Aciclovir 800 mg Tablet
(i) ROUTE OF ADMINISTRATION
Oral
DOSAGE AND ADMINISTRATION
TREATMENT
OF GENITAL HERPES
Initial therapy
200 mg every four hours, five times daily for 10 days
Chronic suppressive therapy
400 mg twice daily for upto 12 months
Intermittent therapy
200 mg five times daily for five days
TREATMENT
OF OTHER HERPES SIMPLEX INFECTIONS (IN HIV)
Adults
and children (two years and above): 200-400 mg five times daily
for 10-14 days.
Children below two years: Half the adult dose
TREATMENT
OF VARICELLA INFECTIONS
Adults
and children: 20 mg/kg (up to 800 mg) four times daily for
5 days
Children below two years: 200 mg four times daily for five days.
TREATMENT
OF HERPES ZOSTER INFECTIONS
Adults: 800 mg five times daily for seven days
(ii)
THERAPEUTIC/DIAGNOSTIC CLAIMS
Health 2000 Aciclovir 800 mg tablet is indicated for the treatment
of Herpes simplex virus infections of the skin and mucous membrane, including
initial and recurrent genital herpes, suppression of recurrent Herpes simplex
infections in immunocompetent patients; prophylaxis of Herpes simplex infection
in immunocompromised patients; varicella (chicken pox) and Herpes zoster (shingles)
infections; and management of severely immunocompromised, namely those with
HIV disease (CD4+ count < 200/cu.mm, including patients with AIDS or severe
ARC) or after bone marrow transplantation.
(iii)
DESCRIPTION OF DOSAGE FORM
Aciclovir is an antiviral drug. Aciclovir capsules and tablets are
formulations for oral administration.
(iv)
CONTRAINDICATIONS
Aciclovir is contraindicated for patients who develop hypersensitivity
or intolerance to the components of the formulations.
WARNINGS
AND PRECAUTIONS
Aciclovir
capsules and tablets are intended for oral ingestion only. Dosage adjustment
is recommended when administering Aciclovir to patients with renal impairment.
In patients with renal impairment, the dose of Aciclovir capsules or tablets
should be modified as shown:
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. 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.
Interaction:
Co-administration of probenecid with intravenous Aciclovir has been
shown to increase Aciclovir half-life and systemic exposure. Urinary excretion
and renal clearance were correspondingly reduced.
(v) SIDE EFFECTS
Gastrointestinal effects, including nausea, vomiting, diarrhoea and
abdominal pain have been reported in some patients.
(vi) TOXIC EFFECTS
MUTAGENIC
AND CARCINOGENIC EFFECTS
The data presented
below includes references to peak steady-state plasma Aciclovir concentrations
observed in humans treated with 800 mg given orally six times a day (dosing
appropriate for treatment of herpes zoster) or 200 mg given orally six times
a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations
in animal studies are expressed as multiples of human exposure to Aciclovir
at the higher and lower dosing schedules.
Aciclovir was tested in lifetime bioassays in rats and mice at single daily doses of upto 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did Aciclovir shorten the latency of tumors. Maximum plasma concentrations were three to six times human levels in the mouse bioassay and one to two times human levels in the rat bioassay.
Aciclovir was tested in 16 genetic toxicity assays. No evidence of mutagenicity was observed in four microbial assays. Aciclovir demonstrated mutagenic activity in two in-vitro cytogenetic assays (one mouse lymphoma cell line and human lymphocytes). No mutagenic activity was observed in five in vitro cytogenetic assays (three Chinese hamster ovary cell lines and two mouse lymphoma cell lines). A positive result was demonstrated in one of two in vitro cell transformation assays, and morphologically transformed cells obtained in this assay formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice. No mutagenic activity was demonstrated in another, possibly less sensitive, in-vitro cell transformation assay.
Aciclovir was clastogenic in Chinese hamsters at 380 to 760 times human dose levels. In rats, Aciclovir produced a non-significant increase in chromosomal damage at 62 to 125 times human levels. No activity was observed in a dominant lethal study in mice at 36 to 73 times human levels.
TERATOGENIC
EFFECTS
Pregnancy Category
B. Aciclovir was not teratogenic in the mouse (450 mg/kg/day, p.o.),
rabbit (50 mg/kg/day, s.c. and i.v.), or rat (50 mg/kg/day, s.c.). These exposures
resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively,
human levels. In a non-standard test, rats were given three s.c. doses of
100 mg/kg Aciclovir on gestation day 10, resulting in plasma levels 63 and
125 times human levels. In this test, there were fetal abnormalities, such
as head and tail anomalies, and maternal toxicity.
There are no adequate and well-controlled studies in pregnant women. A prospective, epidemiological registry of Aciclovir use during pregnancy has been ongoing since 1984. As of June 1996, outcomes of live births have been documented in 494 women exposed to systemic Aciclovir during the first trimester of pregnancy. 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 and definitive conclusions regarding the safety of Aciclovir in pregnant women and their developing fetuses. Aciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Aciclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats (25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels.
At higher doses (50 mg/kg/day, s.c.) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and postnatal study at 50 mg/kg/day, s.c., there was a statistically significant decrease in group mean numbers of corpea lutea, total implantation sites, and live fetuses. No testicular abnormalities were seen in dogs given 50 mg/kg/day, i.v. for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg/day orally for 1 year (six to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.
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