mL (0.18 to 0.41 μg/mL), respectively and following the last 800 mg dose were 2.8 μg/mL (2.3 to 3.1 μg/mL) and 1.8 μg/mL (1.3 to 2.5 μg/mL). In another study, 20 immunocompetent patients with recurrent genital herpes simplex infections given ZOVIRAX® Capsules in dose of 800 mg every 6 hours, 4 times daily for 5 days, the mean steady-state peak and trough concentrations were 1.4 μg/mL (0.66 to 1.8 μg/mL) and 0.55 μg/mL (0.14 to 1.1 μg/mL).

In a multiple-dose crossover study where 23 volunteers received ZOVIRAX® as one 200 mg capsule, one 400 mg tablet and one 800 mg tablet 6 times daily, absorption decreased with increasing dose and the estimated bioavailabilities of acyclovir were 20, 15 and 10%, respectively. The decrease in bioavailability is believed to be a function of the dose and not the dosage form. It was demonstrated that acyclovir is not dose proportional over the dosing range 200 to 800 mg. In this study, steady-state peak and trough concentrations of acyclovir were 0.83 and 0.46 μg/mL, 1.21 and 0.63 μg/mL, and 1.61 and 0.83 μg/mL for the 200, 400 and 800 mg dosage regimens, respectively.

In another study in 6 volunteers, the influence of food on the absorption of acyclovir was not apparent.

A single oral dose bioavailability study in 23 normal volunteers showed that ZOVIRAX® Capsules 200 mg are bioequivalent to 200 mg acyclovir in aqueous solution. In a separate study in 20 volunteers, it was shown that ZOVIRAX® Suspension is bioequivalent to ZOVIRAX® Capsules. In a different single-dose bioavailability/ bioequivalence study in 24 volunteers, one ZOVIRAX® 800 mg Tablet was demonstrated to be bioequivalent to four ZOVIRAX® 200 mg Capsules.

Distribution

Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

Elimination

Following oral administration, the mean plasma half-life of acyclovir in volunteers and patients with normal renal function ranged from 2.5 to 3.3 hours. The mean renal excretion of unchanged drug accounts for 14.4% (8.6 to 19.8%) of the orally administered dose. The only urinary metabolite (identified by high performance liquid chromatography) is 9-[(carboxymethoxy)methyl]guanine.

Special Populations And Conditions

Pediatrics

In general, the pharmacokinetics of acyclovir in children is similar to adults. Mean half-life after oral doses of 300 and 600 mg/m², in children aged 7 months to 7 years, was 2.6 hours (range 1.59 to 3.74 hours).

Orally administered acyclovir in children less than 2 years of age has not yet been fully studied.

Geriatrics

In the elderly, total body clearance falls with increasing age, associated with decreases in creatinine clearance, although there is little change in the terminal plasma half-life. Dosage reduction may be required in geriatric patients with reduced renal function (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency

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).

Clinical Trials

Initial Genital Herpes

Double blind, placebo controlled studies have demonstrated that orally administered ZOVIRAX® 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

In a study of patients who received ZOVIRAX® 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 to 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, ZOVIRAX® (800 mg 5 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, ZOVIRAX® (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain, and reduced the duration of new lesion formation.

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 aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In two trials, ZOVIRAX® was administered at 20 mg/kg four times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered four times daily for 5 to 7 days. Treatment with ZOVIRAX® 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 ZOVIRAX® did not affect varicella zoster virus specific humoral or cellular immune responses at 1 month or 1 year following treatment.

Detailed Pharmacology

See Action And Clinical Pharmacology.

Virology

The quantitative relationship between the in vitro susceptibility of herpes simplex virus (HSV) and varicella-zoster viruses (VZV) to acyclovir and the clinical response to therapy has not been established in man, 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 (ID50), vary greatly depending upon the particular assay used, the cell type employed, and the laboratory performing the test. The ID50 of acyclovir against HSV-1 isolates may range from 0.02 μg/mL (plaque reduction in Vero cells) to 5.9-13.5 μg/mL (plaque reduction in green monkey kidney [GMK] cells). The ID50 against HSV-2 ranges from 0.01 to 9.9 μg/mL (plaque reduction in Vero and GMK cells, respectively).

Using a dye-uptake method in Vero cells, which gives ID50 values approximately 5 to 10-fold higher than plaque reduction assays, 1,417 HSV isolates (553 HSV-1 and 864 HSV-2) from approximately 500 patients were examined over a 5-year period. These assays found that 90% of HSV-1 isolates were sensitive to ≤ 0.9 μg/mL acyclovir and 50% of all isolates were sensitive to ≤ 0.2 μg/mL acyclovir. For HSV-2 isolates, 90% were sensitive to ≤ 2.2 μg/mL and 50% of all isolates were sensitive to ≤ 0.7 μg/mL of acyclovir. Isolates with significantly diminished sensitivity were found in 44 patients. It must be emphasized that neither the patients nor the isolates were randomly selected and, therefore, do not represent the general population. Most of the less sensitive HSV clinical isolates have been relatively deficient in the viral thymidine kinase (TK). Strains with alterations in viral TK or viral DNA polymerase have also been reported.

The ID50 against VZV ranges from 0.17-1.53 μg/mL (yield reduction, human foreskin fibroblasts) to 1.85-3.98 μg/mL (foci reduction, human embryo fibroblasts [HEF]). Reproduction of EBV genome is suppressed by 50% in superinfected Raji cells or P3HR-1 lymphoblastoid cells by 1.5 μg/mL acyclovir. Cytomegalovirus (CMV) is relatively resistant to acyclovir with ID50 values ranging from 2.3-17.6 μg/mL (plaque reduction, HEF cells) to 1.82-56.8 μg/mL (DNA hybridization, HEF cells). The latent state of the genome of any of the human herpesviruses is not known to be sensitive to acyclovir.

Resistance

Prolonged exposure of HSV to subinhibitory concentrations (0.1 μg/mL) of acyclovir in cell culture has resulted in the emergence of a variety of acyclovir-resistant strains. The emergence of resistant strains is believed to occur by “selection” of naturally occurring viruses with relatively low susceptibility to acyclovir. Such strains have been reported in pre-therapy isolates from several clinical studies.

