It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.

GlaxoSmithKline (Ireland) Ltd

GlaxoSmithKline (Ireland) Ltd

Summary of Product Characteristics last updated on medicines.ie: 21/9/2015

Zovirax IV 250mg

1. NAME OF THE MEDICINAL PRODUCT

Zovirax IV for Infusion 250 mg, Powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

The quantity after reconstitution is 25 mg 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.

3. PHARMACEUTICAL FORM

Powder for solution for infusion.

A white to off white freeze-dried sterile powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zovirax IV is indicated for:

 

Non-immunocompromised Patients

Immunocompromised Patients

Severe initial genital herpes

Herpes simplex infection

Recurrent varicella zoster virus infection

Primary and recurrent varicella zoster infection

Prophylaxis of herpes simplex infection

Herpes simplex encephalitis

Herpes simplex encephalitis

4.2 Posology and method of administration

The required dose of Zovirax IV should be administered by slow intravenous infusion over 1 hour.

A course of treatment with Zovirax IV usually lasts 5 days, but this may be adjusted according to the patient's condition and response to therapy. Treatment for herpes encephalitis usually lasts 10 days. Treatment for neonatal herpes usually lasts 14 days for mucocutaneous (skin-eye-mouth) infections and 21 days for dissemination or central nervous system disease.

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

Dosage in adults:

Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Zovirax IV in doses of 5 mg/kg body weight every 8 hours provided renal function is not impaired (see Dosage in renal impairment).

Immunocompromised patients with Varicella zoster infections or patients with herpes encephalitis should be given Zovirax IV. in doses of 10 mg/kg body weight every 8 hours provided renal function is not impaired (see Dosage in renal impairment).

In obese patients dosed with intravenous aciclovir based on their actual body weight, higher plasma concentrations may be obtained (see 5.2 Pharmacokinetic properties). Consideration should therefore be given to dosage reduction in obese patients and especially in those with renal impairment or the elderly.

Dosage for Infants and Children:

The dose of Zovirax IV for infants and children aged between 3 months and 12 years is calculated on the basis of body surface area.

Infants and children 3 months of age or older with herpes simplex (except herpes simplex encephalitis) or varicella zoster infections should be given Zovirax IV in doses of 250 mg per square metre of body surface area every 8 hours if renal function is not impaired.

In immunocompromised infants and children with varicella zoster infections or infants and children with herpes encephalitis, Zovirax IV should be given in doses of 500 mg per square metre of body surface area every 8 hours if renal function is not impaired.

The dosage of Zovirax IV in neonates and infants up to 3 months of age is calculated on the basis of body weight.

The recommended regimen for treatment for known or suspected neonatal herpes is aciclovir 20 mg/kg body weight IV every 8 hours for 21 days for disseminated and CNS disease, or for 14 days for disease limited to the skin and mucous membranes. Patients with impaired renal function require an appropriately modified dose, according to the degree of impairment (see Renal 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). Adequate hydration should be maintained.

Renal impairment:

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

Dosage adjustment for patients with renal impairment is based on creatinine clearance, in units of mL/min for adults and adolescents and in units of mL/min/1.73m2 for infants and children less than 13 years of age.

The following adjustments in dosage are suggested:

Table 1: Dosage adjustments for IV aciclovir in adults and adolescents with renal impairment for treatment of Herpes Simplex virus infections.

Creatinine Clearance

Dosage

25 to 50 mL/min

The recommended dose (5 or 10 mg/kg body weight) should be given every 12 hours.

10 to 25 mL/min

The recommended dose (5 or 10 mg/kg body weight) should be given every 24 hours.

0 (anuric) to 10 mL/min

In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the recommended dose (5 or 10 mg/kg body weight) should be halved and administered every 24 hours.

Patients on haemodialysis

In patients receiving haemodialysis, the recommended dose (5 or 10 mg/kg bodyweight) should be halved and administered every 24 hours and after dialysis.

Table 2: Dosage adjustments for IV aciclovir in neonates, infants and children with renal impairment for treatment of Herpes Simplex virus infections

Creatinine Clearance

Dosage

25 to 50 mL/min/1.73m2

The recommended dose (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be given every 12 hours.

10 to 25 mL/min/1.73m2

The recommended dose (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be given every 24 hours.

0 (anuric) to 10 mL/min/1.73m2

In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the recommended dose (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be halved and administered every 24 hours.

Patients on haemodialysis

In patients receiving haemodialysis, the recommended dose (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be halved and administered every 24 hours and after dialysis.

4.3 Contraindications

Zovirax IV is contraindicated in patients known to be hypersensitive to aciclovir and valaciclovir or to any of the excipients as listed in section 6.1.

4.4 Special warnings and precautions for use

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).

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 (see section 5.1).

In patients receiving aciclovir IV for infusion at higher doses (e.g. for herpes encephalitis), specific care regarding renal function should be taken, particularly when patients are dehydrated or have any renal impairment. Reconstituted Zovirax IV has a pH of approximately 11 and should not be administered by mouth.

