Zovirax Oral (Acyclovir)

ZOVIRAX® Oral

Glaxo Wellcome

Acyclovir

Antiviral Agent

Action And Clinical Pharmacology: See Zovirax Cream. During suppression therapy 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. 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 g/mL (0.47 to 0.54 g/mL) and 0.31 g/mL (0.18 to 0.41 g/mL), respectively and following the last 800 mg dose were 2.8 g/mL (2.3 to 3.1 g/mL) and 1.8 g/mL (1.3 to 2.5 g/mL). In another study, 20 immunocompetent patients with recurrent genital herpes simplex infections given Zovirax capsules in doses of 800 mg every 6 hours, 4 times daily for 5 days, the mean steady-state peak and trough concentrations were 1.4 g/mL (0.66 to 1.8 g/mL) and 0.55 g/mL (0.14 to 1.1 g/mL).

In general, the pharmacokinetics of acyclovir in children is similar to adults. Mean half-life after oral doses of 300 mg/mand 600 mg/m in children ages 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.

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, 1 Zovirax 800 mg tablet was demonstrated to be bioequivalent to 4 Zovirax 200 mg capsules.

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 mg to 800 mg. In this study, steady-state peak and trough concentrations of acyclovir were 0.83 and 0.46 g/mL, 1.21 and 0.63 g/mL, and 1.61 and 0.83 g/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.

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. 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).

Indications And Clinical Uses: Indicated for the following conditions:

The treatment of initial episodes of herpes genitalis.

The suppression of unusually frequent recurrences of herpes genitalis (6 or more episodes/year).

The acute treatment of herpes zoster (shingles) and varicella (chickenpox).

The results of clinical studies suggest that some patients with recurrent genital herpes may derive clinical benefit from the administration of oral acyclovir if taken at the first sign of an impending episode. Those most likely to benefit are patients who experience severe, prolonged recurrences; such intermittent therapy may be more appropriate than suppressive therapy when these recurrences are infrequent.

Early treatment of acute herpes zoster (shingles) in immune competent individuals with oral acyclovir resulted in decreased viral shedding; decreased time to healing; less dissemination; and alleviation of acute pain.

Treatment of varicella (chickenpox) in immune competent patients with oral acyclovir reduced the total number of lesions, accelerated the progression of lesions to the crusted and healed stages, and decreased the number of residual hypopigmented lesions. In addition it decreased fever and constitutional symptoms associated with chickenpox.

The prophylactic use of acyclovir in chickenpox has not been established.

Contra-Indications: For patients who develop hypersensitivity or who are hypersensitive to the components of the formulations (see Supplied).

Manufacturers’ Warnings In Clinical States: Suppressive therapy of herpes genitalis with acyclovir should be considered only for severely affected patients. Periodic evaluation of the need for continued suppressive therapy is recommended. In some patients, there is a tendency for the first recurrent episode to be more severe following cessation of suppressive therapy.

In severely immunocompromised patients, the physician should be aware that prolonged or repeated courses of acyclovir may result in selection of resistant viruses associated with infections which may not respond to continued acyclovir therapy.

Precautions: General: The recommended dosage and length of treatment should not be exceeded (see Dosage). Acyclovir has caused mutagenesis in some acute studies at high concentrations of drug. Also, decreased spermatogenesis was observed in some animals at high parenteral doses. However, no adverse effects on sperm counts were reported in humans given recommended oral doses of acyclovir.

The decision to prescribe a course of suppressive therapy should be weighed in the light of our present knowledge about the long-term effects of acyclovir and must clearly relate to the condition of the patient.

It is suggested that periodic discontinuation of the suppressive regimen occur so that the patient’s status and need for continued suppressive therapy can be monitored.

Whereas cutaneous lesions associated with herpes simplex infections are often pathognomonic, Tzanck smears prepared from lesion exudate or scrapings may assist in the diagnosis. Positive cultures for herpes simplex virus offer the only absolute means for confirmation of the diagnosis. Appropriate examinations should be performed to rule out other sexually transmitted diseases. All patients should be advised to take particular care to avoid potential transmission of virus if active lesions are present while they are on therapy.

Caution should be exercised when administering to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction.

Chickenpox: Although 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. It is unknown whether the treatment of chickenpox in childhood has any effect on long-term immunity. However, there is no evidence to indicate that acyclovir treatment of chickenpox would have any effect on either decreasing or increasing the incidence or severity of subsequent recurrences of herpes zoster (shingles) later in life.

Pregnancy: Teratology studies carried out to date in animals have been negative in general. However, in a non-standard test in rats, there were fetal abnormalities such as head and tail anomalies, and maternal toxicity; since such studies are not always predictive of human response, acyclovir should not be used during pregnancy unless the physician feels the potential benefit justifies the risk of possible harm to the fetus. The potential for high concentrations of acyclovir to cause chromosome breaks in vitro should be taken into consideration in making this decision.

Lactation: Acyclovir is excreted in human milk. Caution should therefore be exercised when it is administered to a nursing mother.

Children: Safety and effectiveness in children less than 2 years of age have not been adequately studied.

Drug Interactions: Co-administration of probenecid with i.v. acyclovir has been shown to increase the mean half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.