Two resistance mechanisms involving viral thymidine kinase (required for acyclovir activation) have been described. These are: (a) selection of thymidine-kinase-deficient mutants that induce little or no enzyme activity after infection, and (b) selection of mutants possessing a thymidine kinase of altered substrate specificity that is able to phosphorylate the natural nucleoside thymidine but not acyclovir. The majority of less susceptible viruses arising in vitro are of the thymidine-kinase-deficient type which have reduced infectivity and pathogenicity and less likelihood of inducing latency in animals.

However, an acyclovir-resistant HSV infection in an immunosuppressed bone marrow transplant recipient on extended acyclovir therapy was found to be due to a clinical isolate which had a normal thymidine kinase but an altered DNA polymerase. This third mechanism of resistance involving herpes simplex virus DNA polymerase is due to the selection of mutants encoding an altered enzyme, which is resistant to inactivation by acyclovir triphosphate.

VZV appears to manifest resistance to acyclovir via mechanisms similar to those seen in HSV.

However, limited clinical investigation has revealed no evidence of a significant change in in vitro susceptibility of VZV with acyclovir therapy, although resistant mutants of this virus can be isolated in vitro in a manner analogous to HSV. Analysis of a small number of clinical isolates from patients who received oral acyclovir or placebo for acute herpes zoster suggests that in vivo emergence of resistant VZV may occur infrequently. Prolonged acyclovir treatment of highly immunocompromised patients with acquired immunodeficiency syndrome and severe VZV may lead to the appearance of resistant virus.

Cross-resistance to other antivirals occurs in vitro in acyclovir-resistant mutants. HSV mutants which are resistant to acyclovir due to an absence of viral thymidine kinase are cross-resistant to other agents which are phosphorylated by herpesvirus thymidine kinase, such as bromovinyldeoxyuridine, ganciclovir and the 2'-fluoropyrimidine nucleosides, such as, 2'-fluoro-5-iodoarabinosyl-cytosine (FIAC).

The clinical response to acyclovir treatment has usually been good for patients with normal immunity from whom HSV having reduced susceptibility to acyclovir has been recovered, either before, during or after therapy. However, certain patient groups, such as the severely immunocompromised (especially bone marrow transplant recipients) and those undergoing chronic suppressive regimens have been identified as being most frequently associated with the emergence of resistant herpes simplex strains, which may or may not accompany a poor response to the drug. The possibility of the appearance of less sensitive viruses must be recognized when treating such patients, and susceptibility monitoring of clinical isolates from these patients should be encouraged.

In summary, the quantitative relationship between the in vitro susceptibility of HSV and VZV to acyclovir and the clinical response to therapy has not been clearly established in man. Standardized methods of virus sensitivity testing are required to allow more precise correlations between in vitro virus sensitivity and clinical response to acyclovir therapy.

Toxicology

Acute Toxicity Studies

Adult Mice and Rats: The acute toxicity of oral acyclovir was determined as shown in Table 6.

Table 6 : Acute Toxicity Studies

Species Sex Route LD50 (mg/kg) 95% Conf. Level Signs
Mouse M Oral > 10 000 - None
Rat M Oral > 20 000 - None

Neonatal, Immature, and Adult Rats

Groups of 10 male and 10 female Charles River CD (Sprague-Dawley) rats were given single large doses (5 different dose levels) of a solution (pH 11.0) of acyclovir by subcutaneous injection when they were 3, 10, 28 and 71 days of age. They were observed for 14 days after treatment and LD50 values were calculated by the Litchfield and Wilcoxon method (see Table 7 below). This study was done to determine if age at exposure affects the acute toxicity of acyclovir; there was no evidence that young rats were more sensitive than older rats to the acute toxic effects of acyclovir.

Table 7 :LD50 in Rats

Age When Treated LD50 (mg/kg body weight)
Males Females
3 Days 1070 1281
10 Days 790 496
28 Days 678 750
71 Days 650 1 477

There was no apparent relationship between length of survival after treatment and age at which treatment was given. Clinical signs for the rats treated at 3 and 10 days of age included red and purple cutaneous blisters, blue areas, scabs, scars, necrotic and sloughed skin, open wounds, body tremors and alopecia. Decreased activity, lacrimation, closed eyelids, red-brown or brown material around the eyes, nose and mouth, ataxia, prostration, body tremors, urine stains around the abdomen or genital area, scabbed or necrotic areas and alopecia were observed in rats treated at 28 and 71 days of age.

Subchronic Oral Toxicity Study

Mice

Four groups each consisting of 28 male and 28 female Charles River CD-1 (ICR) mice were orally dosed by stomach tube for 33 days with suspensions of acyclovir. Daily dose levels were 0, 50, 150 and 450 mg/kg. Hematology and clinical chemistry measurements were made on an additional 8 male and 8 female mice per group (dosed in the same manner) after the first and fourth weeks of dosing and during the 3rd postdose week.

Plasma drug concentrations were measured in pooled samples from an additional 4 male and 4 female mice per group on dose days 1, 15 and 30.

Based on preliminary experiments with rats and mice, the high dose of 450 mg/kg was selected to produce the highest drug plasma levels attainable, in a practical manner, by oral dosing in a rodent species. Averaged drug plasma concentrations ranged from approximately 3.4 (at the low dose) to 11.0 (at the high dose) μg/mL of plasma one hour after oral dosing.

No changes in health, growth rate, hematology and clinical chemistry measurements occurred that could be definitely attributed to dosing with acyclovir. Gross and histopathologic examinations of 16 male and 16 female rats from the high-dose and control groups at the end of the dose period revealed nothing remarkable.

Chronic Toxicity Studies

Lifetime Oral Toxicity Study in Rats Given Acyclovir by Gastric Intubation

Charles River CD (Sprague-Dawley) rats were given suspensions of acyclovir by gavage. There were 50 male and 50 female rats at each of the following dose levels: 0, 50, 150 and 450 mg/kg. After 30 and 52 weeks of treatment, 10 male and 10 female rats from each group were necropsied. The remaining rats were dosed each day until natural mortality decreased a group size to approximately 20% of the number of animals of that sex present in the test groups when the study was started. All remaining rats were killed and necropsied when the 20% cut-off point was reached. This was during week 110 for the male rats and week 122 for the female rats. Tissues from control rats and those in the high-dose group were evaluated by light microscopy. Tissues from rats in the low and mid-dose groups having masses, nodules or unusual lesions were also examined by light microscopy. Fixed tissues from rats that were found dead during the first 52 weeks of the study were also evaluated by light microscopy.

