GlaxoSmithKline (Ireland) Ltd

Zovirax I.V. for Infusion 250 mg, Powder for solution for infusion

Each vial contains 250mg aciclovir (as the sodium salt).

The quantity after reconstitution is 25mg aciclovir per ml.

Each vial contains 26 mg of sodium.

The quantity of sodium after reconstitution in 10 ml of water for injection is approximately 2.587 mg/ml.

The quantity of sodium after reconstitution in 10 ml of NaCl (0.9 % w/v) is approximately 11.587 mg/ml.

For a full list of excipients see section 6.1.

Powder for solution for infusion.

A white to off white freeze-dried sterile powder.

Zovirax I.V. is indicated for:

Dosage in Adults:

Obese patients should be dosed at the recommended adult dose using ideal body weight rather than actual body weight.

The required dose of Zovirax I.V. should be administered by slow intravenous infusion over a one-hour period.

A course of treatment with Zovirax I.V. usually lasts 5 days, but this may be adjusted according to the patient's condition and response to therapy. Treatment for herpes simplex encephalitis usually lasts 10 days.

The duration of prophylactic administration of Zovirax I.V. is determined by the duration of the period at risk.

Patients with renal impairment should be administered Zovirax I.V. with caution. The following modifications in dosage are recommended:

Dosage in children: The dosage of Zovirax I.V. in neonates is calculated on the basis of bodyweight. Although its use in neonates herpes, is still experimental, doses of 10mg/kg have been employed.

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 simplex encephalitis) or varicella zoster infections should be given Zovirax I.V. in doses of 250mg per square metre of body surface area every 8 hours.

In immunocompromised children with varicella zoster infections or children with herpes simplex encephalitis, Zovirax I.V. should be given in doses of 500mg per square metre of 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.

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

Renal impairment: Caution is advised when administering aciclovir i.v. for infusion to patients with impaired renal function. Adequate hydration should be maintained.

Zovirax I.V. is contraindicated 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 (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).

Aciclovir should be administered with caution to patients with hepatic or renal impairment and in the elderly.

Adequate hydration of the patient should be maintained, to avoid rapid increases in blood urea and creatinine associated with I.V. aciclovir and inadequate hydration.

Aciclovir should be administered by slow infusion over one hour and not as a bolus intravenous injection.

Reconstituted Zovirax I.V. has a pH of approximately 11 and should not be administered by mouth.

This medicinal product contains 1.1 mmol sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

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.

Care is also required (with monitoring for changes in renal function) if administering intravenous Zovirax with drugs which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

Experience in humans is limited, so the use of Zovirax Powder for I.V. Infusion should be considered only when the potential benefits outweigh the possibility of unknown risks.

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.

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 human 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 bodyweight/ day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.

Zovirax I.V. for Infusion is generally used in an in-patient hospital population and information on ability to drive and operate machinery is not usually relevant. There have been no studies to investigate the effect of Zovirax on driving performance or the ability to operate machinery.

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.

Severe local inflammatory reactions sometimes leading to breakdown of the skin have occurred when Zovirax I.V. for Infusion has been inadvertently infused into extracellular tissues.

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 overdosage. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered an option in the management of overdose of this drug.

Aciclovir is an antiviral agent which is highly active in vitro against Herpes simplex virus (HSV) types I and II and Varicella zoster virus. Toxicity to mammalian host cells is low.

Aciclovir is phosphorylated after entry into herpes infected cells to the active compound aciclovir triphosphate. The first step in this process is dependent on the presence of the HSV-coded thymidine kinase.

Aciclovir triphosphate acts as an inhibitor of and substrate for the herpes specified DNA polymerase preventing further viral DNA synthesis without affecting normal cellular processes.

From studies with intravenous aciclovir, the terminal plasma half-life has been determined as about 2.9 hours.

Most of the drug is excreted unchanged in 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 10-15% of the dose excreted in the urine. In patients with chronic renal failure, the mean terminal half-life was found to be 19.5 hours.

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.

Sodium Hydroxide

This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6.

Prior to reconstitution: 5 years.

From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at room temperature, unless reconstitution has taken place in controlled and validated aseptic conditions.

Following further dilution to give a concentration not greater than 0.5% w/v of aciclovir, Zovirax is known to be compatible and stable for up to 12 hours (in the named infusion fluids listed in section 6.6) when stored at room temperature (15°C to 25°C).

The reconstituted or diluted solutions should not be refrigerated.

Do not store above 25°C.

For in-use storage conditions, see section 6.3.

Clear colourless, Type I glass bottle (Ph. Eur.) with bromobutyl rubber stoppers or with a bromobutyl rubber stopper with a fluorinated polymer coating and aluminium collars with a polypropylene flip-top cover.

Pack size: 5 vials.

Prepare immediately prior to use. Discard any unused solution. Any unused product or waste materials should be disposed of in accordance with local requirements.

For intravenous infusion only.

For single use only.

Reconstitution: Each vial (containing the equivalent of 250mg aciclovir) should be reconstituted by the addition of 10ml of either Water for Injections BP or Sodium Chloride Intravenous Infusion BP (0.9% w/v). This provides a solution containing 25mg aciclovir per ml.

From the calculated dose, determine the appropriate number of vials to be used. To reconstitute each vial, add the recommended volume of Infusion fluid and shake gently until the contents of the vial have dissolved completely.

Zovirax I.V. for Infusion contains no antimicrobial preservative. Reconstitution and dilution should therefore be carried out either under full aseptic conditions or immediately before use and any unused solution should be discarded.

The reconstituted or diluted solutions should not be refrigerated. Should visible turbidity or crystallisation appear in the solution, before or during the infusion, the mixture should be discarded.

Administration: The required dose of Zovirax I.V. for infusion should be administered by slow intravenous infusion over a one-hour period. After reconstitution Zovirax I.V. for Infusion may be administered by a controlled-rate infusion pump. Alternately, the reconstituted solution may be further diluted to give an aciclovir concentration of not greater than 5mg/ml (0.5% w/v) for administration by infusion.

Add the required volume of reconstituted solution to the chosen infusion solution, as recommended below, and shake well to ensure adequate mixing occurs. For children and neonates, where it is advisable to keep the volume of infusion fluid to a minimum it is recommended that dilution is on the basis of 4ml reconstituted solution (100mg aciclovir) added to 20ml of infusion fluid.

For adults, it is recommended that infusion bags containing 100ml of infusion fluid are used, even when this would give an aciclovir concentration substantially below 0.5% w/v. Thus one 100ml infusion bag may be used for any dose between 250mg and 500mg aciclovir (10 and 20ml of reconstituted solution), but a second bag must be used for doses between 500 and 1000mg. Zovirax when diluted in accordance with the above schedules to give a concentration not greater than 0.5% w/v of aciclovir, is known to be compatible with the following infusion fluids and stable for up to 12 hours at room temperature (15ºC to 25°C).

Sodium Chloride Intravenous Infusion BP (0.45% and 0.9% w/v).

Sodium Chloride (0.18% w/v) and Dextrose (4% w/v) Intravenous Infusion BP.

Sodium Chloride (0.45% w/v) and Dextrose (2.5% w/v) Intravenous Infusion BP.

Compound Sodium Lactate Intravenous Infusion BP (Hartmann's solution).

GlaxoSmithKline (Ireland) Limited

Stonemasons Way,

Rathfarnham,

Dublin 16

Ireland

PA 1077/084/003

Date of first authorisation: 03 May 1983

Date of last renewal: 03 May 2008

04/08/2010