1.    NAME OF THE MEDICINAL PRODUCT

Aciclovir 250mg Powder for Solution for Infusion

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 250mg of aciclovir as the sodium salt For a full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Powder for solution for infusion.

White powder.

4.    CLINICAL PARTICULARS 4.1. Therapeutic indications

Aciclovir for infusion is indicated for the treatment of Herpes simplex infections in immunocompromised patients and severe initial genital herpes in the non-immunocompromised.

Aciclovir for infusion is indicated for the prophylaxis of Herpes simplex infections in immunocompromised patients. Aciclovir for infusion is indicated for the treatment of Varicella zoster infections.

Aciclovir for infusion is indicated for the treatment of herpes encephalitis.

Aciclovir for infusion is indicated for the treatment of Herpes simplex infections in the neonate and infant up to three months of age.

4.2 Posology and method of administration

Route of administration: Slow intravenous infusion over one hour.

A course of treatment with aciclovir for infusion usually lasts five days, but this may be adjusted according to the patient's condition and response to therapy. Treatment for herpes encephalitis usually lasts ten 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 for infusion is determined by the duration of the period at risk. Dosage

Dosage in adults:

Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given aciclovir for infusion in doses of 5mg/kg bodyweight every eight 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 for infusion in doses of 10mg/kg bodyweight every eight 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 in children:

The dose of aciclovir for infusion for children aged between three months and 12 years is calculated on the basis of body surface area.

Children three months of age or older with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given aciclovir for infusion in doses of 250 mg per square metre of body surface area every eight hours if renal function is not impaired.

In immunocompromised children with Varicella zoster infections or children with herpes encephalitis, aciclovir for infusion should be given in doses of 500 mg per square metre body surface area every eight hours if renal function is not impaired.

The dosage of aciclovir for infusion in neonates and infants up to three months of age is calculated on the basis of bodyweight.

The recommended regimen for infants treated for known or suspected neonatal herpes is aciclovir 20 mg/kg body weight IV every eight 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. 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.

Adequate hydration should be maintained.

Dosage in renal impairment:

Caution is advised when administering aciclovir 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:

Dosage adjustments in adults and adolescents:_

4.3.

4.4.

4.5.

4.6.

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.

Administration

The required dose of aciclovir for infusion should be administered by slow intravenous infusion over a one-hour period. After reconstitution aciclovir for infusion 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 5 mg/ml (0.5% w/v) for administration by infusion.

For instructions on reconstitution and dilution of the product before administration see section 6.6.

4.7.

4.8.

Contraindications

Aciclovir for infusion is contraindicated in patients known to be previously hypersensitive to aciclovir and valaciclovir, or to any of the excipients.

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 reduced in patients with renal impairment (see section 4.2). 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 aciclovir treatment.

In patients receiving aciclovir 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 aciclovir for infusion has a pH of approximately 11.0 and should not be administered by mouth. Aciclovir for infusion contains no antimicrobial preservative. Reconstitution and dilution should therefore be carried out under full aseptic conditions immediately before use and any unused solution discarded. The reconstituted or diluted solutions should not be refrigerated.

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

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 intravenous 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 co-administered.

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

Pregnancy and lactation Pregnancy

The use of aciclovir 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 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.

Fertility

There is no information on the effect of aciclovir 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.

Lactation

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

Effects on ability to drive and use machines

Aciclovir 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. However, aciclovir can cause reversible neurological reactions such as confusion, hallucinations, agitation, tremors, somnolence, psychosis and coma, which can all affect the ability to drive and use machinery.

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.

Dosage adjustments in infants and children:

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 >1/1,000 and <1/100, rare >1/10,000 and <1/1,000, very rare <1/10,000.

Blood and lymphatic system disorders

Uncommon: Decreases in haematological indices (anaemia, thrombocytopenia, leucopenia).

Immune system disorders Very rare: Anaphylaxis.

Psychiatric and nervous system disorders

Very rare: Headache, dizziness, confusion, hallucinations, agitation, tremor, ataxia, dysarthria, somnolence, psychotic symptoms, encephalopathy, convulsions and 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, hepatitis and jaundice.