No signs of toxicosis were observed. Plasma samples were collected 1.5 hours after dosing on days 7, 90, 209, 369, 771 (males only) and 852 (females only). Mean plasma levels found in high-dose males (450 mg/kg/day) at the times indicated above were as follows: 1.54, 1.63, 1.39, 1.60 and 1.70 μg/mL (6.84, 7.26, 6.17, 7.10 and 7.56 μM). Corresponding mean plasma levels for the high-dose females for the corresponding time periods were 1.76, 2.38, 2.12, 1.71 and 1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and 8.03 μM). Plasma levels in both males and females at all dose levels after one year of treatment were generally comparable to plasma levels obtained at earlier samplings. Values for laboratory tests including hematology, clinical chemistry and ophthalmoscopy were all within the normal range. There were no drug-induced gross or microscopic lesions and there was no evidence that acyclovir affected survival.

Lifetime Oral Carcinogenicity Study in Rats

There were no signs of toxicosis in Charles River CD (Sprague-Dawley) rats (100 rats/sex/dose group) given acyclovir by oral gavage at 50, 150 and 450 mg/kg in a lifetime oral carcinogenicity study. Mean plasma levels obtained in high-dose males 1.5 hours after dosing at various sampling times during the study were as follows: 1.54, 1.63, 1.39, 1.60 and 1.70 μg/mL (6.84, 7.26, 6.17, 7.10 and 7.56 μM) at days 7, 90, 209, 369 and 771, respectively. Corresponding mean values for the high-dose females were 1.76, 2.38, 2.12, 1.71 and 1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and 8.03 μM) at days 7, 90, 209, 369 and 852, respectively.

Values for clinical laboratory tests including hematology, clinical chemistry, urinalysis, body weight, food consumption and ophthalmoscopy were all within normal ranges. There were no drug-induced gross or microscopic lesions and there was no evidence that acyclovir affected survival, temporal patterns of tumor incidence or tumor counts for benign or malignant neoplasms.

Most of the relatively few rats found dead or moribund during the first 52 weeks of this study suffered dosing accidents as evidenced by postmortem findings of esophageal perforation causing pleural effusion, pneumonia, or mediastinitis.

Lifetime Oral Carcinogenicity Study in Mice

There were no signs of toxicosis in Charles River CD-1 (ICR) mice (115 mice/sex/dose group) given acyclovir by oral gavage at 50, 150 and 450 mg/kg/day in a lifetime oral carcinogenicity study. Mean plasma levels obtained in high-dose males 1.5 hours after dosing at various sampling times during the study were as follows: 2.83, 3.17 and 1.82 μg/mL (12.59, 14.10 and 8.10 μM) at days 90, 365 and 541, respectively. Corresponding mean values for the high-dose females were 9.81, 5.85 and 4.0 μg/mL (43.60, 26.0 and 17.79 μM).

Values for clinical laboratory tests including hematology, body weight and food consumption were all within normal ranges. There were no drug-induced gross or microscopic lesions. Female mice given 150 and 450 mg/kg acyclovir survived significantly longer than control female mice; survival of treated males was comparable to survival of control males. Patterns of tumor incidence and tumor counts for benign or malignant neoplasms were not affected by treatment with acyclovir.

Chronic 12-Month Oral Toxicity Study in Dogs

Purebred Beagle dogs were given 0, 15, 45 or 150 mg/kg/day of acyclovir each day for the first two weeks of a one-year study. There were 9 male and 9 female dogs in each test group. The dogs were given gelatin capsules that contained the appropriate dose. They were treated t.i.d., hence the dosages administered at each of three equally spaced dose periods were 0, 5, 15 and 50 mg/kg. The 45 and 150 mg/kg dose levels induced diarrhea, emesis, decreased food consumption and weight loss in both male and female dogs during the first two weeks of the study. For this reason, during the third week of the study the decision was made to decrease the mid- and high-dosage levels to 30 and 60 mg/kg/day (10 and 20 mg/kg t.i.d.). The low dose of 15 mg/kg/day (5 mg/kg t.i.d.) was unchanged. Dogs given 60 mg/kg/day occasionally vomited and occasionally had diarrhea but did well for the duration of the test, and values for body weight gain and food consumption were comparable to control values.

During the toxicosis induced by the larger doses of acyclovir, plasma levels of the drug were likely very high (as indicated by initial mean values of 24.0 μg/mL (106.6 μM) for high-dose males and 17.4 μg/mL (77.2 μM) for high-dose females when determined 1 hour after the third dose on day 1 of the study). When measured on day 15, plasma levels of acyclovir in high-dose dogs (150 mg/kg/day) were still very high but they decreased later when the dosages were decreased. Values for plasma levels after 12 months of treatment were generally comparable to values recorded after 1, 3 and 6 months of treatment. Thus, there was no indication of enhanced metabolism of acyclovir as a result of chronic treatment.

During the 13th week, some male and female dogs at both the mid- and high-dosage levels had the following signs: tenderness in forepaws, erosion of footpads, and breaking and loosening of nails. Regeneration of lost nails began a few weeks later. Nails regenerated by 6 months (when 3 males and 3 females from each group were killed for an interim sacrifice) and by the end of the study were of generally good quality. There were never any signs of an effect on paws or nails in dogs in the low dose group (15 mg/kg/day).

It is accepted that injury of the corial epithelium that produces nail keratin can result in arrested production of keratin and production of abnormal keratin. The transient toxicosis induced by the large doses (45 and 150 mg/kg/day) of acyclovir given during the first two weeks of the study may have affected the corial epithelium. If there was a transient effect on the corial epithelium (possibly related to direct effects or secondary to drug-induced illness during the first two weeks of the study) later loss of the nail could be a sequella. No discernible effects upon other keratin-producing or keratin-containing tissues were observed. It should be emphasized that the alterations in the nails appeared to be related to the transient toxicosis induced by dose levels of 50 and 150 mg/kg/day tested during the first two weeks of the study and not to the 30 and 60 mg/kg/day dose levels tested subsequently.

