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Acyclovir (Transdermal)
Ointment Zovirax is an antiviral drug effective against herpes viruses. Zovirax Ointment 5% is a formulation for topical administration. Each gram of Zovirax Ointment 5% contains 50 mg of acyclovir in a polyethylene glycol (PEG) base. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl] guanine. Acyclovir is a white, crystalline powder with a molecular weight of 225
daltons, and a maximum solubility in water of 1.3 mg/ml.
Acyclovir is a synthetic acyclic p.r.n. nucleoside analogue with in vitro inhibitory activity against Herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella-zoster, Epstein-Barr and cytomegalovirus. In cell cultures, the inhibitory activity of acyclovir for Herpes simplex virus is highly selective. Cellular thymidine kinase does not effectively utilize acyclovir as a substrate. Herpes simplex virus-coded thymidine kinase, however, converts acyclovir into acyclovir monophosphate, a nucleotide. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication. Acyclovir triphosphate also inhibits cellular alpha-DNA polymerase but to a lesser degree. In vitro, acyclovir triphosphate can be incorporated into growing chains of DNA by viral DNA polymerase and to a much smaller extent by cellular alpha-DNA polymerase. When incorporation occurs, the DNA chain is terminated. Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpesvirus-infected cells. Thus, acyclovir is much less toxic in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form; 3) cellular alpha-DNA polymerase is less sensitive to the effects of the active form. The relationship between in vitro susceptibility of Herpes simplex virus to antiviral drugs and clinical response has not been established. The techniques and cell culture types used for determining in vitro susceptibility may influence the results obtained. Using a quantitative assay to determine the acyclovir concentration producing 50% inhibition of viral cytopathic effect (ID50), 28 HSV-1 clinical isolates has a mean ID50 of 0.17 mcg/ml and 32 HSV-2 clinical isolates had a mean ID50of 0.46 mcg/ml. Results from other studies using different assays have yielded mean ID50 values for clinical HSV-1 isolates of 0.018, 0.03 and 0.043 mcg/ml and for clinical HSV-2 isolates of 0.0027, 0.36 and 0.03 mcg/ml, respectively. Two clinical pharmacology studies were performed with acyclovir ointment 5% in adult immunocompromised patients, 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 one 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) four times a day for seven 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 mcg/ml). The other study included eleven patients with localized varicella-zoster. 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 mcg/ml in eight patients with normal renal function, and from <0.01 to 0.78 mcg/ml in one patient with impaired renal function. Acyclovir excreted in the urine ranged <0.02 to 9.4 percent of the daily dose. Therefore systemic absorption of acyclovir after topical application is minimal. Animal PHARMACOLOGY Topical treatment of guinea
pigs with 10% acyclovir
in polyethylene glycol ointment
for three weeks did not result in cutaneous
irritation or systemic toxicity.
Also, a wide variety of animal
tests by parenteral routes demonstrated that acyclovir
has a low order of toxicity.
Acyclovir ointment 5% is indicated in the management of initial herpes genitalis and in limited non-life threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients. In clinical trials of initial herpes genitalis. 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 with mainly herpes labialis, there was a decrease in duration of viral shedding and a slight decrease in duration of pain. By contrast, in studies of recurrent herpes genitalis and of herpes labialis in nonimmunocompromised patients, there was no evidence of clinical benefit, there was some decrease in duration of viral shedding and a slight decrease in the duration of pain. Diagnosis Whereas cutaneous lesions associated with Herpes simplex infections are often characteristic, the finding of multinucleated giant cells in smears prepared from lesion exudate or scrapings may assist in the diagnosis. Positive cultures for herpes simplex virus offer a reliable means for confirmations of the diagnosis. In genital herpes, appropriate examinations should be performed to rule out other sexually transmitted diseases.
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 other body sites and transmission
of infection to other persons.
Therapy should be initiated as early as possible following onset of
signs and symptoms.
Because ulcerated genital lesions are characteristically tender and sensitive to any contact or manipulation, patients may experience discomfort upon application of ointment. In the controlled trials, mild pain (including transient burning and stinging) was reported by 103 (28.3%) of 364 patients treated with acyclovir and by 115 (31.1%) of 370 patients treated with placebo; treatment was discontinued in 2 of these patients. Other local reactions among acyclovir-treated patients included pruritus in 15 (4.1%), rash in 1 (0.3%) and vulvitis in 1 (0.3%). Among the placebo-treated patients, pruritus was reported by 17 (4.6%) and rash by 1 (0.3%). 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 U.S., spontaneously reported adverse reactions are uncommon. Data are insufficient to support an estimate of their incidence or to establish causation. These events may also occur as proof of the underlying disease process. Voluntary reports of adverse events which have been received since market introduction include: General: edema and/or pain at the application site Skin: pruritus, rash
Clinical experience has
identified no interactions resulting from topical
or systemic administration
of other drugs concomitantly with acyclovir
ointment 5%.
Acyclovir ointment is intended for cutaneous use only and should not be used in the eye.
General The recommended dosage, frequency of applications, and length of treatment should not be exceeded (see DOSAGE AND ADMINISTRATION.) There exist no data which demonstrate that the use of acyclovir ointment 5% will either 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. Carcinogenesis, Mutagenesis, and Impairment of Fertility Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of 50, 150 and 450 mg/kg/day given by gavage. These studies showed no statistically significant difference in the incidence of benign and malignant tumors produced in drug-treated as compared to control animals, nor did acyclovir induce the occurrence of tumors earlier in drug-treated animals as compared to control. In two in vitro cell transformation assays, used to provide preliminary assessment of potential oncogenicity in advance of these more definitive lifetime bioassays in rodents, conflicting results were obtained. Acyclovir was positive at the highest dose used in one system and the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. Acyclovir was negative in another transformation system. No chromosome damage was observed at maximum tolerated parenteral doses of 100 mg/kg acyclovir in rats or Chinese hamsters; higher doses of 500 and 1000 mg/kg were clastogenic in Chinese hamsters. In addition, no activity was found in a dominant lethal study in mice. In 9 of 11 microbial and mammalian cell assays, no evidence of mutagenicity was observed. In two mammalian cell assays (human lymphocytes and L5178Y mouse lymphoma cells in vitro), positive response for mutagenicity and chromosomal damage occurred, but only at concentrations at least 1000 times the plasma levels achieved in humans following topical application. Acyclovir does not impair fertility or reproduction in mice at oral doses up to 450 mg/kg/day or in rats at subcutaneous doses up to 25 mg/kg/day. In rabbits given a high dose of acyclovir (50 mg/kg/day SC), there was a statistically significant decrease in implantation efficiency. Pregnancy Teratogenic Effects: Pregnancy Category C: Acyclovir was not teratogenic in the mouse (450 mg/kg/day, P.O.), rabbit (50 mg/kg/day, S.C. and I.V.), or in standard tests in the rat (50 mg/kg/day S.C.). In a non-standard test in rats, fetal abnormalities, such as head and tail anomalies, were observed following subcutaneous administration of acyclovir at very high doses associated with toxicity to the maternal rat. The clinical relevance of these findings is uncertain. There are no adequate and well-controlled studies in pregnant women. Acyclovir should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether topically applied acyclovir is excreted in breast milk. After oral administration of acyclovir, concentrations have been documented in breast milk in two women and ranged from 0.6 to 4.1 times the corresponding plasma levels. Caution should be exercised when acyclovir ointment is administered to a nursing woman. Pediatric Use Safety and effectiveness
in children have not been established.
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