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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 and neonatal herpes Herpes simplex infections usually lasts 14 days for mucocutaneous (skin-eye-mouth) infections and 21 days for disseminated or central nervous system disease ten days.

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.

Children with impaired renal function require an appropriately modified dose, according to the degree of impairment.

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).

Neonates and infants up to three months of age with Herpes simplex infections should be given aciclovir for infusion in doses of 10 mg/kg bodyweight every eight hours. Treatment for neonatal Herpes simplex infections usually lasts ten days.

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:

Creatinine Clearance       Dosage       

25 to 50 ml/min:              The dose recommended above (5 or 10 mg/kg bodyweight) should be given every 12 hours.

10 to 25 ml/min:              The dose recommended above (5 or 10 mg/kg bodyweight) should be given every 24 hours.

0 (anuric) to 10 ml/min:   In patients receiving continuous ambulatory peritoneal dialysis (CAPD) the dose recommended above (5 or 10 mg/kg bodyweight) should be halved and administered every 24 hours. In patients receiving haemodialysis the dose recommended above (5 or 10 mg/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 20 mg/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 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 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.

5.2       Pharmacokinetic properties

Section 4.3 – contraindication to any of the excipients added.

Section 4.4 - information regarding the use in patients with renal impairment updated as follows:

Use in patients with renal impairment and in elderly patients:

The dose of aciclovir for infusion must be adjusted in patients with impaired renal function in order to avoid accumulation of aciclovir in the body (see Dosage in renal impairment). 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.

Section 4.5 updated as follows:

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 described amongst aciclovir exposed subjects compared with the general population, and any birth defects showed no have not shown any uniqueness or consistent pattern to suggest a common cause.  Caution should be exercised by balancing the potential benefits of treatment against any possible hazard.

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.

Section 4.7 updated as follows:

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.

Section 4.8 updated as follows:

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.

Haematological Blood and lymphatic system disorders

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

Immune system disorders

Very rare: Anaphylaxis.

Neurological Psychiatric and nervous system disorders

Very rare: Headache, dizziness, Reversible neurological reactions such as confusion, hallucinations, agitation, tremors, ataxia, dysarthria, somnolence, psychosis psychotic symptoms, encephalopathy, convulsions and coma have been associated with aciclovir for infusion therapy, usually in medically complicated cases.

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, and vomiting have been reported.

Very rare: Diarrhoea, abdominal pain.

Liver Hepato-biliary disorders

Common: Reversible increases in bilirubin and liver-related enzymes

Very rare: Reversible increases in bilirubin, hepatitis and jaundice have been reported on very rare occasions.

Hypersensitivity and Skin and subcutaneous tissue disorders

Common: Rashes including photosensitivity, urticaria, pruritus

Very rare: fevers and rarely dyspnoea, angioedema and anaphylaxis.

Kidney Renal and urinary disorders

Common: Increases in blood urea and creatinine

Rapid increases in blood urea and creatinine levels may occasionally occur in patients given aciclovir for infusion. This is 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.

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.

Gastrointestinal: Nausea and vomiting have been reported.

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

Hypersensitivity and Skin: Rashes including photosensitivity, urticaria, pruritus, fevers and rarely dyspnoea, angioedema and anaphylaxis.

Severe local inflammatory reactions sometimes leading to breakdown of the skin have occurred when formulations of aciciovir for intravenous use have been inadvertently infused into extravascular tissues.

Kidney: Rapid increases in blood urea and creatinine levels may occasionally occur in patients given aciclovir for infusion. This is 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.

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.

Liver: Reversible increases in bilirubin and liver-related enzymes. Hepatitis and jaundice have been reported on very rare occasions.

Neurological: Reversible neurological reactions such as confusion, hallucinations, agitation, tremors, somnolence, psychosis, convulsions and coma have been associated with aciclovir for infusion therapy, usually in medically complicated cases.

Section 4.9 – typographical amendments