Adverse Reactions: Treatment of Herpes Simplex: Short-term administration (5 to 10 days): The most frequent adverse reactions reported during clinical trials of treatment of genital herpes with oral acyclovir in 298 patients are listed in Table I.

Less frequent adverse reactions, each of which occurred in 1 of 298 patient treatments (0.3%), included: diarrhea, dizziness, anorexia, fatigue, edema, skin rash, leg pain, inguinal adenopathy, medication taste, and sore throat.

Suppression: 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 are listed in Table II.

Evidence so far from clinical trials suggests that the severity and frequency of adverse events is unlikely to necessitate discontinuation of therapy.

Herpes Zoster: The most frequent adverse reactions reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 or 10 days or placebo were as shown in Table III.

Chickenpox: The most frequent adverse events reported during 3 clinical trials of treatment of chickenpox with oral acyclovir or placebo are listed in Table IV.

Observed During Clinical Practice: Based on clinical practice experience in patients treated with oral acyclovir in the U.S., 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 which have been received since market introduction include:

General: fever, headache, pain, peripheral edema, and rarely, anaphylaxis.

Nervous: confusion, dizziness, hallucinations, paresthesia, somnolence (these symptoms may be marked, particularly in older adults). In addition, convulsions have occasionally been reported, usually in patients with renal impairment in whom the dosage was in excess of that recommended, or with other predisposing factors.

Digestive: diarrhea, elevated liver function tests, gastrointestinal distress, nausea.

Hemic and Lymphatic: leukopenia, lymphadenopathy.

Musculoskeletal: myalgia.

Skin: alopecia, pruritus, rash, urticaria.

Special Senses: visual abnormalities.

Urogenital: elevated creatinine.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with acyclovir during oral use is unlikely because of incomplete bioavailability from the gastrointestinal tract. Doses as high as 800 mg 6 times daily for 5 days have been administered to humans without acute untoward effects. In clinical studies, the highest plasma concentration observed in a single patient at these doses was 10.0 g/mL.

I.V. doses administered to humans have been as high as 1 200 mg/m(28 mg/kg) 3 times daily for up to 2 weeks. Peak plasma concentrations have reached 80 g/mL. No acute massive overdosage of acyclovir has been reported; however, in the case of an excessively high ingestion of acyclovir, precipitation of acyclovir in renal tubules may occur if the solubility (2.5 mg/mL) in the intratubular fluid is exceeded. In the event of renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.

Dosage And Administration: Herpes Genitalis: Treatment of Initial Infection: 200 mg every 4 hours, 5 times daily for a total of 1 g daily for 10 days. Therapy should be initiated as early as possible following onset of signs and symptoms.

Suppressive Therapy for Recurrent Disease: The initial recommended dose is 200 mg 3 times daily. This can be increased if breakthrough occurs up to a dosage of 200 mg 5 times daily. If necessary, a dose of 400 mg given twice daily may be considered. Periodic re-evaluation of the need for therapy is recommended.

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

Herpes Zoster: 800 mg every 4 hours, 5 times daily for 7 to 10 days. Treatment should be initiated within 72 hours of the onset of lesions. In clinical trials, the greatest benefit occurred when treatment was begun within 48 hours of the onset of lesions.

Treatment of Chickenpox: 20 mg/kg (not to exceed 800 mg) orally, 4 times daily for 5 days. Therapy should be initiated within 24 hours of the appearance of rash.

Patients with Acute or Chronic Renal Impairment: Comprehensive pharmacokinetic studies have been completed following i.v. acyclovir infusions in patients with renal impairment.

Based on these studies, dosage adjustments are recommended in Table V for genital herpes and herpes zoster indications.

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 supplement dose appears to be necessary after adjustment of the dosing interval.

Availability And Storage: Tablets: Zovirax 200: Each blue, shield-shaped, beveled-edge, compressed tablet, imprinted ZOVIRAX on one side and a triangle on the reverse contains: acyclovir 200 mg. Nonmedicinal ingredients: cellulose, indigotine, lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of 100 and 250. Store between 15 to 25°C. Keep dry and protect from light.

Zovirax 400 Wellstat Pac: Each pink, shield-shaped, beveled-edge, compressed tablet, imprinted with “ZOVIRAX 400” on one side and a triangle on the reverse, contains: acyclovir 400 mg. Nonmedicinal ingredients: cellulose, magnesium stearate, povidone, red iron oxide and sodium starch glycolate. Cartons of 56 blister-packed tablets. Store between 15 and 25°C. Keep dry and protect from light.

Zovirax 800 Zostab Pac: Each blue, biconvex, elongated, scored, compressed tablet, imprinted with “ZOVIRAX 800” on one side, contains: acyclovir 800 mg. Nonmedicinal ingredients: cellulose, indigotine, povidone, magnesium stearate and sodium starch glycolate. Cartons of 50 blister-packed tablets. Store between 15 and 25°C. Keep dry and protect from light.

Suspension: Each 5 mL of off-white, banana-flavored suspension contains: acyclovir 200 mg. Nonmedicinal ingredients: banana flavor, cellulose, glycerin, methylparaben, propylparaben, sorbitol and vanillin. Bottles of 125 mL. Store between 15 and 25°C.

ZOVIRAX® Oral Glaxo Wellcome Acyclovir Antiviral Agent

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