There were no important drug-induced alterations in values for serum biochemical tests, urinalyses and electrocardiographic tests done at appropriate intervals during this study. Values for serum albumin and total protein were slightly decreased in dogs treated at 30 and 60 mg/kg/day for 6 and 12 months. However, all values for these parameters remained within limits accepted as normal.

With the exception of residual alterations in old keratin at the tips of the claws, there were no signs of treatment-related effects in any of the tissues examined by light microscopy. Nor were there meaningful alterations in values for the organs weighed at necropsy. Thus, dose levels up to 60 mg/kg/day were well tolerated for one year. The “no dose effect” dose level of acyclovir was 15 mg/kg/day (5 mg/kg t.i.d.); however, the only adverse effects at 30 or 60 mg/kg/day were changes in nails and footpads (30 and 60 mg/kg/day) and mild gastrointestinal signs (60 mg/kg/day).

Reproduction Studies

Teratology – Rats

Acyclovir was administered to pregnant A.R.S. Sprague-Dawley female rats by subcutaneous injection during the period of organogenesis (day 6 through day 15 of gestation) at dose levels of 0.0, 6.0, 12.5 and 25.0 mg/kg body weight twice daily.

Criteria evaluated for compound effect included maternal body weights, weight gains, appearance and behaviour, survival rates, eye changes, pregnancy rates, and reproduction data. Offspring viability and development were also evaluated.

In addition to the above measurements, designated animals were sacrificed 1 hour after the first dose on day 15 in order to collect samples of maternal blood, amniotic fluid and fetuses for measurements of drug concentration. Mean values from these samples are listed in Table 8.

Table 8 : Acyclovir Concentrations in a Teratology Study in Rats

Dose mg/kg b.i.d., s.c. Plasma fag/mL) Acyclovir Concentrations
Amniotic Fluid fag/mL) Fetal Homogenate
μg/mL (nmoles/g wet wt)
6 N=7 0.26±0.09 0.39±0.06 0.70 (3.13±0.50)
12.5 N=5 0.69±0.20 1.13±0.22 0.96 (4.28±0.67)
25 N=5 1.59±0.55 2.0 ±0.53 1.95 (8.64±2.33)

The values obtained for plasma would represent about 30% of initial plasma levels as judged by the plasma half-life in rodents.

No effects attributable to the administration of acyclovir were noted in comparisons of maternal body weight values, appearance and behaviour, survival rates, pregnancy rates, or implantation efficiencies. In addition, no compound-related differences were noted in evaluations of fetal size, sex and development.

Although the incidences of resorption and fetal viability were within the range of normal variability in all of the groups, slightly greater incidences of resorptions were noted in the high-dose animals sacrificed on days 15 and 19 of gestation; however, clear dose-related trends did not eventuate.

Therefore, acyclovir was not considered teratogenic or embryotoxic when administered to rats at levels up to 50.0 mg/kg of body weight per day during organogenesis.

Teratology – Rabbits

A teratology study was done in New Zealand White rabbits using essentially the same experimental design as in the rat, except that dosing was from day 6 through day 18 of gestation. Also, collection of fetuses, amniotic fluid and samples of maternal blood occurred on day 18 rather than day 15.

No signs of maternal toxicity were observed at any dose, but there was a statistically significant (p < 0.05) lower implantation efficiency in the high-dose group. While there were a few terata observed in the study (in both control and treated animals), there was no apparent association with drug treatment. There was, however, an apparent dose-related response in the number of fetuses having supernumerary ribs. No similar effect was noted in the rat teratology study (see above) or in a reproduction-fertility experiment in mice.

Concentrations of acyclovir were detected in plasma and amniotic fluid samples, as well as in homogenates of fetal tissues. All samples were taken one hour after the first dose on day 18 of gestation. Drug concentrations in amniotic fluid were substantially higher than that of plasma (see Table 9).

Table 9 : Acyclovir Concentrations in a Teratology Study in Rabbits

Dose mg/kg b.i.d., s.c. Plasma fag/mL) Acyclovir Concentrations (Mean and S.E.)
Amniotic Fluid fag/mL) Fetal Homogenate
μg/mL (nmoles/g wet wt)
6 N=4 0.25±0.03 0.89±0.18 0.16 (0.69±0.13)
12.5 N=5 0.25±0.05 8.03±6.37 0.21 (0.92±0.14)
25 N=4 0.39±0.12* 6.16±4.25 0.32 (1.40±0.19)
*N=5

Reproduction – Fertility

Acyclovir was shown not to impair fertility or reproduction in groups of 15 male and 30 female mice in a two-generation fertility study. The mice in this study were given acyclovir by gastric intubation at dosage levels of 50, 150 and 450 mg/kg/day. Males were dosed for 64 consecutive days prior to mating and females for 21 days prior to mating.

In a rat fertility study where groups of 20 male and 20 female rats were given 0, 12.5, 25.0 and 50.0 mg/kg/day by subcutaneous injection, acyclovir was shown not to have an effect on mating or fertility. The males were dosed for 60 days prior to mating and until their mating schedule was completed. Female rats were dosed for 14 days prior to mating and until day 7 of pregnancy. At 50 mg/kg/day s.c. there was a statistically significant increase in post-implantation loss, but no concomitant decrease in litter size.

In 25 female rabbits treated subcutaneously with 50 mg/kg/day acyclovir on days 6 to 18 of gestation, there was a statistically significant decrease in implantation efficiency but no concomitant decrease in litter size. There was also a dose-related increase in the number of fetuses with supernumerary ribs in all drug-treated groups. This increase was not dose-related when the incidence of supernumerary ribs per litter was examined.

In 15 female rabbits treated intravenously with 50 mg/kg/day acyclovir on days 6 to 18 of gestation, there was no effect on either implantation efficiency or litter size.

