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Aciclovir Sodium For Intravenous Infusion B.P.

Document: spc-doc_PL 11311-0519 change

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Aciclovir sodium 250mg for intravenous infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains: Aciclovir sodium corresponding to 250 mg of aciclovir. For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for solution for infusion.

A white or almost white, freeze-dried, crystalline powder, dispensed in clear, colourless vials

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention and treatment of infections caused by herpes simplex virus in immonocompromised patients. Primary and recurrent herpes zoseter infections in immunocompromised patients or in immunocompetent patients. Severe initial herpes genitalis. Herpes simplex virus encephalitis.

4.2 Posology and method of administration

Route of administration:

Slow intravenous infusion over 1 hour.

A course of treatment with Aciclovir sodium intravenous infusion 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 sodium for intravenous infusion is determined by the duration of the period at risk.

Adults:

Patients with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Aciclovir sodium for intravenous infusion in doses of 5mg/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 Aciclovir sodium for intravenous infusion in doses of 10mg/kg body weight 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 those with renal impairment or the elderly.

Children:

The dose of Aciclovir sodium for intravenous infusion 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 sodium for intravenous infusion in doses of 250 mg 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 sodium for intravenous infusion should be given in doses of 500 mg per square metre body surface area every 8 hours if renal function is not impaired.

The dosage of Aciclovir sodium for intravenous infusion 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 acyclovir 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.

Infants and children with impaired renal function require an appropriately modified dose, according to the degree of impairment (see Dosage in renal impairment).

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.

In renal impairment:

Caution is advised when administering Aciclovir sodium for intravenous infusion in 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:

Creatinine Clearance: 25 to 50 ml/min

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

Creatinine Clearance: 10 to 25 ml/min:

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

Creatinine Clearance: 0(anuric) to 10 ml/min

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

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

Dosage adjustments in infants and children:

Creatinine Clearance: 25 to 50 ml/min/1.73 m2

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

Creatinine Clearance: 10 to 25 ml/min/1.73 m2

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

2

Creatinine Clearance: 0(anuric) to 10 ml/min/1.73 m Dosage: 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

Hypersensitivity to acyclovir or valaciclovir or to any of the excipients.

4.4 Special warnings and precautions for use

Adequate hydration should be maintained in patients given i.v. aciclovir. Intravenous doses should be given by infusion over one hour to avoid precipitation of aciclovir in the kidney; rapid or bolus injection should be avoided.

The risk of renal impairment is increased by use with other nephrotoxic drugs. Care is required if administering i.v. aciclovir with other nephrotoxic drugs.

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 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 sodium for intravenous 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 sodium for intravenous infusion has a PH of approximately 11 and should not be administered by mouth.

Product contains sodium (26 mg, approx. 1.13mmol)

Aciclovir sodium for intravenous 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.

Other warnings and precautions:

The labels shall contain the following statements:

For intravenous use only Use only as directed by a doctor Do not store above 25°C.

Store in original container in order to protect from light. Reconstitute or dilute before use.

Use immediately. Do not cool the solution.

Discard any unused solution.

Keep out of sight and reach of children.

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 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 coadministered.

Care should be taken (with monitoring for changes in renal function) when using aciclovir in combination with compounds known to have nephrotoxic effects, e.g. cyclosporine and tacrolimus.

4.6 Fertility, Pregnancy and lactation

Fertility

There is no experience 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.

Pregnancy

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 described amongst aciclovir exposed subjects compared with the general population, and any birth defects have not shown any uniqueness or consistent pattern to suggest a common cause.

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.

Experience in humans is limited; so the use of aciclovir in pregnancy should be considered only when the potential benefits outweigh the possibility of unknown risks (see Preclinical safety data).

Findings from reproduction toxicology studies are included in Section 5.3. Breast-feeding

Following oral administration of 200 mg aciclovir five times a day, the drug is detected in the breast milk at concentrations between 50% and 400% (0.6 to

4.1 times) of 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 aciclovir is to be administered to a nursing mother

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.

The patient may experience undesirable effects (see section 4.8) that could impair their ability to drive, operate machinery etc. If affected, they should not take part in any activities that may put themselves or others at risk.

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

Blood and lymphatic system disorders:

Uncommon; Decreases in haematological indices (anaemia, thrombocytopenia, leukopenia)

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)

Vascular disorders:

Common; Phlebitis

Respiratory, thoracic and mediastinal disorders:

Rare; Dyspnoea

Gastrintestinal disorders:

Common; Nausea, vomiting diarrhoea, abdominal pain Hepato-biliary disorders:

Rare; Reversible increases in bilirubin and liver-related enzymes Very rare; Jaundice, hepatitis

Skin and subcutaneous tissue disorders:

Common; Pruritis, 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 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 Aciclovir sodium for intravenous 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 the internet at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Overdosage of intravenenous 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Anatomical Therapeutical Chemical Classification: ATC code J05A BO 1.

Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including Herpes simplex virus 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 I.V. 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-carboxymethoxy methylguanine 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 1 gram 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 (Cssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7micromolar (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.

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

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.

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.

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

Contents: Aciclovir sodium, lyophilized.

6.2    Incompatibilities

Compatibility is not tested with other infusion fluids than mentioned in Instructions for use and handling.

6.3    Shelf life

5 years. After reconstitution/dilution according to directions: Use immediately.

Special precautions for storage

6.4


None. Storage temperature: Do not store above 25°C. Reconstituted product/diluted product: Use immediately. Reconstitution solvent should be at room temperature (18-25°C). Do not cool solutions due to risk of precipitation. Discard any unused solution.

6.5 Nature and contents of container

Vials made of clear, colourless glass, closed with rubber stoppers (chlorobutyl rubber) and sealed with aluminium caps provided with a polypropylene disc.

Pack sizes:

250mg: 3 and 5.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Dissolve and dilute under full aseptic conditions immediately before use. Dissolve in water for injections or sodium chloride injection 9 mg/ml and dilute with one of the following infusion fluids: Sodium Chloride 9 mg/ml (0.9% w/v), Sodium Chloride 4.5 mg/ml (0.45% w/v), Sodium Chloride 1.8 mg/ml (0.18% w/v) and Glucose 40 mg/ml (4% w/v), Sodium Chloride 4.5 mg/ml (0.45% w/v) and Glucose 25 mg/ml (2.5% w/v) or Ringer-Lactate. The liquid must have room temperature (18-25°C). Maximum concentration: 5 mg of aciclovir per ml (though 25 mg of aciclovir per ml if using controlled rate infusion pump). Any unused solution should be discarded. Solutions for intravenous infusion prepared by mixing with the above-mentioned infusion fluids are chemically stable for at least 12 hours at room temperature (18-25°C) provided that the aciclovir concentration is not more than 5 mg/ml (0.5% w/v).

Ready prepared solutions should not be refrigerated as aciclovir might precipitate.

7    MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited

3 Howard Road

Eaton Socon

St Neots

Cambridgeshire

PE198ET

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0519

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15 February 2002

10    DATE OF REVISION OF THE TEXT

11/02/2015