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Zovirax Oral (Acyclovir)
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Pharmacology
Information not available
Information not available
Indications
Antiviral Agent
Antiviral Agent
Contraindications
In patients who develop hypersensitivity or who are hypersensitive to the components of the acyclovir or valacyclovir formulations.
In patients who develop hypersensitivity or who are hypersensitive to the components of the acyclovir or valacyclovir formulations.
Safety Information / Warning
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.
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 the 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.
Care should be taken to maintain adequate hydration in patients receiving high doses of acyclovir.
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 24hours 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 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.
A postmarketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of acyclovir. The registry findings have not shown an increase in the number of birth defects amongst acyclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.
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 2years of age have not been adequately studied.
Drug Interactions : No clinically significant interactions have been identified.
Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine increase the area under the curve (AUC) of acyclovir by this mechanism, and reduce acyclovir renal clearance. Similarly, increases in plasma AUCs of acyclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of acyclovir.
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 the 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.
Care should be taken to maintain adequate hydration in patients receiving high doses of acyclovir.
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 24hours 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 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.
A postmarketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of acyclovir. The registry findings have not shown an increase in the number of birth defects amongst acyclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.
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 2years of age have not been adequately studied.
Drug Interactions : No clinically significant interactions have been identified.
Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine increase the area under the curve (AUC) of acyclovir by this mechanism, and reduce acyclovir renal clearance. Similarly, increases in plasma AUCs of acyclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of acyclovir.
Side Effects / Adverse Effects
Treatment of Herpes Simplex: Short-term administration (5to 10days): The most frequent adverse reactions reported during clinical trials of treatment of genital herpes with oral acyclovir in 298patients are listed in TableI.
Less frequent adverse reactions, each of which occurred in 1 of 298patient 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 400mg (two 200mg capsules) 2times daily are listed in TableII.
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 3clinical trials of treatment of herpes zoster (shingles) with 800mg of oral acyclovir 5times daily for 7or 10days or placebo were as shown in TableIII.
Chickenpox: The most frequent adverse events reported during 3clinical 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, 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 and peripheral edema.
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, gastrointestinal distress, nausea.
Hematological and Lymphatic: very rarely anemia, leukopenia, lymphadenopathy and thrombocytopenia.
Hypersensitivity and Skin: alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, rashes including photosensitivity, pruritus, urticaria, and rarely dyspnea, angioedema and anaphylaxis.
Liver: rare reports of reversible increases in bilirubin and liver related enzymes. Hepatitis and jaundice have been reported on very rare occasions.
Musculoskeletal: myalgia.
Special Senses: visual abnormalities.
Urogenital: elevated creatinine. Acute renal failure has been reported on very rare occasions.
Treatment of Herpes Simplex: Short-term administration (5to 10days): The most frequent adverse reactions reported during clinical trials of treatment of genital herpes with oral acyclovir in 298patients are listed in TableI.
Less frequent adverse reactions, each of which occurred in 1 of 298patient 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 400mg (two 200mg capsules) 2times daily are listed in TableII.
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 3clinical trials of treatment of herpes zoster (shingles) with 800mg of oral acyclovir 5times daily for 7or 10days or placebo were as shown in TableIII.
Chickenpox: The most frequent adverse events reported during 3clinical 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, 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 and peripheral edema.
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, gastrointestinal distress, nausea.
Hematological and Lymphatic: very rarely anemia, leukopenia, lymphadenopathy and thrombocytopenia.
Hypersensitivity and Skin: alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, rashes including photosensitivity, pruritus, urticaria, and rarely dyspnea, angioedema and anaphylaxis.
Liver: rare reports of reversible increases in bilirubin and liver related enzymes. Hepatitis and jaundice have been reported on very rare occasions.
Musculoskeletal: myalgia.
Special Senses: visual abnormalities.
Urogenital: elevated creatinine. Acute renal failure has been reported on very rare occasions.
Overdose
Symptoms and Treatment: Acyclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested up to 20 g acyclovir on a single occasion, with no unexpected adverse effects. In clinical studies, the highest plasma concentration observed in a single patient at these doses was 10 µg/mL.
I.V.doses administered to humans have been as high as 1200mg/m 2 (28mg/kg) 3times daily for up to 2weeks. Peak plasma concentrations have reached 80µg/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 (2.5mg/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.
Symptoms and Treatment: Acyclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested up to 20 g acyclovir on a single occasion, with no unexpected adverse effects. In clinical studies, the highest plasma concentration observed in a single patient at these doses was 10 µg/mL.