Product contains sodium (26 mg, 1.13 mmol)

4.5 Interaction with other medicinal products and other forms of interaction

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. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

In patients receiving IV aciclovir, caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. 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.

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).

4.6 Fertility, pregnancy and lactation

Fertility

See Clinical Studies in section 5.3

Pregnancy

The use of Zovirax Powder for IV 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.

Breast-feeding

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.

4.7 Effects on ability to drive and use machines

Zovirax IV 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.

4.8 Undesirable effects

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 to <1/10); uncommon (>1/1000 to <1/100) rare (>1/10,000 to <1/1000); very rare (<1/10,000).

Blood and lymphatic system disorders

Uncommon:

Decreases in haematological indices (anaemia, thrombocytopenia, leukopenia)

Immune system disorders

Very rare:

Anaphylaxis

Psychiatric and nervous system disorders

Very rare:

Headache, dizziness, 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).

Vascular disorders

Common:

Phlebitis

Respiratory, thoracic and mediastinal disorders

Very rare:

Dyspnoea

Gastrointestinal disorders

Common:

Nausea, vomiting

Very rare:

Diarrhoea, abdominal pain

Hepato-biliary disorders

Common:

Reversible increases in liver-related enzymes

Very rare:

Reversible increases in bilirubin, jaundice, hepatitis

Skin and subcutaneous tissue disorders

Common:

Pruritus, urticaria, rashes (including photosensitivity)

Very rare:

Angioedema

Renal and urinary disorders

Common:

Increases in blood urea and creatinine

Rapid increases in blood urea and creatinine levels are believed to be related to the peak plasma levels and the state of hydration of the patient. To avoid this effect, when administered intravenously the drug should not be given as an intravenous bolus injection but by slow infusion over a one-hour period.

Very rare:

Renal impairment, acute renal failure, renal pain

Adequate hydration should be maintained. Renal impairment usually responds rapidly to rehydration of the patient and/or dosage reduction or withdrawal of the drug. Progression to acute renal failure, however, can occur in exceptional cases.

Renal pain may be associated with renal failure.

General disorders and administration site conditions

Very rare:

Fatigue, fever, local inflammatory reactions

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; Email: medsafety@hpra.ie.

4.9 Overdose

Symptoms and Signs

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.

Treatment

Patients should be observed closely for signs of toxicity. 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: group Anti infective, ATC code J05AB01.

Mechanism of Action

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.

5.2 Pharmacokinetic properties

Elimination

In adults, 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.

When aciclovir is given one hour after 1 gram of probenecid, the terminal half-life and the area under the plasma concentration time curve, are extended by 18% and 40% respectively.

Absorption

In adults, mean steady state peak plasma concentrations (Cssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 micromolar (5.1 microgram/mL), 43.6 micromolar (9.8 microgram/mL) and 92 micromolar (20.7 microgram/mL) respectively. The corresponding trough levels (Cssmin) 7 hours later were 2.2 micromolar (0.5 microgram/mL), 3.1 micromolar (0.7 microgram/mL) and 10.2 micromolar (2.3 microgram/mL) respectively. In children over 1 year of age similar mean peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 was substituted for 10 mg/kg. In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 micromolar (13.8 microgram/mL) and the Cssmin to be 10.1 micromolar (2.3 microgram/mL). A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a Cmax of 83.5 micromolar (18.8 microgram/mL) and Cmin of 14.1 micromolar (3.2 microgram/mL).

The terminal plasma half-life in these patients was 3.8 hours. In the elderly, total body clearance falls with increasing age and is 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.

In a clinical study in which morbidly obese female patients (n=7) were dosed with intravenous aciclovir based on their actual body weight, plasma concentrations were found to be approximately twice that of normal weight patients (n=5), consistent with the difference in body weight between the two groups.

Distribution

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.

5.3 Preclinical safety data

Fertility

There is no information on the effect of aciclovir oral formulations or IV. 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.

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.

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Hydroxide

6.2 Incompatibilities

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

6.3 Shelf life

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.

6.4 Special precautions for storage

Do not store above 25°C.

For in-use storage conditions, see section 6.3.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

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 250 mg 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 25 mg 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 IV 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 IV for infusion should be administered by slow intravenous infusion over a one-hour period. After reconstitution Zovirax IV 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 5 mg/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 4 mL reconstituted solution (100 mg aciclovir) added to 20 mL of infusion fluid.

For adults, it is recommended that infusion bags containing 100 mL of infusion fluid are used, even when this would give an aciclovir concentration substantially below 0.5% w/v. Thus one 100 mL infusion bag may be used for any dose between 250 mg and 500 mg aciclovir (10 and 20 mL of reconstituted solution), but a second bag must be used for doses between 500 and 1000 mg. 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 (15°C 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).

7. MARKETING AUTHORISATION HOLDER

GlaxoSmithKline (Ireland) Ltd.,

12 Riverwalk,

Citywest Business Campus,

Dublin 24.

8. MARKETING AUTHORISATION NUMBER(S)

PA 1077/084/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 03 May 1983

Date of last renewal: 03 May 2008

10. DATE OF REVISION OF THE TEXT

September 2015

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.