SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Aciclovir Powder for Infusion 250mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 250mg Aciclovir (as the sodium salt) in a freeze-dried sterile powder form.

For excipients, see 6.1

3    PHARMACEUTICAL FORM

Powder for Solution for Infusion

Sterile powder for infusion packaged in colourless 20ml glass vials

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

•    Treatment and prophylaxis of Herpes simplex virus infections in immunocompromised patients.

•    Treatment of severe initial genital herpes in non-immunocompromised patients.

•    Treatment of Herpes simplex encephalitis.

•    Treatment of Varicella zoster infections.

•    Treatment of Herpes simplex infections in the neonate and in infants up to age 3 months.

4.2.    Posology and method of administration

Route of administration: Slow intravenous infusion over 1 hour.

A course of treatment with Aciclovir I.V. 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 disseminated or central nervous system disease.

The duration of prophylactic administration of Aciclovir I.V. 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 Aciclovir I.V. in doses of 5mg/ kg bodyweight 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 Aciclovir I.V. in doses of 10mg/ kg bodyweight every 8 hours, provided renal function is not impaired (see Dosage in renal impairment).

In obese patients dosed with intravenous acyclovir 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 in children: The dose of Aciclovir I.V. for children aged between 3 months and 12 years is calculated on the basis of body surface area.

Children 3 months of age or older with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Aciclovir I.V. in doses of 250mg per square metre of body surface area every 8 hours if renal function is not impaired.

In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, Aciclovir 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.

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

The recommended regimen for infants treated for known or suspected neonatal herpes is aciclovir 20mg/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. Infants and children with impaired renal function require an appropriately modified dose, according to the degree of impairment (see Dosage in renal impairment).

Dosage in the elderly:

The possibility of renal impairment in the elderly must be considered and 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 I.V. 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/min1.73m² for infants and children less than 13 years of age. The following adjustments in dosage are suggested:

Dosage adjustments in adults and adolescents:

25 - 50 ml/min	The dose recommended above (5 or 10mg/kg bodyweight) should be given every 12 hours.
10 - 25 ml/min	The dose recommended above (5 or 10mg/kg bodyweight) should be given every 24 hours.
0 (anuric) - 10 ml/min	In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the doses recommended above (5 or 10mg/kg bodyweight) should be halved and given every 24 hours. In patients receiving haemodialysis, the dose recommended above (5 or 10mg/kg bodyweight) should be halved and administered every 24 hours and after dialysis.

Dosage adjustments in infants and children:

Creatinine clearance	Dosage
25 to 50 ml/min/1.73m2	The dose recommended above (250 or 500 mg/m2 body surface area or 20mg/kg body weight) should be given every 12 hours.
10 to 25 ml/min/1.73m2	The dose recommended above (250 or 500 mg/m2 body surface area or 20mg/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 dose recommended above (250 or 500 mg/m2 body surface area or 20 mg/kg body weight) should be halved and administered every 24 hours. In patients receiving haemodialysis the dose recommended above (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

Known hypersensitivity to aciclovir or valaciclovir or to any of the excipients.

4.4 Special warnings and precautions for use

If renal function is impaired, the intravenous dose must be adjusted in order to avoid accumulation of Aciclovir in the body (see Dosage in renal impairment above).

When higher doses of Aciclovir are administered (e.g. for herpes encephalitis), specific care, regarding renal function should be exercised, especially if the patient is dehydrated or has any renal impairment.

Elderly patients are likely to have reduced renal function and therefore the need for dose reduction 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 acyclovir treatment.

Reconstituted aciclovir for infusion has a pH of approximately 11.0 and should not be administered by mouth.

This vial contains approximately 26mg of sodium in total. The sodium content should be taken into consideration when prescribing to patients requiring sodium restriction.

Aciclovir Powder for Infusion 250mg does not contain an antimicrobial preservative. Reconstitution and dilution should, therefore, be performed under full aseptic conditions, immediately before use, and any unused solution should be discarded. Reconstituted or diluted solutions should not be refrigerated.

