ACICVIR
Acyclovir dispersible tablets 200mg, 400mg & 800mg
Presentation
Tablet- Dispersible: 200 mg
White, pentagonal flat bevelled edge tablet debossed "G" on one side and "AC 200" on the other side.
Tablet-Dispersible: 400 mg
White, pentagonal flat bevelled edge tablet debossed "G" on one side and "AC 400" on the other side.
Tablet-Dispersible: 800 mg
White, modified-rectangle, biconvex tablet debossed "G" on one side and "AC 800" on the other side.
Uses
Actions
Acyclovir 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 cytomegalovirus (CMV). In cell culture, acyclovir has the greatest anti viral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.
The inhibitory activity of acyclovir for HSV-1, HSV-2, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, non-infected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV converts acyclovir to acyclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Acyclovir 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 acyclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir 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 acyclovir 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 acyclovir is not clear.
Pharmacokinetics
Acyclovir is only partially absorbed from the gut. Mean steady-state peak plasma concentrations (Cssmax) following doses of 200mg administered four-hourly were 3.1 microMol (0.7 mcg/ml) and equivalent trough plasma levels (Cssmin) were 1.8 microMol (0.4 mcg/ml). Corresponding Cssmax levels following doses of 400mg and 800mg administered four-hourly were 5.3 microMol (1.2 mcg/ml) and 8 microMol (1.8 mcg/ml) respectively, and equivalent Cssmin levels were 2.7 microMol (0.6 mcg/ml) and 4 microMol (0.9 mcg/ml).
In adults the terminal plasma half-life of acyclovir after administration of intravenous acyclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of acyclovir is substantially greater than creatinine clearance, indicating that tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug. 9-Carboxymethoxy-methylguanine is the only significant metabolite of acyclovir and accounts for approximately 10-15% of the administered dose recovered from the urine. When acyclovir is given one hour after 1 gram of probenecid the terminal half-life and the area under the plasma concentration/time curve is extended by 18% and 40%, respectively.
In adults, mean Cssmax levels following a one-hour infusion of 2.5 mg/kg, 5mg/kg and 10 mg/kg were 22.7 microMol (5.1 mcg/ml), 43.6 microMol (9.8 mcg/ml) and 92 microMol (20.7 mcg/ml), respectively. The corresponding Cssmin levels 7 hours later were 2.2 microMol (0.5 mcg/ml), 3.1 microMol (0.7 mcg/ml), and 10.2 microMol (2.3 mcg/ml), respectively. In children over 1 year of age similar mean Cssmax and Cssmin levels were observed when a dose of 250mg/m2 was substituted for 5mg/kg and a dose of 500 mg/m2 was substituted for 10 mg/kg. In neonates and young infants (0-3 months of age) treated with doses of 10mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 microMol (13.8 mcg/ml) and the Cssmin to be 10.1 microMol (2.3 mcg/ml). The terminal plasma half-life in these patients was 3.8 hours. 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.
In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean acyclovir half-life during haemodialysis was 5.7 hours. Plasma acyclovir levels dropped approximately 60% during dialysis. 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.
Studies have shown no apparent changes in the pharmacokinetic behaviour of acyclovir or zidovudine when both are administered simultaneously to HIV-infected patients.
Indications
Acicvir is indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes.
Acicvir is indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immune-competent patients.
Acicvir is indicated for the prophylaxis of herpes simplex infections in immune-compromised patients.
Acicvir is indicated for the treatment of acute herpes zoster (shingles) infections; for the reduction of the duration and severity of acute symptoms and rash, for the reduction of all zoster-associated pain and for the reduction of the incidence and duration of post-herpetic neuralgia.
Acicvir is indicated for the management of patients with severe AIDS who have a CD4 count of less than 50/microL. Studies have shown that acyclovir given in conjunction with anti-retroviral therapy reduced mortality in patients with advanced HIV disease.
Acicvir preceded by one month's treatment with intravenous acyclovir is indicated for patients undergoing allogenic bone marrow transplantation who are at risk of developing CMV infection while immunosuppressed. Studies have shown that oral acyclovir reduced mortality in allogenic bone marrow transplant recipients. In addition oral acyclovir provided effective prophylaxis for herpes virus disease.
Dosage and Administration
Dosage for treatment of Herpes Simplex in Adults
For treatment of herpes simplex infections, 200mg Acicvir 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 may have to be extended.
In severely immune-compromised patients (e.g. after marrow transplants) 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 Acicvir should be taken four times daily at approximately six-hourly intervals.
Many patients may be conveniently managed on a regimen of 400mg Acicvir taken twice daily at approximately twelve-hourly intervals.
Dosage titration down to 200mg Acicvir taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals, may prove effective.
