Herpevex 800mg Tablet: Aciclovir 800.00 mg.
Pharmacology: Pharmacodynamics: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) type I and II and varicella zoster virus (VZV). The inhibitory activity of aciclovir for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal uninfected cells does not use aciclovir effectively as a substrate, hence toxicity of mammalian host cells is low. However, TK encoded by HSV and VZV 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 DNS replication with resultant chain termination following its incorporation into the viral DNA.
Prolonged or repeated courses of aciclovir is severely immune-compromised individuals may result in the selective 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 isolate and clinical response to aciclovir therapy is not clear.
Pharmacokinetics: The absorption of Aciclovir from the gut is only partial. Following doses of 200 mg, 400 mg and 800 mg, administered four-hourly, the mean steady state peak plasma concentrations (CssMax) were 3.1 micromol (0.7 micrograms/ml), 5.3 micromol (1.2 micrograms/ml) and 8 micromol (1.8 micrograms/ml), respectively. Equivalent trough plasma levels (CssMin) were 1.8 micromol (0.4 micrograms/ml), 2.7 micromol (0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml), respectively.
The terminal plasma half life of aciclovir is about 2.9 hours after intravenous administration in adults. Tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug is indicated by the fact that renal clearance of aciclovir is substantially greater than creatinine clearance. Most of the drug is excreted unchanged. The only significant metabolite of aciclovir, 9 - carboxymethoxymethyl-guanine, accounts for approximately 10-15% of the administered dose recovered from the urine. The terminal half life of aciclovir and the area under the plasma concentration time curve is extended by 18% and 40%, respectively, when it is administered one hour after 1 gram of probenecid.
Following a one hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg in adults, the mean steady state peak plasma concentrations (Cssmax) were 22.7 microMol (5.1 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml), respectively. The corresponding trough levels (Cssmin), 7 hours later, were 2.2 microMol (0.5 micrograms/ml), 3.1 microMol (0.7 micrograms/ml), and 10.2 microMol (2.3 micrograms/ml), respectively.
When a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 for 10 mg/kg, in children over 1 year of age, similar mean peak (Cssmax) and trough (Cssmin) levels were observed. The Cssmax was found to be 61.2 microMol (13.8 micrograms/ml) and Cssmin to be 10.1 microMol (2.3 micrograms/ml) in neonates and young infants (0-3 months of age) treated every 8 hours with doses of 10mg/kg, administered by infusion over a one-hour period. The terminal plasma half life of aciclovir was 3.8 hours in these patients.
In the elderly, although there is little change in the terminal plasma half life, total body clearance falls with increasing age associated with decreases in creatinine clearance.
The mean terminal half life was found to be 19.5 hours in patients with chronic renal failure. During haemodialysis, the mean aciclovir half life was 5.7 hours with plasma aciclovir levels dropping approximately 60%.
Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.
Herpevex tablets are indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes.
Herpevex tablets are indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.
Herpevex tablets are indicated for the prophylaxis of herpes simplex infections in immunocompromised patients. Herpevex tablets are indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.
Ensure that patients on high doses of aciclovir are adequately hydrated.
Dosage in adults: Treatment of herpes simplex infections: 200 mg Herpevex should be taken five times daily at approximately four hourly intervals omitting the night time dose. Treatment should continue for 5 days, but in severe initial infections this may have to be extended.
In severe immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400 mg Herpevex 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.
Suppression of herpes infections in immunocompetent patients: 200 mg Herpevex should be taken four times daily at approximately six- hourly intervals.
Many patients may be conveniently managed on a regimen of 400 mg Herpevex twice daily at approximately twelve-hourly intervals.
Dosage titration down to 200 mg Herpevex 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 infection on total daily doses of 800 mg Herpevex.
Therapy should be interrupted periodically at intervals of six to twelve months, in order to observe possible chances in the natural history of the disease.
Prophylaxis of herpes simplex infections in immunocompromised patients: 200 mg Herpevex should be taken four times daily at approximately sixhourly intervals.
In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg Herpevex or alternatively, intravenous dosing could be considered.
The duration of prophylactic administration is determined by the duration of the period at risk.
Treatment of varicella and herpes zoster infections 800 mg Herpevex should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.
In severely, immunocompromised 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 of herpes zoster yields better results if initiated as soon as possible after the onset of the rash. Treatment of chickenpox in immunocompetent patients should begin within 24 hours after onset of the rash.
Dosage in the elderly: In the elderly, total aciclovir body clearance declines along with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of Herpevex 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 by intravenous infusion. However for patients with severe renal impairment (creatinine clearance less than 10 ml/ minute) an adjustment of dosage to 200 mg aciclovir twice daily at approximately twelve-hourly intervals is recommended.
In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800 mg aciclovir twice daily at approximately twelve - hourly intervals for patients with severe renal impairment (creatinine clearance less than 10 ml/ minute), and to 800 mg aciclovir three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 - 25 ml/ minute).
Route of administration: Oral.
Symptoms and signs: Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20g aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).
Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage.
Management: Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
Herpevex tablets are contra-indicated in patients known to be hypertensive to aciclovir or valaciclovir.
Hydration status: Care should be taken to maintain adequate hydration in patients receiving higher dose oral regimens e.g. for the treatment of herpes zoster infection (4g daily), in order to avoid the risk of possible renal toxicity.
The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man. Aciclovir was not found to be carcinogenic in long term studies in the rat and the mouse. 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 aciclovir on fertility.
The data currently available from clinical studies is not sufficient to conclude that treatment with Herpevex reduces the incidence of chickenpox-associated complications in immunocompetent patients.
A post- marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Herpevex. The birth defects described amongst Herpevex exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause.
Caution should however be exercised by balancing the potential benefits of treatment against any possible hazard.
Following oral administration of 200 mg Herpevex 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 0.3 mg/kg/day. Caution is therefore advised if Herpevex is to be administered to a nursing woman. Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice.
In a non-standard test in rats, foetal abnormalities were observed. But only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.
Gastrointestinal: nausea, vomiting, diarrhoea and abdominal pains have been reported.
Haematological: very rarely, anaemia, leukopenia and thrombocytopenia.
Hypersensitivity and skin: rashes including photosensitivity, urticaria, pruritis and rarely dyspnoea, angioedema and anaphylaxis.
Kidney: rare reports of increases in blood urea and creatinine. Acute renal failure has been reported on very rare occasions.
Liver: rare reports of reversible rises in bilirubin and liver related enzymes. Hepatitis and jaundice have been reported on very rare occasions.
Neurological: headaches. Occasionally, reversible neurological reactions, notably dizziness, confusional states, hallucinations, somnolence, convulsions and coma have been reported, usually in patients with renal impairment in whom the dosage was in excess of that recommended or with other predisposing factors.
Other: fatigue. Occasional reports of accelerated diffuse hair loss. 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.
No clinically significant interactions have been identified.
Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. Similarly increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppresant 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 aciclovir.
Store below 30°C, protected from light and humidity.
J05AB01 - aciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Tab 800 mg (white to off-white, oblong, scored on one side) x 3 x 12's.