Skin and subcutaneous tissue disorders

Common: Rashes including photosensitivity, urticaria, pruritus

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 peak plasma levels and the state of hydration of the patient. To avoid this effect 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 of the patient should be maintained. Renal impairment developing during treatment with aciclovir for infusion 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 and crystalluria.

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 formulations of aciclovir for intravenous use have been inadvertently infused into extravascular 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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

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 a management option in the event of symptomatic overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1.    Pharmacodynamic properties

ATC Code: J05A B01, Direct Acting Antiviral

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 1 and 2 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-1, HSV-2, VZV and EBV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected 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.

5.2.    Pharmacokinetic properties

In adults, the terminal plasma half-life of aciclovir after administration of aciclovir for infusion 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 10 to 15% of the dose excreted in the urine.

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

In adults, mean steady state peak plasma concentrations (C_maxss) 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 (C_minss) 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 one year of age similar mean peak (C_maxs) and trough (C_minss) 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 three months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the C_max;s was found to be 61.2 micromolar (13.8 microgram/ml) and the C_miniss.to be 10.1 micromolar (2.3 microgram/ml). A separate group of neonates treated with 15 mg/kg every eight 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.

5.3.

6.

6.1.

6.2.

6.3.

6.4.

6.5.

6.6.

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.

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.

Preclinical safety data

The results of a wide range of mutagenicity test in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.

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

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.

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.

There is no experience of the effect of aciclovir for infusion on human fertility. Aciclovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.

PHARMACEUTICAL PARTICULARS List of excipients Sodium hydroxide Incompatibilities

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

Unopened - Three years

For reconstituted solutions, chemical and physical in-use stability has been demonstrated for at least 24 hours at 25°C. From a microbiological point of view, once opened, the 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 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Following dilution using the fluids detailed in section 6.6, chemical and physical in-use stability has been demonstrated for up to 12 hours at 25°C. From a microbiological point of view the diluted solution should be used immediately. If not used immediately in-use storage times and conditions are the responsibility of the user. Special precautions for storage Unopened: Do not store above 25°C Keep the vials in the outer carton.

After reconstitution: Do not store above 25°C (see 6.3 Shelf Life).

Nature and contents of container

Packs* of one, five or ten Type II colourless glass 10ml vials stoppered with a chlorobutyl stopper and an aluminium and polypropylene flip-off cap.

*Not all pack sizes may be marketed Instructions for use and handling

Reconstitution:

Aciclovir 250mg for infusion should be reconstituted using 10ml of either Water for Injections PhEur or Sodium Chloride Intravenous Infusion BP (0.9% w/v) to provide a solution containing 25mg aciclovir per ml.

From the calculated dose, determine the appropriate number and strength 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.

The reconstituted solution appears light yellow and slightly opalescent.

After reconstitution aciclovir powder for solution for infusion 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 5 mg/ml (0.5% w/v) for administration by infusion:

For further dilution, 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 20 ml 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 100 ml infusion bag may be used for any dose between 250mg and 500mg aciclovir (10 and 20 ml of reconstituted solution) but a second bag must be used for doses between 500 and 1000mg.

When diluted in accordance with the recommended schedules, aciclovir for infusion is known to be compatible with the following infusion fluids:

-    sodium chloride intravenous infusion BP (0.45% and 0.9% w/v);

-    sodium chloride (0.18% w/v) and glucose (4% w/v) intravenous infusion BP

-    sodium chloride (0.45% w/v) and glucose (2.5% w/v) intravenous infusion BP

-    compound sodium lactate intravenous infusion BP (Hartmann's Solution).

Aciclovir for infusion, when diluted in accordance with the above schedule will give an aciclovir concentration not greater than 0.5% w/v.

Since no antimicrobial preservative is included, reconstitution and dilution must be carried out under full aseptic conditions, immediately before use, and any unused solution discarded.

Should any visible turbidity or crystallisation appear in the solution before or during infusion, the preparation should be discarded.

7.

8.

9.

10.

MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited Ash Road North Wrexham LL13 9UF United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 29831/0320

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 6 May 2008 DATE OF REVISION OF THE TEXT

04/2015

ftWOCKHARDT

103376/6

B10100-06