This information is intended for use by health professionals

1. Name of the medicinal product

Aciclovir 400mg/5ml Oral Suspension

2. Qualitative and quantitative composition

Aciclovir 400mg/5ml

3. Pharmaceutical form

Oral Suspension

4. Clinical particulars
4.1 Therapeutic indications

Aciclovir Suspension is indicated for the following:

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

2. The suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.

3. The prophylaxis of herpes simplex infections in immunocompromised patients.

4. The treatment of herpes zoster (shingles) and varicella (chickenpox) infections.

4.2 Posology and method of administration

For oral administration

Adults:

Treatment of herpes simplex infections:

200mg five times daily, at approximately 4 hourly intervals, omitting the night time 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 400mg.

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, four times daily (every six hours).

Many patients may be managed on a regimen of 400mg twice a day (every twelve hours).

Dosage titration down to 200mg three times daily (every eight hours) or even twice daily (every twelve hours), may prove effective.

Some patients may experience break-through infections on total daily doses of 800mg Aciclovir Suspension.

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 four times daily (every six hours)

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

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

Treatment of herpes zoster and varicella infections:

800mg, five times daily (every four hours), 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.

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 of neonatal herpes virus infections, intravenous aciclovir is recommended.

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

Treatment of varicella infections:

6 years and over:

800mg four times daily

2 to 5 years:

400mg four times daily

Under 2 years:

200mg four times daily.

Treatment should continue for five days.

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

Elderly:

In the elderly, total aciclovir body clearance declines along with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of suspension 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, twice daily (every 12 hours) is recommended.

In the treatment of herpes zoster and varicella infections it is recommended to adjust the dosage to 800mg of suspension twice daily (every 12 hours) for patients with severe renal impairment (creatinine clearance less than 10ml/minute) and to 800mg three times daily (six to eight hourly) for patients with moderate renal impairment (creatinine clearance in the range 10 to 25ml/minute).

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 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 4.8 Undesirable Effects). Prolonged or repeated courses of aciclovir in severely immune-compromised individuals may result in the section of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment (see section 5.1).

Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral dose regimens e.g. for the treatment of herpes zoster infection (4g daily), in order to avoid the risk of possible renal toxicity. 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 Aciclovir Oral Suspension reduces the incidence of chickenpox associated complications in immunocompetent patients.

Excipients in the formulation

This product contains liquid maltitol, a source of fructose and therefore should not be given to those with a hereditary fructose intolerance.

This product contains parahydroxybenzoates which may cause allergic reaction (possibly delayed).

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 coadministered. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

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

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 described amongst Aciclovir exposed subjects have not shown any 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 however be exercised by balancing the potential benefits of treatment against any possible hazard.

Fertility

There is no evidence that Aciclovir Oral Suspension has any effect on female human fertility.

In a study of 20 male patients with normal sperm count, oral aciclovir 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. See clinical studies in section 5.3

Breast-feeding

Following oral administration (200mg 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. Therefore it is advised that the suspension is used with caution whilst breast feeding.

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 patient's ability to drive or operate machinery.

There have been no studies to investigate the effect of acyclovir 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 ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000.

Blood and the lymphatic system disorders

Very rare: Anaemia, leukopenia, thrombocytopenia.

Immune System:

Rare: Anaphylaxis.

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 are usually reported in patients with renal impairment, or with other predisposing factors (see 4.4 Special Warnings and Precautions for Use).

Respiratory, thoracic and mediastinal disorders

Rare: Dyspnoea.

Gastro-Intestinal

Common: Nausea, vomiting, diarrhoea, abdominal pains.

Hepato-biliary

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 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

Renal and urinary disorders

Rare: Increase in blood urea and creatinine.

Very rare: Acute renal failure, renal pain.

Renal pain may be associated with renal failure and crystalluria.

General disorders

Common: 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs and symptoms: 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).

Management: 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. Pharmacological properties
5.1 Pharmacodynamic properties

Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV).

The inhibitory activity of aciclovir for HSV I, HSV II and VZV 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 and VZV 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.

Prolonged or repeated courses of aciclovir in severely immunocompromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment.

Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK; however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro-determined sensitivity of HSV isolates and clinical response to aciclovir therapy is not clear.

5.2 Pharmacokinetic properties

Aciclovir is only partially absorbed from the gut. Mean steady-state peak plasma concentrations (Cssmax) following doses of 200mg aciclovir administered four-hourly were 3.1 microMol (0.7 micrograms/ml) and the equivalent trough plasma levels (Cssmin) were 1.8 microMol (0.4 micrograms/ml). Corresponding steady-state plasma concentrations following doses of 400mg and 800mg aciclovir administered four-hourly were 5.3 microMol (1.2 micrograms/ml) and 8 microMol (1.8 micrograms/ml) respectively and equivalent trough plasma levels were 2.7 microMol (0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml).

In adults the terminal plasma half-life after administration of intravenous 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-carboxymethoxymethylguanine is the only significant metabolite of aciclovir, and accounts for 10-15% 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 is extended by 18% and 40% respectively.

In adults, mean steady state-peak plasma concentrations (Cssmax) following a one hour infusion of 2.5mg/Kg, 5mg/Kg and 10mg/Kg were 22.7 microMol (5.1 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml) respectively. The corresponding trough levels (Cssmin) 7 hours later were 2.2 microMol (0.5 micrograms/ml), 3.1 microMol (0.7 micrograms/ml) and 10.2 microMol (2.3 micrograms/ml), respectively.

In children over 1 year of age similar mean peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250mg/m2 was substituted for 5mg/Kg and a dose of 500mg/m2 was substituted for 10mg/Kg.

In neonates (0 to 3 months of age) treated with doses of 10mg/Kg administered by infusion over a one-hour period every 8 hours the Css max was found to be 61.2 microMol (13.8 micrograms/ml) and Cssmin to be 10.1 microMol (2.3 micrograms/ml). The terminal plasma half-life in these patients was 3.8 hours. A separate group of neonates treated with 15mg/Kg every 8 hours showed approximate dose proportional increases, with Cmax of 83.5 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml).

In the elderly, total body clearance falls with increasing age 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.

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.

5.3 Preclinical safety data

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man. Aciclovir was not found to be carcinogenic in long term studies in the rat and the mouse. Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of aciclovir on fertility. There is no experience of the effect of Aciclovir Suspension on human female fertility. Aciclovir Suspension has been shown to have no definite effect upon sperm count, morphology or motility in man.

Teratogenicity

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits 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.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium methyl hydroxybenzoate (E219)

Sodium propyl hydroxybenzoate (E217)

Citric acid monohydrate (E330)

Xanthan gum (E415)

Liquid maltitol (E965)

Nectar flavour (containing ethyl vanillin, propylene glycol, lactic acid, nature identical and natural flavouring substances)

Purified water.

6.2 Incompatibilities

None known

6.3 Shelf life

24 months – unopened

1 month - opened

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Bottle:

Amber (Type III) glass

Closures:

HDPE, EPE wadded, tamper evident, child resistant closure

Pack:

100ml

6.6 Special precautions for disposal and other handling

Keep out of the reach of children. Shake well before use.

7. Marketing authorisation holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE

8. Marketing authorisation number(s)

PL 00427/0120

9. Date of first authorisation/renewal of the authorisation

21.09.04

10. Date of revision of the text

25/07/2017