4.1. Therapeutic indications

Treatment of herpes simplex virus (HSV) infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).

Suppression of recurrent herpes simplex virus infections.

Prevention of herpes simplex virus infections in immunocompromised patients.

Treatment of herpes zoster infections.

4.2. Posology and method of administration

Aciclovir tablets may be dispersed in a minimum of 50 ml of water or swallowed whole with a little water. Ensure that patients on high doses of acyclovir are adequately hydrated.

Dosage in adults

Treatment of herpes simplex infections: 200 mg Aciclovir should be taken five times daily at approximately four hourly intervals omitting the night timed dose. Treatment should continue for 5 days, but in severe initial infections this may have to be extended.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400 mg 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: 200 mg Aciclovir should be taken four times daily at approximately six-hourly intervals.

Many patients may be conveniently managed on a regimen of 400 mg Aciclovir twice daily at approximately twelve-hourly intervals.

Dosage titration down to 200 mg Aciclovir taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals may prove effective.

Some patients may experience break-through infection on total daily doses of 800 mg 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: 200 mg Aciclovir should be taken four times daily at approximately six-hourly intervals.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg Aciclovir, or alternatively, intravenous dosing could be considered.

The duration of prophylactic administration is determined by the duration of the period at risk.

Treatment of varicella and herpes zoster infections: 800 mg Aciclovir should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.

Dosing should begin as early as possible after the start of an infection: Treatment of herpes zoster yields better results if initiated as soon as possible after the onset of the rash. Treatment of chickenpox in immunocompetent patients should begin within 24 hours after onset of the rash.

Dosage in children

Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: Children aged two years and over should be given adult dosages and children below the age of two years should be given half the adult dose.

For treatment on neonatal herpes virus infections, intravenous aciclovir is recommended.

Treatment of varicella infection

6 years and over:

2 - 5 years:

Under 2 years:

800 mg Aciclovir four times daily.

400mg Aciclovir four times daily.

200mg Aciclovir four times daily.

Treatment should continue for five days.

Dosing may be more accurately calculated as 20 mg/kg bodyweight (not to exceed 800 mg) Aciclovir four times daily.

No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children.

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).

Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained.

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 safe by intravenous infusion. However for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200 mg 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).

4.3. Contraindications

Aciclovir tablets are contraindicated in patients known to be hypersensitive to aciclovir, valaciclovir or to any of the excipients.

4.4. Special warnings and precautions for use

Hydration status:

Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir.

The risk of renal impairment is increased by use with other nephrotoxic drugs.

The data currently available from clinical studies is not sufficient to conclude that treatment with acyclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

This medicine contains less than 1 mmol sodium (23mg) per dosage unit, that is to say, essentially 'sodium-free'.

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)

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).

Aciclovir should also be used with caution in patients with underlying neurological abnormalities, severe hepatic or electrolyte abnormalities or significant hypoxia.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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. Similarly 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 co-administered. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

The risk of renal impairment is increased by the concomitant use of other nephrotoxic drugs.

Antivirals: fatigue has been associated with the combined use of aciclovir and zidovudine.

Aciclovir may increase serum theophylline levels.

4.6. Fertility, pregnancy and lactation

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 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.

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.

Lactation

Following oral administration of 200mg aciclovir five times a day, aciclovir has been detected in 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.

See clinical studies in section 5.2

4.7. Effects on ability to drive and use machines

The clinical status of the patient and the adverse event profile of aciclovir should be borne in mind when considering the patients' ability to drive or operate machinery.

There have been no studies to investigate the effects of aciclovir on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

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, not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Very rare: Anaemia, leukopenia, thrombocytopenia

Not known: Haematological changes, including megaloblastic anaemia

Immune system disorders

Rare: Anaphylaxis

Not known: Lymphadenopathy

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 Special Warnings and Precautions for Use)

Not known: Paraesthesia

Eye disorders

Not known: Visual abnormalities

Cardiovascular disorders

Not known: Peripheral oedema

Respiratory, thoracic and mediastinal disorders

Rare: Dyspnoea

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, abdominal pains

Hepatobiliary disorders

Rare: Reversible rises in bilirubin and liver related enzymes

Very rare: Hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common: Pruritus, rashes (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

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).

Not known: Erythema multiforme, and toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Not known: Myalgia

Renal and urinary disorders

Rare: Increases in blood urea and creatinine

Very rare: Acute renal failure, renal pain

Renal pain may be associated with renal failure and crystalluria

Not known: Renal impairment

Renal impairment is usually reversible but may progress to acute renal failure

General disorders and administration site conditions

Common: Fever, fatigue

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

Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20g aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

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 a management option in the event of symptomatic overdose.