DNA polymerase inhibitors (antivirals).

Aciclovir

Zovirax Double Strength Suspension

Suspension

Zovirax Double Strength Suspension is indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes. Zovirax Double Strength Suspension is indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.

Zovirax Double Strength Suspension is indicated for the prophylaxis of herpes simplex infections in immunocompromised patients.

Zovirax Double Strength Suspension is indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

Route of Administration: Oral

Dosage in Adults

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 this may have to be extended.

In severely immunocompromised patients (eg after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400mg Zovirax 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 simplex infections in immunocompetent 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 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 infection 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.

Prophylaxis of herpes simplex infections in immunocompromised patients:

200mg Zovirax should be taken four times daily at approximately six hourly intervals.

In severely immunocompromised patients (eg after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400mg Zovirax 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: 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 immunocompromised patients (eg 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 Children

Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: 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.

Treatment of varicella infections:

6 years and over: 800mg Zovirax four times daily.

2 - 6 years: 400mg Zovirax four times daily.

Under 2 years: 200mg Zovirax four times daily.

Treatment should continue for five days.

Dosing may be more accurately calculated as 20mg/kg body weight (not to exceed 800mg) Zovirax four times daily.

No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children.

Zovirax Double Strength Suspension 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^oC but it is recommended that all dilutions are freshly prepared.

Dosage in the Elderly

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Dosage in Renal Impairment below).

Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained.

Dosage in Renal Impairment

Caution is advised when administering aciclovir to patients with impaired renal function. Adequate hydration should be maintained.

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 10ml/minute) an adjustment of dosage to 200mg 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 800mg aciclovir twice daily at approximately twelve-hourly intervals for patients with severe renal impairment (creatinine clearance less than 10ml/minute), and to 800mg aciclovir three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 to 25ml/minute).

Dosage in children: The dose of Zovirax I.V. for children aged between 3 months and 12 years is calculated on the basis of body surface area. Children with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Zovirax I.V. in doses of 250 mg per square metre of body surface area every 8 hours. In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, Zovirax I.V. should be given in doses of 500 mg per square metre body surface area every 8 hours if renal function is not impaired. Children with impaired renal function require an appropriately modified dose, according to the degree of impairment. The dosage of Zovirax I.V. in neonates and infants up to 3 months of age is calculated on the basis of body weight. Neonates and infants up to 3 months of age with Herpes simplex infections should be given Zovirax I.V. in doses of 10 mg/kg body weight every 8 hours. Treatment for neonatal herpes simplex infections usually lasts 10 days.

Dosage in the elderly: In the elderly, total aciclovir body clearance declines in parallel with creatinine clearance. Special attention should be given to dosage reduction in elderly patients with impaired creatinine clearance.

Zovirax Double Strength Suspension is contra-indicated in patients known to be hypersensitive to aciclovir or valaciclovir.

Use in patients with renal impairment and in elderly patients:

Aciclovir is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment. Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment.

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

The data currently available from clinical studies is not sufficient to conclude that treatment with aciclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

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 immunosuppressant 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.

The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of undesirable effects in terms of frequency:- Very common 1/10, common 1/100 and <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000.

Blood and lymphatic system disorders:

Very rare: Anaemia, leukopenia, thrombocytopenia

Immune system disorders:

Rare: Anaphylaxis

Psychiatric and nervous system disorders:

Common: Headache, dizziness

Very rare: Agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma.

The above events are generally reversible and are usually reported in patients with renal impairment, or with other predisposing factors.

Respiratory thoracic and mediastinal disorders:

Rare: Dyspnoea

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, abdominal pains

Hepato-biliary disorders

Rare: Reversible rises in bilirubin and liver related enzymes

Very rare: Hepatitis, jaundice

Skin and subcutaneous tissue disorders:

Common: Pruritus, rashes (including photosensitivity)

Uncommon: Urticaria. Accelerated diffuse hair loss.

Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain.

Rare: Angioedema

Renal and urinary disorders:

Rare: Increases in blood urea and creatinine

Very rare: Acute renal failure, renal pain.

Renal pain may be associated with renal failure and crystalluria.

General disorders and administration site conditions:

Common: Fatigue, fever

GlaxoSmithKline(GSK)

(POM)

17 June 2009