Aciclovir
Oral Formulation
Tablets
PRESENTATIONS
Tablets:
Zovirax Tablets 200 mg are blue, shield shaped tablets. Branded ZOVIRAX on one face and a triangle on the other. May be slightly mottled.
Zovirax Tablets 400 mg are pink, shield shaped tablets. Branded ZOVIRAX 400 on one face and a triangle on the other. May be slightly mottled.
INDICATIONS
Zovirax Oral Formulations are indicated for the treatment of Herpes simplex virus infections of the skin and mucous membrane, including initial and recurrent genital herpes.
Zovirax Oral Formulations are indicated for the suppression (prevention of recurrences) of recurrent Herpes simplex infections in immune-competent patients. Zovirax Oral Formulations are indicated for the prophylaxis of Herpes simplex infections in immune-compromised patients.
Zovirax Oral Formulations are indicated for the treatment of Varicella (Chickenpox) and Herpes zoster (Shingles) infections.
DOSAGE AND ADMINISTRATION
Dosage for treatment of Herpes simplex in adults:
For treatment of Herpes simplex infections, 200mg Zovirax should be taken five times daily at approximately four-hourly intervals omitting the night time dose. Treatment should continue for five days but in severe initial infections may have to be extended.
In severely immune-compromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400mg or alternatively, intravenous dosing could be considered.
Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear.
Dosage for suppression of Herpes simplex in adults:
For suppression of Herpes simplex infections in immune-competent patients, 200mg Zovirax should be taken four times daily at approximately six-hourly intervals.
Many patients may conveniently managed on a regiment of 400mg Zovirax taken twice daily at approximately twelve-hourly intervals.
Dosage titration down to 200mg Zovirax taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals, may prove effective.
Some patients may experience break-through infections on total daily doses of 800mg Zovirax.
Therapy should be interrupted periodically at intervals of six to twelve months in order to observe possible changes in the natural history of the disease.
Dosage for prophylaxis of Herpes simplex in adults:
For prophylaxis of Herpes simplex infections in immune-compromised patients, 200mg Zovirax should be taken four times daily at approximately six-hourly intervals.
In severely immune-compromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400mg or, alternatively, intravenous dosing could be considered.
The duration of prophylactic administration is determined by the duration of the period at risk.
Dosage for treatment of Varicella and Herpes zoster in adults:
For treatment of Varicella and Herpes zoster infections, 800mg Zovirax should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.
In severely immune-compromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.
Dosing should begin as early as possible after the start of an infection; treatment yields better results if initiated as soon as possible after onset of the rash.
Dosage in children
For treatment of Herpes simplex infections, and for prophylaxis of Herpes simplex: infections in the immune-compromised, children aged two years and over should be given adult dosages and children below the age of two years should be given half the adult dose.
For treatment of Varicella infections, children over the age of six years can be given 800mg Zovirax four times daily and children between the ages of two and six years can be given 400mg Zovirax four times daily. Children below the age of two years can be given 200mg Zovirax four times daily. Dosing may be more accurately calculated as 20mg Zovirax/kg body weight (not exceed 800mg) four times daily. Treatment should continue for five days.
Therapy should be initiated at the earliest sign and symptoms.
No specific data are available on the suppression of Herpes simplex infections or the treatment of Herpes zoster infections in immune-competent children.
Dosage in the elderly
In the elderly, total aciclovir body clearance declines in parallel with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of Zovirax should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.
Dosage in renal impairment:
In the management of Herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of aciclovir above levels that have been established safe by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than l0 ml/minute) an adjustment of dosage to 200mg twice daily at approximately twelve-hourly intervals is recommended.
In the treatment of Varicella and Herpes zoster infections it is recommended to adjust the dosage to 800mg twice daily, at approximately twelve-hourly intervals, for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) and to 800mg three times daily, at intervals of approximately eight hours, for patients with moderate renal impairment (creatinine clearance in the range 10 to 25 ml/minute).
Mode of Action
Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including Herpes simplex virus (HSV) types 1 and 2, Varicella zoster virus (VZV), Epstein Barr virus (EBV) and Cytomegalo virus (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-l followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.