In a rat peri- and postnatal study (20 female rats per group), acyclovir was given subcutaneously at 0, 12.5, 25 and 50 mg/kg/day from 17 days of gestation to 21 days postpartum. At 50 mg/kg/day s.c. there was a statistically significant decrease in the group mean numbers of corpora lutea, total implantation sites and live fetuses in the F1 generation. Although not statistically significant, there was also a dose-related decrease in group mean numbers of live fetuses and implantation sites at 12.5 mg/kg/day and 25 mg/kg/day s.c.

In a dose-range finding study with 5 female rabbits the intravenous administration of acyclovir at a dose of 100 mg/kg/day from days 6 to 8 of pregnancy, a dose known to cause obstructive nephropathy, caused a significant increase in fetal resorptions and a corresponding decrease in litter size. At a maximum tolerated intravenous dose of 50 mg/kg/day in rabbits there were no drug-related reproductive effects.

In a subchronic toxicity study where groups of 20 male and 20 female rats were given intraperitoneal doses of acyclovir at 0, 20, 80 or 320 mg/kg/day for one month, and followed for a one-month postdose period, there was testicular atrophy. Some histologic evidence of recovery of sperm production was evident 30 days postdose, but this was insufficient time to demonstrate full reversibility.

Groups of 25 male and 25 female rats were administered intraperitoneal doses of acyclovir at 0, 5, 20 or 80 mg/kg/day for 6 months. Ten male and 10 female rats in each group were continued undosed for 13 weeks. Testicular atrophy was limited to high-dose rats given 80 mg/kg/day for 6 months. Organ weight data and light microscopy defined full reversibility of the testicular atrophy by the end of the postdose recovery period.

In a 31-day dog study (16 males and 16 females per group) where acyclovir was administered intravenously at levels of 50, 100 and 200 mg/kg/day, testicles were normal in dogs at 50 mg/kg. Doses of 100 or 200 mg/kg/day caused death of some dogs due to cytostatic effects (bone marrow and gastrointestinal epithelium) and aspermic testes or testes with scattered aspermic tubules. It cannot be ruled out that the testicular change may have been primary, however, similar changes can be observed secondary to severe stress in moribund dogs.

Developmental Toxicity Studies

Neonatal Rats - Subchronic Study

Acyclovir dissolved in 0.4% sterile saline was given by subcutaneous injection to Charles River CD (Sprague-Dawley) neonatal rats for 19 consecutive days, beginning on the 3rd post-partum day. The dose levels tested were 0, 5, 20 and 80 mg/kg body weight. There were 12 litters (each consisting of 5 male and 5 female neonates nursing the natural dam) at each dose level. The dams were not treated. Neonates were removed from each group for necropsy and microscopic evaluation of a wide variety of tissues, including eyes and multiple sections of brain, after they had been treated for 5, 12 or 19 days and after a 3-week postdose drug-free period (at which time they were 45 days of age). Hematologic (hemoglobin, packed cell volume, RBC, WBC and differential cell counts) and clinical chemistry (BUN) tests were done after 16 days of treatment and repeated 18 days after the last (19th) dose was given.

Blood was collected from some neonates 30 minutes after treatment on day 1, on day 9 and at the end of the dose period for the determination of concentrations of acyclovir in plasma. The largest concentration of acyclovir in plasma was 99.1 μg/mL (440.5 μM) found in pooled plasma collected from 6 female high-dose (80 mg/kg) neonates 30 minutes after the first dose was given. Treatment with acyclovir did not increase mortality in the neonatal period.

Rats in the low-dose group gained as much body weight as the respective control rats. Significant (p < 0.05) reductions in mean body weight values were observed in mid- and high-dose group male and female neonates during the treatment period. Rats in the high-dose group partially compensated by gaining significantly more body weight than the controls during the postdose recovery period. There was a minimal but significant increase in BUN for male (p < 0.01) and female (p < 0.05) neonates in the high-dose group on dose day 16. This finding may be of biological importance because there were minimal accumulations of nuclear debris in renal collecting ducts and loops of Henle in kidney sections taken from high-dose neonates after 19 days of treatment and examined by light microscopy. This was the only time period (and the kidney was the only organ) in which minimal effects on developing organ systems were detected. Thus, 5 mg/kg was clearly a no effect dose level and 20 mg/kg caused only minimal decreases in body weight gain.

Eye examinations and light microscopy did not reveal adverse effects on ocular development. It should be emphasized that there was no morphologic or functional evidence of adverse effects on developing brain or other portions of the central nervous system. Thus, acyclovir is distinctly different than cytosine arabinoside which was reported to produce prominent cerebellar and retinal dysplasia in neonatal rats.

Mutagenicity And Other Short-Term Studies

Acyclovir has been tested for mutagenic potential in a number of in vitro and in vivo systems:November 10, 2014 Page 27 of 38

Microbial

Acyclovir was tested for mutagenic activity in the Ames Salmonella plate assay; in a preincubation modification of the Ames assay; in the Rosenkrantz E. coli polA+/polA- DNA repair assay; and in the eukaryote S. cerevisiae, D-4. All studies were performed both in the presence and absence of exogenous mammalian metabolic activation. Acyclovir gave no positive responses in any of these systems.

The previous Salmonella studies were extended to extremely high concentrations in order to achieve toxicity. No positive effects were observed either in the presence or absence of exogenous mammalian metabolic activation, at concentrations of acyclovir up to 300 mg/plate or 80 mg/mL.

Mammalian Systems

Acyclovir was tested for mutagenic activity in cultured L5178Y mouse lymphoma cells, heterozygous at the thymidine kinase (TK) locus, by measuring the forward mutation rate to TK-deficiency (TK+/- → TK-/-; additional studies were performed at the HGPRT locus and at the Ouabain-resistance marker in these same cells. All studies were performed in the presence and in the absence of exogenous mammalian metabolic activation. The test compound was mutagenic at the TK locus at high concentrations (400 -2,400 μg/mL). (By comparison, the upper limit of acyclovir peak plasma levels following oral dosing of 200 mg q4h is 0.9 μg/mL). It was negative at the HGPRT locus and Ouabain-resistance marker. Identical results were obtained with and without metabolic activation.

Inconclusive results with no apparent dose-related response were obtained when acyclovir mutagenicity was studied at each of 3 loci (APRT, HGPRT and Ouabain-resistance) in Chinese hamster ovary (CHO) cells, both in the presence and absence of exogenous metabolic activation.

