Action And Clinical Pharmacology: 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 a-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; 3) cellular a-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 herpesvirus replication. No effect on latent nonreplicating 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. In 1 study of 35 immunocompromised patients with herpes simplex or varicella-zoster infection given acyclovir 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 acyclovir 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).
Indications And Clinical Uses: 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 per year); the acute treatment of herpes zoster (shingles).
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.
Contra-Indications: In patients who develop hypersensitivity or who are hypersensitive to the components of the formulation (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.
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 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.
Pregnancy: Teratology studies carried out to date in animals have been negative in general. However, in a nonstandard 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 acyclovir 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: Coadministration 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.
Evidence so far from clinical trials suggests that the severity and frequency of adverse events is unlikely to necessitate discontinuation of therapy.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage of 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 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 dose recommended 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 one 400 mg tablet (two 200 mg tablets) given twice daily may be considered. Periodic re-evaluation of the need for therapy is recommended.
Administration of acyclovir for intermittent therapy is one 200 mg tablet 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.
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 IV 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: 200 mg: Each blue, round, flat-faced, beveled-edged, compressed tablet, engraved “APO” over “200” on one side, contains: acyclovir 200 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose; coloring agent: indigotine lake. Bottles of 100, 250, 500 and 1 000.
400 mg: Each pink, round, flat-faced, beveled-edged, compressed tablet, engraved “APO” over “400” on one side, contains: acyclovir 400 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose; coloring agent: red ferric oxide. Bottles of 100, 250, 500 and 1 000. Unit dose packages of 56 and 100.
800 mg: Each blue, biconvex, oval, scored, compressed tablet, engraved “APO 800” on one side, contains acyclovir 800 mg. Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose; coloring agent: indigotine lake (Blue #2) and brilliant Blue FCF lake. Bottles of 100, 250 and 500. Unit dose packages of 50 and 100.
Store at controlled room temperature (20 to 25°C) in a dry place and protected from light.
APO®-ACYCLOVIR Apotex Acyclovir Antiviral Agent
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