4.1. Therapeutic indications

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

Zovirax I.V. is indicated for the prophylaxis of Herpes simplex infections in immunocompromised patients.

Zovirax I.V. is indicated for the treatment of Varicella zoster infections.

Zovirax I.V. is indicated for the treatment of herpes encephalitis.

Zovirax I.V. is indicated for the treatment of Herpes simplex infections in the neonate and infant up to 3 months of age.

4.2. Posology and method of administration

Route of administration: Slow intravenous infusion over 1 hour.

A course of treatment with Zovirax 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 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 Zovirax 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 Zovirax I.V. in doses of 5 mg/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 Zovirax I.V. 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 who receive aciclovir intravenously based on their actual body weight, increased plasma concentrations may be obtained (see 5.2 Pharmacokinetic properties). A dose reduction should therefore be considered in obese patients, especially in patients with renal impairment or in elderly patients.

Dosage in infants and children: The dose of Zovirax I.V. for infants and children aged between 3 months and 12 years is calculated on the basis of body surface area.

Infants and children 3 months of age or older with Herpes simplex (except herpes encephalitis) or Varicella zoster infections should be given Zovirax I.V. 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, Zovirax I.V. 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 Zovirax 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 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).

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 Zovirax 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/min/1.73 m2 for infants and children less than 12 years of age. The following adjustments in dosage are suggested:

Dosage adjustments in adults and adolescents with renal impairment for treatment of Herpes Simplex or Varicella Zoster virus infections:

Creatinine Clearance

Dosage for Herpes simplex infection or Varicella zoster

Dosage for Herpes encephalitis or immune-compromised patients with Varicella zoster

25 to 50 ml/min

5 mg/kg body weight given every 12 hours.

10 mg/kg body weight given every 12 hours.

10 to 25 ml/min

5 mg/kg body weight given every 24 hours.

10 mg/kg body weight given every 24 hours.

0 (anuric) to 10 ml/min

2.5 mg/kg body weight given every 24 hours.

5 mg/kg body weight given every 24 hours.

Patients on haemodialysis

2.5 mg/kg body weight given every 24 hours after dialysis.

5 mg/kg body weight given every 24 hours after dialysis.

Dosage adjustments in neonates, infants and children with renal impairment for treatment of Herpes Simplex or Varicella Zoster virus infections:

Creatinine Clearance

(mL/min/1.73 m2)

Dosage for Herpes simplex infection or Varicella zoster

Dosage for Herpes encephalitis or immune-compromised patients with Varicella zoster

25 to 50 ml/min

250 mg/m2 body surface area given every 12 hours.

500 mg/m2 body surface area given every 12 hours.

10 to 25 ml/min

125 mg/m2 body surface area given every 12 hours.

250 mg/m2 body surface area given every 12 hours.

0 (anuric) to 10 ml/min

62.5 mg/m2 body surface area given every 12 hours.

125 mg/m2 body surface area given every 12 hours.

Patients on haemodialysis

62.5 mg/m2 body surface area given every 12 hours after dialysis.

125 mg/m2 body surface area given every 12 hours after dialysis.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Severe cutaneous adverse reactions:

Cases of severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and erythema multiforme (EM) have been reported in patients treated with aciclovir.

As SCARs can be life-threatening or fatal, if signs and symptoms suggestive of SCARs appear, treatment with aciclovir must be discontinued immediately, and alternative treatment should be given. Patients who have developed SCARs with the use of aciclovir or valaciclovir must not receive aciclovir (see Contraindications and Adverse Reactions).

Adequate hydration should be maintained in patients given i.v. 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 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 Posology and method of administration). 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 the reported cases, these reactions were generally reversible on discontinuation of treatment (see section 4.8 Undesirable effects). 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 Zovirax I.V. 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 Zovirax I.V. has a pH of approximately 11 and should not be administered by mouth. Product contains sodium (26mg, approx. 1,13mmol). To be taken into consideration by patients on a controlled sodium diet.

Zovirax I.V. 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 infusion only

Keep out of the reach and sight of children

Store below 25°C

Prepare immediately prior to use

Discard unused solution

Excipients

250mg: This medicinal product contains 28.03 mg sodium per vial, equivalent to 1.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

500mg: This medicinal product contains 56.06 mg sodium per vial, equivalent to 2.8% 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 Zovirax caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma concentrations 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 Zovirax with drugs which affect other aspects of renal physiology (e.g. cyclosporin, 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

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 1 g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

See clinical studies in section 5.2

Pregnancy:

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

Caution should therefore be exercised by balancing the potential benefits of treatment against any possible hazard. Findings from reproduction toxicology studies are included in Section 5.3.

Breast-feeding:

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 concentrations. These concentrations would potentially expose nursing infants to aciclovir dosages of up to 0.3 mg/kg body weight/day. Caution is therefore advised if Zovirax 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 ≥ 1/1,000 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 4.4 Special Warnings and Precautions for Use).

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: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) (see Special warnings and precautions for use), angioedema.

Renal and urinary disorders:

Common: increases in blood urea and creatinine.

Rapid increases in blood urea and creatinine concentrations are believed to be related to the peak plasma concentrations 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 Zovirax I.V. 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Patients 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 of this drug.