Acyclovir, at a concentration of 50 μg/mL (222 μM) for a 72-hour exposure, has been shown to cause a statistically significant increase in the incidence of morphologically-transformed foci resulting from treating BALB/C-3T3 cells in vitro in the absence of exogenous metabolic activation. The morphologically transformed foci have been shown to grow as tumours following transplantation into immunosuppressed, syngeneic, weanling mice. Tumour tissues were diagnosed as being either undifferentiated sarcomas or lymphosarcomas.

Acyclovir, at concentrations between 8 and 64 μg/mL for 18 hours' exposure, did not induce any morphologically-transformed foci among C3H/10T ½ cells treated in vitro in the absence of exogenous metabolic activation.

Acyclovir, at concentrations of 62.5 and 125 μg/mL for a 48-hour exposure, did not induce any chromosome aberrations in cultured human lymphocytes in the absence of exogenous metabolic activation. At higher concentrations, 250 and 500 μg/mL for 48 hours exposure, acyclovir caused a significant increase in the incidence of chromosome breakage. There was also a significant dose-related decrease in mitotic index with exposure to acyclovir.

Acyclovir, at doses of 25 and 50 mg/kg/day i.p. for 5 consecutive days, did not produce a dominant lethal effect in male BKA (CPLP) mice. Further, there was no evidence of a dominant lethal effect on Charles River CD-1 (ICR) male and female mice treated orally at dose levels of 50, 150 and 450 mg/kg/day as summarized for the Two Generation Reproduction/ Fertility Study.

Acyclovir, at single intraperitoneal doses of 25, 50 and 100 mg/kg, failed to induce chromosome aberrations in bone marrow cells of Chinese hamsters when examined 24 hours after dosing. At higher nephrotoxic doses (500 and 1,000 mg/kg), a blastogenic effect was seen. (An intraperitoneal dose of 500 mg/kg produces mean peak plasma levels in Chinese hamsters of 611 μg/mL (2.72 mM) which is 680 times higher than the upper limit of human peak plasma levels during oral dosing of 200 mg q4h).

Acyclovir, at single intravenous doses of 25, 50 and 100 mg/kg, failed to induce chromosome aberrations in bone marrow cells of male and female rats when examined at 6, 24 and 48 hours after treatment.

Thus, all these studies showed that acyclovir does not cause single-gene mutations but is capable of breaking chromosomes.

Immunotoxicology Studies

Acyclovir was subjected to a number of in vitro and in vivo immunological tests.

In two in vivo tests, lymphocyte-mediated cytotoxicity and neutrophil chemotaxis, acyclovir showed no inhibitory effects at concentrations as high as 135 μg/mL (600 μM). The compound inhibited rosette formation approximately 50% at 0.9 μg/mL (4 μM).

In four in vivo tests in mice which measured cell-mediated immunity (complement-dependent cellular cytotoxicity, complement-independent cellular cytotoxicity, delayed hypersensitivity and graft vs. host reaction) acyclovir showed no inhibitory effects at single doses up to 200 mg/kg given on day 2 after antigenic stimulation.

Four daily doses of 100 mg/kg/day had no significant effect on Jerne hemolysin plaques or circulating antibody on day 7 after antigenic stimulation. When the Jerne hemolysin plaques and antibody titers were examined four days after antigenic challenge and one day after the last drug dose, 100 mg/kg showed only a slight suppressive effect. However, 200 mg/kg produced some weight loss (-2.2 g), a moderate reduction in the number of Jerne hemolysin plaques (PFC/spleen were reduced to 33% of control, PFC/107 WBC to 46.5% of control). However, there was only a small reduction in the circulating hemagglutinin titer (from 8.3 to 6.5) and the circulating hemolysin titer (from 9.5 to 8.3) at 200 mg/kg.

In experiments in mice designed to test whether acyclovir would potentiate the immunosuppressive effect of azathioprine on antibody formation, it was found that the effects of the two drugs were no more than additive. Only the 200 mg/kg dose of acyclovir showed an increased suppression of antibody response when given in combination with azathioprine at doses above 25 mg/kg.

Studies were carried out to evaluate the influence of acyclovir in vitro on human lymphocyte function. Inhibitory effects on blastogenesis were seen only in assays examining peak concentrations of potent mitogens, phytohemagglutinin (PHA) and concanavalin A (Con A), and only at concentrations of drug above 50 μg/mL (222 μM) and were much less with monilia and tetanus toxoid antigens, where the blastogenic response is characteristically less vigorous. There was very little effect on cytotoxicity or LIF production except at concentrations of 200 μg/mL (890 μM) where there has already been demonstrated to be a direct cytotoxic effect. These inhibitory concentrations are far in excess of anticipated levels from doses selected for clinical application and over 1,000-fold higher than the concentration required to inhibit herpesvirus multiplication in vitro.

The effect of acyclovir on human cells was measured. A concentration of 11.2 - 22.5 μg/mL (50-100 μM) inhibits the division of fibroblasts to a variable extent, depending on the experimental design and the confluency of the monolayer. The magnitude of this effect was less than that caused by adenine arabinoside or human leukocyte interferon when these three antiviral agents were compared at clinically relevant concentrations. Acyclovir also inhibited thymidine incorporation by peripheral blood mononuclear cells stimulated by PHA or three different herpesvirus antigens. A linear dose-response curve was observed with these cells, and their proliferation was 50% inhibited by 22.5 μg/mL (100 μM) acyclovir. Inhibition was exerted on T-cell proliferation without apparent effect on the release of lymphokines or on monocyte function.

It should also be mentioned that there was no evidence of adverse effects on the immune system in the detailed subchronic and chronic animal tests covered earlier in this summary except at excessively high doses (50 to 100 mg/kg b.i.d.) in dogs where marked lymphoid hypoplasia occurred.

REFERENCES

1. Balfour HH, Jr., Kelly JM, Suarez CS, Heussner RC, Englund JA, Crane DD et al. Acyclovir treatment of varicella in otherwise healthy children. J Pediatr 1990; 116(4):633-639.

2. Balfour HH, Jr., Rotbart HA, Feldman S, Dunkle LM, Feder HM, Jr., Prober CG et al. Acyclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Acyclovir Varicella Study Group. J Pediatr 1992; 120(4 Pt 1):627-633.

