ACICLOVIR 500 MG POWDER FOR SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Aciclovir 500 mg Powder for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Aciclovir Hikma 500 mg: each vial contains 500 mg aciclovir as the sodium salt.

Excipient with known effect:

Aciclovir Hikma 500 mg: each vial contains 52.2 mg of sodium.

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 is indicated for:

– the treatment of Herpes simplex infections in immunocompromised patients and severe initial genital herpes in the non-immunocompromised.

– the prophylaxis of Herpes simplex infections in immunocompromised patients.

– treatment of shingles (Varicella zoster virus) in immunocompetent patients in whom a serious course of the illness can be anticipated.

– treatment of initial and recurrent Varicella zoster infections in immunocompromised patients.

– the treatment of herpes encephalitis.

– the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.

4.2 Posology and method of administration

Posology

Adults:

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

Immunocompromised patients with Varicella zoster infections or patients with herpes encephalitis should be given Aciclovir 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 section 5.2). Consideration should therefore be given to dosage reduction in obese patients and especially in those with renal impairment or the elderly.

Paediatric population:

The dose of Aciclovir 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 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 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 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 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 Renal impairment).

Elderly:

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

Adequate hydration should be maintained.

Renal impairment:

Caution is advised when administering Aciclovir 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/1.73 m2 for infants and children less than 13 years of age. The following adjustments in dosage are suggested:

Dosage adjustments in adults and adolescents:

Dosage adjustments in infants and children:

Method of administration:

Intravenous use

Slow intravenous infusion over 1 hour.

A course of treatment with Aciclovir 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 infections 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 is determined by the duration of the period at risk.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance – aciclovir, or valaciclovir, or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Adequate hydration should be maintained in patients given IV or high oral doses of 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 IV aciclovir with other nephrotoxic drugs.

Contact with the eyes and the unprotected skin must be avoided.

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).

Dosage in the elderly: 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. It is recommended that the state of hydration and the creatinine clearance should be evaluated before the administration of high dosages of aciclovir, especially in elderly patients, who may have reduced renal function despite a normal serum creatinine concentration. 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).

In patients receiving Aciclovir 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 has a pH of approximately 11 and should not be administered by mouth.

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).

Aciclovir Hikma 500 mg:

This medicinal product contains 52.2 mg sodium per vial, equivalent to 2.61% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction 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.

If lithium is administered concurrently with high dose aciclovir IV, the lithium serum concentration should be closely monitored because of the risk of lithium toxicity. 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).

An experimental study on five male subjects indicates that concomitant therapy with aciclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with aciclovir.

4.6 Fertility, pregnancy and lactation

Pregnancy:

The use of aciclovir should be considered only when the potential benefits outweight 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. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Breastfeeding:

Following oral administration of 200 mg 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/day. Caution is therefore advised if Aciclovir is to be administered to a nursing woman.

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 acyclovir 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.

4.7 Effects on ability to drive and use machines

Aciclovir 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 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 > 1/1,000 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, 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.

Hepatobiliary 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 intravenous bolus injection but by slow infusion over a one-hour period.

Very rare: renal impairment, acute renal failure and 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 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 aciclovir 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, Nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05AB01.

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.

Resistance to aciclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. Reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.

Monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy has revealed that virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent host and is found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).

5.2 Pharmacokinetic properties

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).

Distribution

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.

Elimination

In adults, the terminal plasma half-life of aciclovir after administration of aciclovir 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.

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 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide (used to adjust pH).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been demonstrated for 12 hours at 15° –25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Store below 25°C.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vials closed with bromobutyl rubber stoppers secured by aluminium collars.

20 ml vial containing 500 mg aciclovir.

Pack sizes of 5 and 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution:

Aciclovir should be reconstituted using the following volumes of either Water for

Injections or Sodium Chloride Intravenous Injection (0.9% w/v) to provide a solution containing 25 mg aciclovir per ml:

Formulation Volume of fluid for reconstitution

500 mg vial          20 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.

Administration:

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

After reconstitution Aciclovir 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.

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 mg and 1000 mg.

When diluted in accordance with the recommended schedules, 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 (0.45% and 0.9% w/v)

Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion

Sodium Chloride (0.45% w/v) and Glucose (2.5% w/v) Intravenous Infusion

Compound Sodium Lactate Intravenous Infusion (Hartmann's So­lution).

Aciclovir 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.

The reconstituted or diluted solutions should not be refrigerated.

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

7 MARKETING AUTHORISATION HOLDER

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mo, N° 8, 8A e 8B

Fervença

2705–906 Terrugem SNT

Portugal