Other warnings and precautions:

The labels shall contain the following statements:

For intravenous infusion only Keep out of reach of children Do not store above 25°C

After reconstitution and dilution use immediately Discard any unused portion.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically significant interactions have been identified.

Aciclovir is eliminated mainly unchanged in the urine via active renal tubular secretion. Concomitant administration of any drugs that compete with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism, and reduce its renal clearance. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

Caution is required during concurrent intravenous administration of aciclovir 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 co-administered.

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

4.6 Pregnancy and lactation

Fertility

See clinical Studies in section 5.2 Pregnancy

The use of aciclovir should be exercised only when the potential benefits of treatment outweigh the possibility of any unknown risks.

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

Lactation

Following oral administration of Aciclovir 200mg five times a day, the drug has been detected in breast milk in concentrations of between 0.6 to 4.1 times the corresponding plasma levels. As these levels could potentially expose nursing infants to dosages of Aciclovir of up to 0.3mg/kg/day, caution is advised if the drug is to be administered to a nursing woman.

4.7 Effects on ability to drive and use machines

Aciclovir 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 aciclovir 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 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

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 the drug should not be given as an i.v. bolus injection but by slow infusion over a 1 h 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 aciclovir i.v. for infusion has been inadvertantly infused into extracellular tissues.

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

Patient 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Aciclovir is a synthetic purine nucleoside analogue structurally related to guanine. In-vitro and in-vivo, Aciclovir demonstrates antiviral 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-I, followed in decreasing order of potency by HSV-II, VZV, EBV and CMV. This activity is due to intracellular conversion of Aciclovir by viral thymidine kinase to aciclovir monophosphate with subsequent conversion to the diphosphate and then to the active triphosphate form. Aciclovir triphosphate inhibits viral DNA synthesis and replication by inhibiting the viral DNA polymerase enzyme as well as being incorporated into the viral DNA. The inhibitory activity of Aciclovir against HSV1, HSV11 and VZV is highly selective for infected cells: thymidine kinase in normal, non-infected cells does not use Aciclovir effectively as a substrate, therefore, toxicity to the host cells is low.

5.2. Pharmacokinetic properties

Following intravenous administration of Aciclovir in adults, the terminal plasma halflife is about 2.9 hours. Aciclovir is excreted through the kidney by both glomerular filtration and tubular excretion, mainly as unchanged drug with 10 to 15% appearing in the urine as the 9-carboxymethoxymethylguanine metabolite. Prior administration of probenecid increases the half-life and the area under the plasma concentration/time curve of Aciclovir.

Infusion over one hour of 2.5mg, 5mg, 10mg and 15mg Aciclovir per kg body weight in adults has produced mean steady state peak plasma concentrations of 5.1, 9.8, 20.7 and 23.6pg/ml, respectively. The corresponding trough levels 7 hours later were 0.5, 0.7, 2.3 and 2.0pg/ml, respectively. Similar mean peak and trough levels were observed in children aged over one year when doses of 250mg/m² and 500mg/m² were substituted for 5mg/kg and 10mg/kg respectively.

In neonates (0 to 3 months of age) treated with doses of 10mg/kg administered by infusion over a one hour period every 8 hours the Cssmax was found to be 61.2 micromolar ( 13.8pg/ml) and the Cssmin to be 10.1 micromolar (2.3pg/ml). A separate group of neonates treated with 15mg/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. Although there is little change in the terminal plasma half-life of Aciclovir in the elderly, there is an age-related decrease in total body clearance associated with decreases in creatinine clearance.

In patients with chronic renal failure, the mean terminal half-life was found to be 19.5 hours. During haemodialysis, the mean half-life of Aciclovir was 5.7 hours and plasma levels of the drug declined by approximately 60% during dialysis. Concentrations of Aciclovir in cerebrospinal fluid are approximately 50% of those achieved in plasma. Protein binding ranges from 9 to 33% and drug interactions that involve displacement from binding sites are not anticipated.