The inhibitory activity of aciclovir for HSV-l, HSV-2, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, non-infected cell does not use aciclovir effectively as a substrate, hence toxicity to mammalian host cells is low, however, TK encoded by HSV, VZV and EBV converts aciclovir to aciclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.
Prolonged or repeated courses of aciclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK: however, strains with altered viral TK or DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro-determined sensitivity of HSV isolates and clinical response to aciclovir therapy is not clear.
Pharmacokinetics
Aciclovir is only partially absorbed from the gut. Mean steady-state peak plasma concentrations (Css max) following doses of 200mg administered 4-hourly were 0.68 μg/ml and the equivalent through plasma levels (Css min) were 0.36 μg/ml). Corresponding steady-state plasma concentrations following doses of 800mg administered 4-hourly were 1.56 μg/ml and 0.79 μg/ml) respectively.
Most of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance indicating that tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug.
9-carboxymethoxymethylguanine is the only significant metabolite of aciclovir and accounts for 10-15 % of the total amount of the drug recovered in the urine. In patients with chronic renal failure, the mean terminal half life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels, dropped approximately 60 % during dialysis.
In the elderly, total body clearance falls with increasing age associated with decreases in creatinine-clearance, although there is little change in the terminal plasma half-life.
Contra-indications
Zovirax Tablets and Zovirax Suspensions are contraindicated in patients known to be hypersensitive to aciclovir or intolerance to the components of the formulation.
Precautions and Warnings
Mutagenicity:
The result of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.
Carcinogenicity:
Aciclovir was not carcinogenic in long term studies in the rat and the mouse.
Teratogenicity:
Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice.
Although aciclovir was not teratogenic in standard animal studies, the drugs potential for causing chromosome breaks at high concentration should be taken into consideration in making this determination.
Fertility:
Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of orally administered aciclovir on fertility. There is no experience of the effect of Zovirax on human female fertility. Zovirax have been shown to have no definitive effect upon sperm count, morphology or motility in man.
Pregnancy:
Limited data are available on the use of aciclovir in pregnancy. Aciclovir should not be used during pregnancy unless the potential benefit justifies the potential risk of the foetus.
Lactation:
Following oral administration of 200mg Zovirax five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.
Drug interactions
Probenecid increases the aciclovir mean half life and area under the plasma concentration-time curve. Other drugs affecting renal physiology could potentially influence the pharmacokinetics of aciclovir.
Adverse reactions
Skin rashes have been reported in a few patients receiving Zovirax Oral Formulations; the rashes have resolved on withdrawal of the drug. Gastrointestinal effects, including nausea, vomiting, diarrhoea and abdominal pains have been reported in some patients receiving Zovirax Oral Formulation. In double-blind, placebo-controlled trials the incidence of gastrointestinal events has not been found to differ between placebo and aciclovir recipients. Reversible neurological reactions, notably dizziness, confusional states, hallucinations and somnolence, have occasionally been reported, usually in patients with renal impairment or other predisposing factors.
Occasional reports of accelerated diffuse hair loss have been received. As this type of hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain.
Other events reported rarely in patients receiving oral formulations of Zovirax include mild, transient rises in bilirubin and liver-related enzymes, small increase in blood urea and creatinine, small decreases in haematological indices, headaches and fatigue.
Overdosage
Aciclovir is only partly absorbed in the gastrointestinal tract. It is unlikely that serious toxic effects would occur if a dose of up to 5g were taken on a single occasion. No data are available on the consequences of the ingestion of higher doses.
Treatment:
Ingestion of doses of aciclovir in excess of 5g warrants close observation of the patient. Aciclovir is dialysable by haemodialysis.
Storage Recommendations
Store below 25°C Keep dry.
Further information
All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesions are present.
HARUS DENGAN RESEP DOKTER
Packaging quantities
Zovirax Tablets 200mg, Box of 5 blisters of 5's,
Reg. No. DKI0282001310A1
Zovirax Tablets 400mg, Box of 7 blisters of 10's,
Reg. No. DKI0282001310B1
Manufactured and Packed by
GlaxoSmithKline Australia Pty Ltd
Boronia, Australia
Imported by
PT. Glaxo Wellcome Indonesia
Jakarta, Indonesia
0 Komentar
Penulisan markup di komentar