Some patients may experience breakthrough infections on total daily doses of 800mg Acicvir.
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 immuno-compromised patients, 200mg Acicvir should be taken four times daily at approximately six-hourly intervals. In severely immune-compromised patients (e.g. after marrow transplants) 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 Herpes Zoster in Adults
For treatment of herpes zoster infections, 800mg Acicvir 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, ideally within 48 hours, certainly within 72 hours.
Dosage in patients with severe AIDS with CD4 Count < 50/microlitre
For management of patients with severe AIDS who have a CD4 count of less than 50/microL, 800mg Acicvir should be taken four times daily at approximately six-hourly intervals. In patients with advance HIV disease, study treatment was 12 months but it is likely that these patients would continue to benefit from a longer duration of treatment.
Dosage in allogenic bone marrow transplant patients
For management of allogenic bone marrow recipients, 800mg Acicvir should be taken four times daily at approximately six-hourly intervals. This would normally be preceded by up to one month's therapy with intravenous acyclovir. The duration of treatment studied was 6 months (from 1 to 7 months post-transplant).
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 the adult dosages and children below the age of 2 years should be given half the adult dose.
No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immune-competent children.
Limited data suggest that for management of children, over two years of age, with severe AIDS who have a CD4 count of less than 50/microlitre, the adult dose may be given.
Dosage in the Elderly
In the elderly, total acyclovir body clearance declines in parallel with creatinine clearance. Adequate hydration of elderly patients taking high doses of Acicvir should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.
Dosage in Renal Impairment
In the treatment and prophylaxis of herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of acyclovir above levels that have been established safe by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200mg twice daily at approximately twelve-hourly intervals is recommended.
In the treatment of herpes zoster infections and in the management of severely immuno-compromised patients 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
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).
Administration
Acicvir Dispersible Tablets may be swallowed whole with a little water or dispersed in a minimum of 50ml of water.
Contraindications
Acicvir Tablets are contraindicated in patients known to be hypersensitive to acyclovir.
Warnings and Precautions
Patients should be advised to take precautions against transmitting their virus infection to others, particularly when active lesions are present.
Mutagenicity
The results of a wide range of mutagenicity tests in vitro and in vivo indicate that acyclovir does not pose a genetic risk to humans.
Carcinogenicity
Acyclovir was not carcinogenic in long-term studies in the rat and the mouse.
Teratogenicity
Systemic administration of acyclovir in internationally accepted standard tests did not produce embryotoxic or tertogenic effects in rabbits, rats 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.
Fertility
Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of acyclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of orally administered acyclovir on fertility.
There is no experience of the effect of Acicvir Tablets on human female fertility. Consider the potential benefits of treatment against any possible hazard.
Lactation
Following oral administration of 200mg Acicvir five times a day, acyclovir has been detected in breast milk. Tablets have been shown to have no definitive effect upon sperm count, morphology or motility in humans.
Pregnancy
Limited data are available on the use of acyclovir in pregnancy. Caution should therefore be exercised by balancing at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to acyclovir doses of up to 0.3mg/kg/day. Caution is therefore advised if Acicvir is to be administered to a nursing woman.
Adverse Effects
Skin rashes have been reported in a few patients receiving acyclovir; the rashes have resolved on withdrawal of the medicine.
Gastrointestinal effects, including nausea, vomiting, diarrhoea and abdominal pains, have been reported in some patients receiving acyclovir. In double-blind, placebo-controlled trials, the incidence of gastrointestinal events has not been found to differ between placebo and acyclovir 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 acyclovir therapy is uncertain.
Other events reported rarely in patients receiving oral formulations of acyclovir include mild transient rises in bilirubin and liver related enzymes, small increases in blood urea and creatinine, small decreases in haematological indices, headaches and fatigue.
In patients receiving anti-retroviral therapy, no significant increase in toxicity was associated with the addition of acyclovir.
Interactions
Probenecid increases the acyclovir mean half-life and area under the plasma concentration/time curve. Other drugs affecting renal physiology could potentially influence the pharmacokinetics of acyclovir. However, clinical experience has not identified other drug interactions with acyclovir.
Overdosage
Symptoms and Signs
Acyclovir is only partly absorbed in the gastrointestinal tract. It is unlikely that serious toxic effects would occur if a dose of up to 5g was taken on a single occasion. No data are available on the consequences of the ingestion of higher doses.
Single intravenous doses of up to 80 mg/kg have been inadvertently administered adverse effects.
Treatment
Ingestion of doses of acyclovir in excess of 5g warrants close observation of the patient.
Acyclovir is dialysable by haemodialysis.
Pharmaceutical Precautions
Store below 25°C (77°F).
Protect from light and moisture.
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