acyclovir 200 MG per 5 ML Oral Suspension
WARNINGS
Acyclovir is intended for oral ingestion only.
Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS : Observed During Clinical Practice and OVERDOSAGE: ).
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.
DRUG INTERACTIONS
Drug Interactions: See CLINICAL PHARMACOLOGY : Pharmacokinetics.
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.
Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid.
Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored.
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 (see DOSAGE AND ADMINISTRATION ).
DESCRIPTION
Acyclovir is a synthetic nucleoside analogue active against herpesviruses.
Each teaspoonful (5 mL) of acyclovir oral suspension, USP, for oral administration, contains 200 mg of acyclovir and the inactive ingredients artificial banana flavor, carboxymethylcellulose sodium, glycerin, methylparaben 0.1% (added as a preservative), microcrystalline cellulose, propylparaben 0.02% (added as a preservative), purified water, and sorbitol.
Acyclovir is a white, crystalline powder with the molecular formula C 8 H 11 N 5 O 3 and a molecular weight of 225.
The maximum solubility in water at 37°C is 2.5 mg/mL.
The pka’s of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]- 6H-purin-6-one; it has the following structural formula: VIROLOGY: Mechanism of Antiviral Action: Acyclovir 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).
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV.
This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue.
The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes.
In vitro , acyclovir triphosphate stops replication of herpes viral DNA.
This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.
The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized.
Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC 50 ), vary greatly depending upon a number of factors.
Using plaque-reduction assays, the IC 50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2.
The IC 50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL.
Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC 50 of 1.35 mcg/mL.
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase.
Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection.
While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated.
TK-negative mutants may cause severe disease in infants and immunocompromised adults.
The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.
Acyclovir Structural Formula
HOW SUPPLIED
Acyclovir oral suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) Bottle of 1 pint (473 mL) – 68788-0715-4 Store at 20° – 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Manufactured by: Hi-Tech Pharmacal Co., Inc.
Amityville, NY 11701 Rev.
810:01 5/09 MG #19296
GERIATRIC USE
Geriatric use Of 376 subjects who received acyclovir in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over.
No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects.
The duration of pain after healing was longer in patients 65 and over.
Nausea, vomiting, and dizziness were reported more frequently in elderly subjects.
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.
With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS : Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION ).
INDICATIONS AND USAGE
Herpes Zoster Infections: Acyclovir oral suspension, USP is indicated for the acute treatment of herpes zoster (shingles).
Genital Herpes: Acyclovir oral suspension, USP is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.
Chickenpox: Acyclovir oral suspension, USP is indicated for the treatment of chickenpox (varicella).
PEDIATRIC USE
Pediatric use Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.
PREGNANCY
Pregnancy Teratogenic effects Pregnancy Category B.
Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC).
These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels.
There are no adequate and well-controlled studies in pregnant women.
A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999.
There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes.
The occurrence rate of birth defects approximates that found in the general population.
However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
Nursing mothers Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels.
These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day.
Acyclovir should be administered to a nursing mother with caution and only when indicated.
INFORMATION FOR PATIENTS
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 acyclovir, or they have any other questions.
Patients should be advised to maintain adequate hydration.
Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the zoster rash.
Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.
Genital Herpes Infections: Patients should be informed that acyclovir is not a cure for genital herpes.
There are no data evaluating whether acyclovir will prevent transmission of infection to others.
Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners.
Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding.
If medical management of genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.
Chickenpox: 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.
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.
The frequency and severity of episodes of untreated genital herpes may change over time.
After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with acyclovir oral suspension.
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 per 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.
Intravenous acyclovir oral suspension is indicated for the treatment of varicellazoster infections in immunocompromised patients.
When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox.
There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms.
Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of acyclovir oral suspension should be modified as shown in Table 3: Table 3: Dosage Modification for Renal Impairment Normal Dosage Regimen Creatinine Clearance (mL/min/1.73 m 2 ) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours > 10 0-10 200 200 every 4 hours, 5x daily every 12 hours 400 mg every 12 hours > 10 0-10 400 200 every 12 hours every 12 hours 800 mg every 4 hours > 25 10-25 0-10 800 800 800 every 4 hours, 5x daily every 8 hours every 12 hours 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 supplemental dose appears to be necessary after adjustment of the dosing interval.