GlaxoSmithKline (Ireland) Ltd

Zovirax 200 mg/5ml Oral Suspension.

Oral Suspension containing 200mg aciclovir per 5ml.

Excipients:

Liquid Sorbitol (non-crystallising) (E420) 2.25 g/5 ml

Methyl parahydroxybenzoate (E218) 5 mg/5 ml

Propyl parahydroxybenzoate (E216) 1.0 mg/5 ml

For full list of excipients, see section 6.1

Oral Suspension.

Off-white, banana flavoured oral suspension

Zovirax Suspension is indicated for the treatment of Herpes simplex virus infections of the skin and mucous membranes, including initial and recurrent genital herpes.

Zovirax Suspension is indicated for the suppression (prevention of recurrences) of recurrent Herpes simplex infections in immunocompetent patients.

Zovirax Suspension is indicated for the prophylaxis of Herpes simplex infections in immunocompromised patients.

Zovirax Suspension is indicated for the treatment of Varicella (chickenpox) and Herpes zoster (shingles) infections. Studies have shown that early treatment of shingles with Zovirax has a beneficial effect on pain and can reduce the incidence of post-herpetic neuralgia (zoster-associated pain).

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 immunocompromised patients (e.g. 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.

Dosage for suppression of Herpes simplex in adults.

For 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 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 immunocompromised patients, 200mg Zovirax should be taken four times daily at approximately six-hourly 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 400mg Zovirax 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 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 the infection; treatment yields better results if initiated as soon as possible after onset of the rash.

Dosage for management of severely immunocompromised patients.

For management of severely immunocompromised patients, 800mg Zovirax should be taken four times daily at approximately six-hourly intervals. In the management of bone marrow recipients this would normally be preceded by up to the months therapy with intravenous Zovirax (see Zovirax IV for infusion prescribing information).

Dosage in children.

For 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.

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 can be given 400mg Zovirax four times daily. Children below the age of two years can be given 200mg Zovirax four times daily.

Treatment should continue for five days.

Dosing may be more accurately calculated as 20mg/kg bodyweight (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.

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 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 by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200 mg twice daily at approximately twelve-hourly intervals is recommended.

In the treatment of Varicella and Herpes zoster infections it is recommended that the dosage be adjusted to 800 mg twice daily at approximately twelve-hourly intervals for patients with severe renal impairment (creatinine clearance less than l0 ml/minute), and to 800 mg three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range l0-25 ml/minute).

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

Patients with rare hereditary problems of fructose intolerance should not take this medicine

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 (see section 4.2). 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 (see section 4.8).

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

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.

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 however be exercised by balancing the potential benefits of treatment against any possible hazard.

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.

Lactation: Following oral administration of 200 mg aciclovir 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 Zovirax is to be administered to a nursing woman.

The clinical status of the patient and the adverse event profile of Zovirax should be borne in mind when considering the patient's ability to drive or operate machinery. There have been no studies to investigate the effect of Zovirax on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

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 usually reported in patients with renal impairment, or with other predisposing factors (see section 4.4).

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.

General disorders and administration site conditions

Common: Fatigue, fever

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.

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 I and II and 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 I, HSV II, 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 immunocompromised 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.

a) General characteristics of the active substances.

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

In adults the terminal plasma half life of aciclovir after administration of intravenous aciclovir is about 2.9 hours. 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 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 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 22.7 µMol (5.1 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml), respectively. The corresponding C^ssmin levels 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. In children over 1 year of age similar mean C^ssmax and C^ssmin levels were observed when a dose of 250 mg/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 61.2 microMol (13.8 micrograms/ml) and the C^ssmin to be 10.1 microMol (2.3 micrograms/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.

There is no information on the effect of aciclovir oral formulations or i.v. for infusion on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

NON-CLINICAL INFORMATION

• Mutagenicity

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.

• Carcinogenicity

Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.

• 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.

Liquid Sorbitol (non-crystallising) [E420]

Glycerol

Dispersible cellulose

Methyl parahydroxybenzoate [E218]

Propyl parahydroxybenzoate [E216]

Banana Flavour

Vanillin

Purified water

Not applicable

Undiluted: 3 years

Diluted: 4 weeks

Do not store above 25°C.

125 ml amber glass bottle with white, child resistant cap containing a homogenous opaque white, viscous suspension having the taste and odour of banana. The pack contains a polypropylene double ended 5 ml/2.5 ml spoon.

Zovirax Oral Suspension 200mg/5ml may be diluted with an equal volume of either Syrup BP or Liquid Sorbitol (non-crystallising), Ph.Eur.

The diluted product is stable for 4 weeks at 25°C but it is recommended that all dilution's are freshly prepared.

GlaxoSmithKline (Ireland) Limited,

Stonemasons Way,

Rathfarnham,

Dublin 16.

PA 1077/084/005

Date of first authorisation: 24th March 1986

Date of last renewal: 24th March 2006

04/08/2010