3. Barry DW, Blum MR. Antiviral drugs: acyclovir, in Recent Advances in Clinical Pharmacology. Turner P, Shand DG (eds) Churchill Livingstone, Edinburgh 1983.

4. Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of five years experience with acyclovir. Pharmacological and Clinical Approaches to Herpesviruses and Virus Chemotherapy, Aiso, Japan, September 10-13 1984.

5. Barry DW, Nusinoff-Lehrman S, Ellis MN, Biron KK, Furman PA. Viral resistance, clinical experience. Scand J Infect Dis Suppl 1985; 47:155-164.

6. Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of five years experience with acyclovir. Proceedings of the International Symposium on Pharmacological and Clinical Approches to Herpes Viruses and Virus Chemotherapy, Elsever, Amsterdam 1985;269-270.

7. Biron KK, Elion GB. Effect of acyclovir combined with other antiherpetic agents on varicella zoster virus in vitro. Am J Med 1982; 73(1A):54-57.

8. Boelaert J, Schurgers M, Daneels R, Van Landuyt HW, Weatherley BC. Multiple dose pharmacokinetics of intravenous acyclovir in patients on continuous ambulatory peritoneal dialysis. J Antimicrob Chemother 1987; 20(1):69-76.

9. Bryson YJ, Dillon M, Lovett M, Acuna G, Taylor S, Cherry JD et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N Engl J Med 1983; 308(16):916-921.

10. Burns WH, Saral R, Santos GW, Laskin OL, Lietman PS, McLaren C et al. Isolation and characterisation of resistant Herpes simplex virus after acyclovir therapy. Lancet 1982; 1(8269):421-423.

11. Christophers J, Sutton RN. Characterisation of acyclovir-resistant and -sensitive clinical herpes simplex virus isolates from an immunocompromised patient. J Antimicrob Chemother 1987; 20(3):389-398.

12. Cole NL, Balfour HH, Jr. Varicella-Zoster virus does not become more resistant to acyclovir during therapy. J Infect Dis 1986; 153(3):605-608.

13. Collins P, Bauer DJ. The activity in vitro against herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral agent. J Antimicrob Chemother 1979; 5(4):431-436.

14. Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 1986; 18 Suppl B:103-112.

15. Collins P. Viral sensitivity following the introduction of acyclovir. Am J Med 1988; 85(2A):129-134.

16. Collins P, Larder BA, Oliver NM, Kemp S, Smith IW, Darby G. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir. J Gen Virol 1989; 70 ( Pt 2):375-382.

17. Crumpacker CS, Schnipper LE, Zaia JA, Levin MJ. Growth inhibition by acycloguanosine of herpesviruses isolated from human infections. Antimicrob Agents Chemother 1979; 15(5):642-645.

18. Crumpacker CS, Schnipper LE, Marlowe SI, Kowalsky PN, Hershey BJ, Levin MJ. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med 1982; 306(6):343-346.

19. Darby G, Inglis MM, Larder BA. Mechanisms of resistance to nucleoside analogue inhibitors of herpes simplex virus. 6th Int Congr Virol 1984;(Abstract #W34-5).

20. De Clercq E, Descamps J, Verhelst G, Walker RT, Jones AS, Torrence PF et al. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis 1980; 141(5):563-574.

21. De Clercq E. Comparative efficacy of antiherpes drugs in different cell lines. Antimicrob Agents Chemother 1982; 21(4):661-663.

22. Dekker C, Ellis MN, McLaren C, Hunter G, Rogers J, Barry DW. Virus resistance in clinical practice. J Antimicrob Chemother 1983; 12 Suppl B:137-152.

23. Douglas JM, Davis LG, Remington ML, Paulsen CA, Perrin EB, Goodman P et al. A double-blind, placebo-controlled trial to the effect of chronically administered oral acyclovir on sperm production in men with frequently recurrent genital herpes. J Infect Dis 1988 Mar; 157:588-93.

24. Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 1984; 310(24):1551-1556.

25. Dunkle LM, Arvin AM, Whitley RJ, Rotbart HA, Feder HM, Jr., Feldman S et al. A controlled trial of acyclovir for chickenpox in normal children. N Engl J Med 1991; 325(22):1539-1544.

26. Ellis MN, Keller PM, Martin JL, Strauss SE, Nusinoff-Lehrman S etal. Characterization of an HSV-2 clinical isolate containing an ACV-resistant mutant which produces a thymidine kinase with altered substrate specificity. Ninth Int Herpesvirus Workshop, Seattle, Washington, August 24-29 1984.

27. Ellis MN, Keller PM, Fyfe JA, Martin JL, Rooney JF, Straus SE et al. Clinical isolate of herpes simplex virus type 2 that induces a thymidine kinase with altered substrate specificity. Antimicrob Agents Chemother 1987; 31(7):1117-1125.

28. Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL, Scholl DR, Balfour HH, Jr. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med 1990; 112(6):416-422.

29. Erlich KS, Jacobson MA, Koehler JE, Follansbee SE, Drennan DP, Gooze L et al. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial. Ann Intern Med 1989; 110(9):710-713.

30. Erlich KS, Mills J, Chatis P, Mertz GJ, Busch DF, Follansbee SE et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 320(5):293-296.

31. Field HJ, Darby G, Wildy P. Isolation and characterization of acyclovir-resistant mutants of herpes simplex virus. J Gen Virol 1980; 49(1):115-124.

32. Field HJ. The problem of drug-induced resistance in viruses, in Problems of Antiviral Therapy. Stuart-Harris CH, Oxford J (Eds) Academic Press, London 1983.

33. Fyfe K. Recurrence patterns of genital herpes after cessation of more then 5 years of chronic acyclovir suppression. VIII Int Conf AIDS/III Std Wrld Cong 1992;(B240).

34. Huff JC, Bean B, Balfour HH, Jr., Laskin OL, Connor JD, Corey L et al. Therapy of herpes zoster with oral acyclovir. Am J Med 1988; 85(2A):84-89.

35. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr JW, Stanat SC et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990; 112(3):187-191.

36. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. The Acyclovir Study Group. JAMA 1991; 265(6):747-751.

37. Krasny HC, Liao SH, de Miranda P, Laskin OL, Whelton A, Lietman PS. Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. Am J Med 1982; 73(1A):202-204.

38. Kurtz T. Safety and efficacy of long-term suppressive cyclovir treatment of frequently recurring genital herpes: year 5 results. 30th Intersci Conf Antimicrob Agents Chemother 1990;270.

39. Laskin OL, Longstreth JA, Whelton A, Krasny HC, Keeney RE, Rocco L et al. Effect of renal failure on the pharmacokinetics of acyclovir. Am J Med 1982; 73(1A):197-201.

40. Lau RJ, Emery MG, Galinsky RE. Unexpected accumulation of acyclovir in breast milk with estimation of infant exposure. Obstet Gynecol 1987; 69(3 Pt 2):468-471.

41. Lehrman SN, Douglas JM, Corey L, Barry DW. Recurrent genital herpes and suppressive oral acyclovir therapy. Relation between clinical outcome and in-vitro drug sensitivity. Ann Intern Med 1986; 104(6):786-790.

42. Marlowe S, Douglas J, Corey L, Schnipper L, Crumpacker C. Sensitivity of HSV genital isolates after oral acyclovir. 24th Interscience Conf Antimicrob Ag Chemother, Washington, DC, October 8-10 1984.

43. Mattison HR, Reichman RC, Benedetti J, Bolgiano D, Davis LG, Bailey-Farchione A et al. Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes. Am J Med 1988; 85(2A):20-25.

44. McLaren C, Sibrack CD, Barry DW. Spectrum of sensitivity of acyclovir of herpes simplex virus clinical isolates. Am J Med 1982; 73(1A):376-379.

45. McLaren C, Ellis MN, Hunter GA. A colorimetric assay for the measurement of the sensitivity of herpes simplex viruses to antiviral agents. Antiviral Res 1983; 3(4):223-234.

46. McLaren C, Corey L, Dekket C, Barry DW. In vitro sensitivity to acyclovir in genital herpes simplex viruses from acyclovir-treated patients. J Infect Dis 1983; 148(5):868-875.

47. Mertz GJ, Critchlow CW, Benedetti J, Reichman RC, Dolin R, Connor J et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA 1984; 252(9):1147-1151.

48. Mertz GJ, Jones CC, Mills J, Fife KH, Lemon SM, Stapleton JT et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA 1988; 260(2):201-206.

49. Mertz GJ, Eron L, Kaufman R, Goldberg L, Raab B, Conant M et al. Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am J Med 1988; 85(2A):14-19.

50. Meyer LJ, de Miranda P, Sheth N, Spruance S. Acyclovir in human breast milk. Am J Obstet Gynecol 1988; 158(3 Pt 1):586-588.

51. Mindel A, Weller IV, Faherty A, Sutherland S, Hindley D, Fiddian AP et al. Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984; 2(8394):57-59.

52. Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in general practice. N Z Med J 1989; 102(863):93-95.

53. Naib ZM, Nahmias AJ, Josey WE, Zaki SA. Relation of cytohistopathology of genital herpesvirus infection to cervical anaplasia. Cancer Res 1973; 33(6):1452-1463.

54. Nilsen AE, Aasen T, Halsos AM, Kinge BR, Tjotta EA, Wikstrom K et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet 1982; 2(8298):571-573.

55. Nusinoff-Lehrman S, Hunter G, Rogers J, Corey L, Davis G. The in vitro acyclovir sensitivity of herpesvirus shed by patients receiving suppressive oral therapy. 24th Interscience Conf Antimicrob Ag Chemother, Washington, DC, October 8-10 1984;(Abstract #1015).

56. O'Brien JJ, Campoli-Richards DM. Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989; 37(3):233-309.

57. Pahwa S, Biron K, Lim W, Swenson P, Kaplan MH, Sadick N et al. Continuous varicella-zoster infection associated with acyclovir resistance in a child with AIDS. JAMA 1988; 260(19):2879-2882.

58. Parker AC, Craig JI, Collins P, Oliver N, Smith I. Acyclovir-resistant herpes simplex virus infection due to altered DNA polymerase. Lancet 1987; 2(8573):1461.

59. Parris DS, Harrington JE. Herpes simplex virus variants restraint to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 1982; 22(1):71-77.

60. Preblud SR, Arbeter AM, Proctor EA, Starr SE, Plotkin SA. Susceptibility of vaccine strains of varicella-zoster virus to antiviral compounds. Antimicrob Agents Chemother 1984; 25(4):417-421.

61. Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA 1984; 251(16):2103-2107.

62. Shah GM, Winer RL, Krasny HC. Acyclovir pharmacokinetics in a patient on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1986; 7(6):507-510.

63. Sibrack CD, Gutman LT, Wilfert CM, McLaren C, St Clair MH, Keller PM et al. Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeficient child. J Infect Dis 1982; 146(5):673-682.

64. Straus SE, Seidlin M, Takiff H, Jacobs D, Bowen D, Smith HA. Oral acyclovir to suppress recurring herpes simplex virus infections in immunodeficient patients. Ann Intern Med 1984; 100(4):522-524.

65. Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, DiGiovanna JJ et al. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984; 310(24):1545-1550.

66. Straus SE, Croen KD, Sawyer MH, Freifeld AG, Felser JM, Dale JK et al. Acyclovir suppression of frequently recurring genital herpes. Efficacy and diminishing need during successive years of treatment. JAMA 1988; 260(15):2227-2230.

67. Vinckier F, Boogaerts M, De Clerck D, De Clercq E. Chronic herpetic infection in an immunocompromised patient: report of a case. J Oral Maxillofac Surg 1987; 45(8):723-728.

68. Wade JC, Newton B, McLaren C, Flournoy N, Keeney RE, Meyers JD. Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial. Ann Intern Med 1982; 96(3):265-269.

69. Wade JC, McLaren C, Meyers JD. Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 1983; 148(6):1077-1082.

Last reviewed on RxList: 1/7/2016
This monograph has been modified to include the generic and brand name in many instances.

Zovirax - User Reviews

Zovirax User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Zovirax sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Sex & Relationships

Get tips to boost your love life.