- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyAdults: Treatment of herpes simplex infections: 200mg aciclovir should be taken five times daily at approximately four hourly intervals omitting the night time dose. Treatment should continue for five days, but in severe initial infections this may have to be extended.In severely immunocompromised patients (eg after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400mg aciclovir or alternatively intravenous dosing could be considered.Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear.Suppression of herpes simplex infections in immunocompetent patients: 200mg aciclovir should be taken four times daily at approximately six-hourly intervals.Many patients may be conveniently managed on a regime of 400mg aciclovir twice daily at approximately twelve-hourly intervals.Dosage titration down to 200mg aciclovir taken three times daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals, may prove effective.Some patients may experience break-through infections on total daily doses of 800mg aciclovir.Therapy should be interrupted periodically at intervals of six to twelve months, in order to observe possible changes in the natural history of the disease.Prophylaxis of herpes simplex infections in immunocompromised patients: 200mg aciclovir should be taken four times daily at approximately six hourly intervals.In severely immunocompromised patients (eg after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400mg aciclovir or, alternatively, intravenous dosing could be considered.The duration of prophylactic administration is determined by the duration of the period at risk.Dosage in the paediatric population: Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: children aged two years and over should be given the adult doses and children below the age of two years should be given half the adult dose. Treatment of varicella infection: children under 2 years should be given 200mg four times daily. Children aged 2-5 years should be given 400mg four times daily. Children aged 6 years and over should be given 800mg four times daily. Treatment should continue for 5 days. Dosing may be more accurately calculated as 20mg/kg bodyweight (not to exceed 800mg four times daily). A liquid formulation might be more suitable for small children.No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children. When treatment of herpes zoster infections is required in immunocompromised children, intravenous dosing should be considered.Dosage in the elderly: The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Dosage in renal impairment below). In the elderly, total aciclovir body clearance declines along with creatinine clearance.Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.Dosage in renal impairment: Caution is advised when administering aciclovir to patients with impaired renal function. Adequate hydration should be maintained.In the management of herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of aciclovir above levels that have been established by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than 10ml/minute) an adjustment of dosage to 200mg aciclovir twice daily at approximately twelve-hourly intervals is recommended.In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800 mg aciclovir twice daily at approximately twelve - hourly intervals for patients with severe renal impairment (creatinine clearance less than 10 ml/minute), and to 800 mg aciclovir three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 25 ml/minute).
Method of administrationAdministration: Patients who experience difficulty in swallowing the tablets may disperse them in a minimum of 50ml water which should be stirred before drinking.For oral administration.
PregnancyExperience in humans is limited so the use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks. Herpes simplex encephalitis and varicella pneumonia constitute a significant risk for mother and foetus and primary genital herpes may retard intrauterine growth and increase the risk of premature birth and neonatal herpes infection. (See section 5.3 Preclinical Safety Data). Aciclovir readily crosses the placenta and levels in cord blood are higher than in maternal serum. 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. 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.
Breast-feedingFollowing oral administration of 200mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6-4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if aciclovir is to be administered to a nursing mother.
Blood and the lymphatic system disordersVery rare: Anaemia, leucopenia and thrombocytopenia.
Immune system disordersRare: Anaphylaxis.
Nervous system disordersCommon: Dizziness and headache.Very rare: Reversible neurological reactions including agitation, tremor, ataxia, dysarthria, psychotic symptoms, encephalopathy, drowsiness, confusional states, hallucinations, somnolence, convulsions, coma and malaise. These effects were usually reported in patients receiving high doses of aciclovir (usually given intravenously), with renal impairment, or with other predisposing factors (see section 4.4). Aciclovir should be used with caution in patients with underlying neurological abnormalities.
Respiratory, thoracic and mediastinal disordersRare: Dyspnoea
Gastrointestinal disordersCommon: Nausea, vomiting, diarrhoea and abdominal pain. Hepato-biliary disordersRare: Reversible rises in bilirubin and liver related enzymes. Very rare: Hepatitis and jaundice.
Skin and sub-cutaneous tissue disordersCommon: Skin rashes, pruritus (including photosensitivity).Uncommon: Urticaria, accelerated diffuse hair loss .Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain.Rare: Angioedema, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis.
Renal and urinary disordersRare: Increases in blood urea and creatinine; renal impairment, usually during intravenous therapy, which is usually reversible and responds to hydration and/or dosage reduction but may progress to acute renal failure in patients with predisposing factors.Very rare: Acute renal failure, renal painRenal pain may be associated with renal failure.
General disordersCommon: Fatigue, fever.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.
Symptoms and signsAciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20 g aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (eg nausea and vomiting) and neurological effects (eg headache and confusion). Overdosage of i.v. 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.
TreatmentPatients 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.
DistributionThere is a wide distribution to various tissues, including the CSF where concentrations achieved are about 50% of those achieved in plasma. Protein binding is reported to range from 9-33%. Aciclovir crosses the placenta and is excreted in breast milk in concentrations approximately 3 times higher than those in maternal serum.
Metabolism and EliminationRenal excretion is the major route of elimination by both glomerular filtration and tubular secretion. The terminal or beta-phase half-life is reported to be about 2-3 hours for adults without renal impairment. As aciclovir persists in the plasma of patients with renal insufficiency, in chronic renal failure this value is increased and may be up to 19.5 hours in anuric patients. As renal function decreases, a greater percentage of the drug is eliminated by metabolic conversion to carboxymethoxymethyl guanine. During haemodialysis the half-life is reduced to 5.7 hours, with 60% of a dose of aciclovir being removed in 6 hours. Faecal excretion may account for about 2% of a dose. In neonates and young infants (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 microMol (13.8 micrograms/ml) and Cssmin to be 10.1 microMol (2.3 micrograms/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).
Shelf-lifeThree years from the date of manufacture.
Shelf-life after dilution/reconstitutionNot applicable.
Shelf-life after first openingNot applicable.
Actavis UK Ltd
Actavis UK Ltd, a subsidiary of Accord Healthcare Ltd, Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
+44 (0)1271 311 200
+44 (0)1271 385 257