CONTRAINDICATIONS: Aciclovir is contraindicated for patients who develop hypersensitivity to Aciclovir or Valaciclovir.

DESCRIPTION: Aciclovir is a synthetic nucleoside analogue active against herpes viruses. Tablet of Aciclovir contain 200 mg and 400 mg of Aciclovir.

VIROLOGY:

Mechanism of antiviral action:  Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).

Drug resistance: resistance of HSV and VZV to Aciclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase.

CLINICAL PHARMACOLOGY:

Pharmacokinetics: plasma protein binding: 9% to 33%, plasma elimination half-life: 2.5 to 3.3 h. Average oral bioavailability: 10% to 20% (Bioavailability decreases with increasing dose).  There was no effect of food on the absorption of Aciclovir.

Special populations: adults with impaired renal function: The half-life and total body clearance of Aciclovir are dependent on renal function.

Geriatrics: Aciclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function.

Clinical trials:

Initial genital herpes: Double-blind, placebo-controlled studies have demonstrated that orally administered Aciclovir 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: double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered Aciclovir given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients.

Herpes zoster infections: in a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, Aciclovir (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.

Chickenpox: three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients ages 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. Treatment with Aciclovir 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.

WARNINGS: Aciclovir tablets are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with Aciclovir therapy. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving Aciclovir therapy.

PRECAUTIONS: dosage adjustment is recommended when administering Aciclovir to patients with renal impairment. Caution should also be exercised when administering Aciclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous Aciclovir.

Information for Patients:  patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered Aciclovir or they have any other questions.

Herpes zoster: there are no data on treatment initiated more than 72 hours after onset of the zoster rash.

Genital herpes infections: patients should be informed that Aciclovir is not a cure for genital herpes.

Chickenpox: adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash.

Pregnancy: Pregnancy Category B.

Nursing Mothers:   Aciclovir should be administered to a nursing mother with caution and only when indicated.

Pediatric Use: safety and effectiveness of oral formulations of Aciclovir in pediatric patients less than 2 years of age have not been established.

Geriatric Use: elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events.

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

SIDE EFFECTS:

Herpes simplex:

Short term administration: the most frequent adverse events reported with Aciclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting.

Long term administration:  the most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg 2 times daily for 1 year were nausea (4.8%) and diarrhea (2.4%).

Herpes zoster:  the most frequent adverse event reported with 800 mg of oral Aciclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%).

Chickenpox:  the most frequent adverse event reported with oral Aciclovir at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days was diarrhea (3.2%).

Observed during clinical practice: in addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Aciclovir.

General:  anaphylaxis, angioedema, fever, headache, pain, peripheral edema.

Nervous: aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment.

Digestive: diarrhea, gastrointestinal distress, nausea.

Hematologic and lymphatic: anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.

Hepatobiliary tract and pancreas: elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.

Musculoskeletal: myalgia.

Skin: alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Special senses:  visual abnormalities.

Urogenital:  renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria.

OVERDOSAGE: overdoses involving ingestion of up to 20 g have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.

DOSAGE AND ADMINISTRATION:

Acute treatment of herpes zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.

Genital herpes:            

Treatment of initial genital herpes: 200 mg every 4 hours, 5 times daily for 10 days.

Chronic suppressive therapy for recurrent disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily.

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

Treatment of chickenpox:

Children (2 years of age and older):    20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox.

Adults and children over 40 kg:    800 mg 4 times daily for 5 days.

Patients with acute or chronic renal impairment:  in patients with renal impairment, the dose of Aciclovir should be modified as shown:

Table. Dosage Modification for Renal Impairment

Hemodialysis:  for patients who require hemodialysis, the mean plasma half-life of Aciclovir 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 supplemental dose appears to be necessary after adjustment of the dosing interval.

How Supplied: Each pack of Ruz-Aciclovir 200 mg or 400 mg tablets contain 30 tablets in 3 blisters.

storage: Store below 25°C, protect from moisture and light.

Reference: PDR 2000, page 1324-7

                  USPDI for Professional Health Care, 2004, Page 26-32

                  Martindale 2005, Page 626