I.V.doses administered to humans have been as high as 1200mg/m 2 (28mg/kg) 3times daily for up to 2weeks. Peak plasma concentrations have reached 80µg/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 (2.5mg/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.
Recommended Dosage
Herpes Genitalis: Treatment of Initial Infection: 200mg every 4hours, 5times daily for a total of1g daily for 10days. Therapy should be initiated as early as possible following onset of signs and symptoms.
Suppressive Therapy for Recurrent Disease: The initial recommended dose is 200mg 3times daily. This can be increased if breakthrough occurs up to a dosage of200mg 5times daily. If necessary, a dose of400mg given twice daily may be considered. Periodic re-evaluation of the need for therapy is recommended.
Administration of acyclovir for intermittent therapy is 200mg every 4hours, 5times daily for 5days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.
Herpes Zoster: 800mg every 4hours, 5times daily for 7to 10days. Treatment should be initiated within 72hours of the onset of lesions. In clinical trials, the greatest benefit occurred when treatment was begun within 48hours of the onset of lesions.
Treatment of Chickenpox: 20mg/kg (not to exceed 800mg) orally, 4times daily for 5days. Therapy should be initiated within 24hours 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 TableV for genital herpes and herpes zoster indications.
Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5hours. 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.
Information for the Patient: See Blue Section--Information for the Patient “Zovirax Oral”.
Herpes Genitalis: Treatment of Initial Infection: 200mg every 4hours, 5times daily for a total of1g daily for 10days. Therapy should be initiated as early as possible following onset of signs and symptoms.
Suppressive Therapy for Recurrent Disease: The initial recommended dose is 200mg 3times daily. This can be increased if breakthrough occurs up to a dosage of200mg 5times daily. If necessary, a dose of400mg given twice daily may be considered. Periodic re-evaluation of the need for therapy is recommended.
Administration of acyclovir for intermittent therapy is 200mg every 4hours, 5times daily for 5days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.
Herpes Zoster: 800mg every 4hours, 5times daily for 7to 10days. Treatment should be initiated within 72hours of the onset of lesions. In clinical trials, the greatest benefit occurred when treatment was begun within 48hours of the onset of lesions.
Treatment of Chickenpox: 20mg/kg (not to exceed 800mg) orally, 4times daily for 5days. Therapy should be initiated within 24hours 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 TableV for genital herpes and herpes zoster indications.
Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5hours. 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.
Information for the Patient: See Blue Section--Information for the Patient “Zovirax Oral”.
Supplied / Packaging
Tablets: Zovirax 200: Each blue, shield-shaped, beveled-edge, compressed tablet, imprinted “ZOVIRAX” on one side and a triangle on the reverse contains: acyclovir 200mg. Nonmedicinal ingredients: cellulose, indigotine, lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of100and 250. Store between 15to 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 400mg. Nonmedicinal ingredients: cellulose, magnesium stearate, povidone, red iron oxide and sodium starch glycolate. Cartons of56 blister-packed tablets. Store between 15and25°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 800mg. Nonmedicinal ingredients: cellulose, indigotine, povidone, magnesium stearate and sodium starch glycolate. Cartons of50 blister-packed tablets. Store between 15and25°C. Keep dry and protect from light.
Suspension: Each 5mL of off-white, banana-flavored suspension contains: acyclovir 200mg. Nonmedicinal ingredients: banana flavor, cellulose, glycerin, methylparaben, propylparaben, sorbitol and vanillin. Bottles of125mL. Store between 15and25°C.
Tablets: Zovirax 200: Each blue, shield-shaped, beveled-edge, compressed tablet, imprinted “ZOVIRAX” on one side and a triangle on the reverse contains: acyclovir 200mg. Nonmedicinal ingredients: cellulose, indigotine, lactose, magnesium stearate, povidone and sodium starch glycolate. Bottles of100and 250. Store between 15to 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 400mg. Nonmedicinal ingredients: cellulose, magnesium stearate, povidone, red iron oxide and sodium starch glycolate. Cartons of56 blister-packed tablets. Store between 15and25°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 800mg. Nonmedicinal ingredients: cellulose, indigotine, povidone, magnesium stearate and sodium starch glycolate. Cartons of50 blister-packed tablets. Store between 15and25°C. Keep dry and protect from light.
Suspension: Each 5mL of off-white, banana-flavored suspension contains: acyclovir 200mg. Nonmedicinal ingredients: banana flavor, cellulose, glycerin, methylparaben, propylparaben, sorbitol and vanillin. Bottles of125mL. Store between 15and25°C.
