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Zovirax Information Zovirax Information

ZOVIRAX Oral Formulations

Aciclovir 200mg, 400mg or 800mg Dispersible Tablets.

Aciclovir Suspension 200mg/5mL

Pharmaceutical Form

Dispersible Tablets.
Oral suspension.

Qualitative and Quantitative Composition

Dispersible Tablet 200mg: blue, biconvex, shield-shaped, clear film coated, impressed with ZOVIRAX 200 on one side and a triangle on the other.

Dispersible Tablet 400mg: pale pink, biconvex, shield-shaped, clear film-coated, impressed with ZOVIRAX 400 on one side and a triangle on the other.

Dispersible Tablet 800mg: white, biconvex, elongated, clear film-coated, impressed with ZOVIRAX 800 on one side and scored on the other.

Suspension 200mg/5mL: white, banana-flavoured, oral suspension containing 200mg Aciclovir in each 5mL.

Clinical Particulars

Therapeutic Indications

ZOVIRAX Oral Formulations are indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes 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 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.

ZOVIRAX Oral Formulations are indicated for the management of patients with severe AIDS who have a CD4 count of less than 50/mcL. Studies have shown that oral ZOVIRAX given in conjunction with anti-retroviral therapy (mainly oral RETROVIR) reduced mortality in patients with advanced HIV disease.

ZOVIRAX Oral Formulations, preceded by one month's treatment with intravenous ZOVIRAX, are indicated for patients undergoing allogenic bone marrow transplantation who are at risk of developing CMV infection while immunosuppressed. Studies have shown that oral ZOVIRAX reduced mortality in allogenic bone marrow transplant recipients. In addition oral ZOVIRAX 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 ZOVIRAX 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 ZOVIRAX should be taken four times daily at approximately six-hourly intervals.

Many patients may be conveniently managed on a regimen 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 breakthrough 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 immunocompromised patients, 200mg ZOVIRAX 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 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, ideally within 48 hours, certainly within 72 hours.

Dosage in patients with severe aids with CD4 count <50/mcL

For management of patients with severe AIDS who have a CD4 count of less than 50/mcL, 800mg ZOVIRAX should be taken four times daily at approximately six-hourly intervals. In patients with advanced 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 ZOVIRAX 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 ZOVIRAX (see ZOVIRAX IV for infusion prescribing information). 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/mcL, the adult dose may be given.

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 treatment and prophylaxis 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 10mL/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 immunocompromised 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 10mL/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 25mL/minute).

Administration

ZOVIRAX Dispersible Tablets may be swallowed whole with a little water or dispersed in a minimum of 50mL of water.

ZOVIRAX Suspension 200mg/5mL may be diluted with an equal volume of either Syrup BP or Sorbitol Solution 70% (non-crystallising) BP. The diluted product is stable for 4 weeks at 25�C but it is recommended that all dilutions are freshly prepared.

Contraindications

ZOVIRAX Tablets and ZOVIRAX Suspensions are contraindicated in patients known to be hypersensitive to aciclovir or valaciclovir.

Special Warnings and Special Precautions for Use

Hydration status : Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir.

Use During Pregnancy and Lactation

Teratogenicity

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic 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 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 tablets on human female fertility. ZOVIRAX tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.

Pregnancy

A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of ZOVIRAX. The registry findings have not shown an increase in the number of birth defects amongst ZOVIRAX exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.

Caution should therefore be exercised by balancing the potential benefits of treatment against any possible hazard.

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.

Effects on the Ability to Drive and Use Machines

No data.

Interaction with Other Medicaments and Others Forms of Interaction

No clinically significant interactions have been identified.

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any medicines 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 immunosuppressant agent used in transplant patients have been shown when the medicines are coadministered. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

Undesirable Effects

Gastrointestinal: Nausea, vomiting, diarrhoea and abdominal pains have been reported.

Haematological: Very rarely, anaemia, leukopenia and thrombocytopenia.

Hypersensitivity and skin: Rashes including photosensitivity, urticaria, pruritus 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, convulsions, somnolence 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.

In patients receiving anti-retroviral therapy (mainly oral RETROVIR) no significant increase in toxicity was associated with the addition of ZOVIRAX.

Overdose

Symptoms & 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.

Pharmacological Properties

Pharmacodynamic Properties

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 Cytomegalovirus (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.

The inhibitory activity of aciclovir 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 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.

All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesions are present.

Pharmacokinetic Properties

Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (C_ssmax) following doses of 200mg administered four-hourly were 3.1microMol (0.7mcg/mL) and equivalent trough plasma levels (C_ssmin) were 1.8microMol (0.4mcg/mL). Corresponding C_ssmax levels following doses of 400mg and 800mg administered four-hourly were 5.3microMol (1.2mcg/mL) and 8microMol (1.8mcg/mL) respectively, and equivalent C_ssmin levels were 2.7microMol (0.6mcg/mL) and 4microMol (0.9mcg/mL).

In adults the terminal plasma half life of aciclovir after administration of intravenous aciclovir is about 2.9 hours. Most of the medicine 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-Carboxymethoxy- methylguanine is the only significant metabolite of aciclovir and accounts for approximately 10-15% of the administered dose recovered from the urine. When aciclovir 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 C_ssmax levels following a one-hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg were 22.7microMol (5.1mcg/mL), 43.6microMol (9.8mcg/mL) and 92microMol (20.7mcg/mL), respectively. The corresponding C_ssmin levels 7 hours later were 2.2microMol (0.5mcg/mL), 3.1microMol (0.7mcg/mL) and 10.2microMol (2.3mcg/mL), respectively. In children over 1 year of age similar mean C_ssmax and C_ssmin levels were observed when a dose of 250mg/m² was substituted for 5mg/kg and a dose of 500mg/m² was substituted for 10mg/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 C_ssmax was found to be 61.2microMol (13.8mcg/mL) and the C_ssmin to be 10.1microMol (2.3mcg/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 aciclovir half life during haemodialysis was 5.7 hours. Plasma aciclovir 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 aciclovir or zidovudine when both are administered simultaneously to HIV infected patients.