5.3 Preclinical safety data

Results of various in-vivo and in-vitro mutagenicity tests indicate that Aciclovir is unlikely to pose a genetic risk in man. Aciclovir did not show any carcinogenic activity in lifetime studies in rats and mice.

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 only after such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

At doses of Aciclovir greatly in excess of those used therapeutically, largely reversible effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported. Aciclovir tablets have been shown to have no definite effects on sperm count, morphology or motility in man.

There is no experience of the effect of Aciclovir intravenous infusions on human female fertility. Two-generation studies in mice did not reveal any effects of orally administered Aciclovir on fertility.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Hydroxide Water for Injections *

*almost completely removed during lyophilisation

6.2    Incompatibilities

Aciclovir Powder for Infusion 250mg is compatible with the infusion fluids listed below (see Instructions for use and handling 6.6, below). Compatibility with other agents has not been established.

6.3 Shelf life

Unopened: 3 years

After first opening: not applicable

6.4 Special precautions for storage

Do not store above 25°C. Store the vials in the original packaging. After reconstitution use immediately. Discard any unused portion

6.5 Nature and contents of container

Colourless glass type 1 vials closed with bromobutyl rubber stopper and aluminium seal with a blue flip-off cap.

Pack sizes: Vials of 20ml each containing the equivalent of 250mg of Aciclovir packaged per 1 or 5 in a box.

6.6 Special precautions for disposal

Reconstitution: The contents of each vial (equivalent to 250mg Aciclovir) should be reconstituted by adding 10ml of Water for Injections B.P. and shaking gently until the powder has fully dissolved. This provides a solution containing Aciclovir 25mg per ml. The calculated dose can be used to determine the number of vials to be used.

Administration: The required dose of Aciclovir should be administered by slow intravenous infusion over a one hour period.

After reconstitution, the solution containing 25mg Aciclovir per ml may be administered by a controlled-rate infusion pump.

Alternatively, the reconstituted solution may be further diluted to give an Aciclovir concentration of not greater than 5mg per ml (0.5% w/v) for administration by infusion.

The required volume of reconstituted solution (containing 25mg Aciclovir per ml) should be added to the chosen infusion solution, as recommended below, and then shaken well to ensure adequate mixing.

For children and neonates, where lower infusion volumes are generally required, the recommended dilution is based on the addition of 4ml reconstituted solution (Aciclovir 100mg) to 20ml of infusion fluid.

For adults, use of infusion bags containing 100ml of infusion fluid is recommended, even when this would result in an Aciclovir concentration significantly below 0.5% w/v. A 100ml infusion bag may be used for any dose between 250 - 500mg Aciclovir but a second bag must be used for doses between 500 - 1,000mg.

When diluted as recommended, the drug is compatible with the following infusion fluids and is stable for up to 12 hours at room temperature (15°C to 25°C):

Sodium Chloride Intravenous Infusion B.P. 0.45% and 0.9% w/v Sodium Chloride 0.18% w/v and Dextrose 4% w/v Intravenous Infusion B.P. Sodium Chloride 0.45% w/v and Dextrose 2.5% w/v Intravenous Infusion B.P. Compound Sodium Lactate Intravenous Infusion B.P. (Hartmann's solution)

Reconstitution and dilution should be performed immediately before use, under full aseptic conditions, and any unused solution should be discarded. The formulation does not contain an antimicrobial preservative.

The reconstituted or diluted solution should not be refrigerated.

If turbidity or crystallisation appear in the solution prior to or during an infusion, the solution should be discarded.

Please refer to enclosed patient information leaflet

7    MARKETING AUTHORISATION HOLDER

Mercury Pharma International Ltd 4045, Kingswood Road,

City West Business Park,

Co Dublin, Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 02848/0190

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/02/2002

10 DATE OF REVISION OF THE TEXT

23/08/2012