SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Aciclovir 5% w/w Cream Boots Antiviral Cold Sore Cream

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1g of Cream contains 50mg aciclovir.

For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Cream.

White to off-white cream.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of Herpes Simplex virus infections of the lips and face (Herpes labialis). This product is not recommended for use in immunocompromised patients.

Do not use in eyes.

4.2    Posology and method of administration

Method of Administration For cutaneous use.

Adults and Children:

Treatment should be initiated as soon as possible after the start of the infection, ideally during the prodromal period or when the lesions first appear.

A thin film of cream should be applied to the infected and immediately adjacent skin areas 5 times daily at 4 hour intervals during the day omitting the night time application.

Treatment should be continued for 5 days, followed by a further 5 days treatment if healing has not occurred.

Patients should wash their hands before and after applying the cream, and avoid unnecessary rubbing of the lesion or touching them with a towel, to avoid aggravating or transferring the infection.

Use in elderly:

No special comment

4.3    Contraindications

Hypersensitivity to aciclovir, valaciclovir, propylene glycol or any other ingredients of the preparation listed in Section 6.1.

4.4    Special warnings and precautions for use

In severely immunocompromised patients (e.g. AIDS patients or recipients of bone marrow transplants) oral dosing should be considered. Such patients should be encouraged to consult a physician concerning the treatment of any infection,

Cold Sore sufferers must avoid transmitting the virus particularly when active lesions are present.

The cream must not be applied to the mucous membranes (e.g. in the oral cavity, the eye or the vagina), as local irritation may occur. Particular care must be taken to avoid contact with the eye.

The excipient propylene glycol can cause skin irritations.

The excipient cetyl alcohol can cause local skin reactions(e.g. contact dermatitis).

Only recommended for use on cold sores on the lips and face.

Aciclovir cream contains a specially formulated base and should not be diluted or used as a base for the incorporation of other medicaments.

4.5    Interaction with other medicinal products and other forms of interaction

Probenecid increases the mean half-life and area under the plasma concentration curve of the systemically administered aciclovir. Other drugs affecting renal physiology could potentially influence the pharmacokinetics of aciclovir. However this is likely to be of little relevance to the cutaneous application of aciclovir.

No interactions with other drugs have been described for topical aciclovir.

4.6 Fertility, pregnancy and breast-feeding

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.

No specific studies of topical aciclovir have been carried out in pregnant women or nursing mothers.

So far, no relevant plasma levels have been measured and no systemic effects have been observed.

However, use of the cream should be considered only when the potential benefit outweighs the possibility of unknown risks.

Teratogenicity:

In internationally accepted standard tests the systemic administration of aciclovir did not produce embryotoxic or teratogenic effects in rabbits, rats or mice.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure to indicate little relevance to clinical use (see section 5.3)

Fertility:

Foetal abnormalities were observed in non-standard tests in rats, but only following such high sub-cutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses greatly in excess of those employed therapeutically. Two generation studies in mice did not reveal any effect of orally administered aciclovir on fertility.

There is no experience of the effect of aciclovir tablets on human female fertility. Aciclovir tablets have been shown to have no definite effect upon sperm count, morphology or motility in man.

Breast-feeding:

Following oral administration of 200 mg 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 breast fed infants to aciclovir doses of up to 0.3mg/kg/day.

See clinical studies in section 5.2

4.7 Effects on ability to drive and use machines

None known.

4.8    Undesirable effects

Frequency: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare >1/10,000, <1/1,000), very rare (<1/10,000).

Immune system disorders: Very rare:

•    Immediate hypersensitivity reactions including angioedema and urticaria

Skin and subcutaneous tissue disorders: Uncommon:

•    Transient burning or stinging following application of aciclovir cream

•    Mild drying or flaking of the skin

•    Itching Rare:

•    Erythema

•    Contact dermatitis following application. Where sensitivity tests have

been conducted, the reactive substances have most often been shown to be components of the cream rather than the active ingredient (aciclovir)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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.

4.9    Overdose

Overdose is unlikely to occur, if the cream is applied locally and as indicated. There are no reports concerning an overdose of aciclovir cream.

No untoward effects would be expected if the entire contents of a 20g tube of the cream were ingested. Doses of 800mg five times daily (4 g per day), have been administered without adverse effects. Single intravenous doses of up to

80mg/kg have been inadvertently administered without adverse effects. However the accidental, repeated overdose of oral aciclovir, over several days has resulted in gastrointestinal effects (nausea and vomiting) and neurological effects (headache and confusion).Aciclovir is dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Aciclovir is a pharmacologically inactive substance. After penetration into cells which are infected with herpes simplex virus types I and II (HSV I & HSV II) or varicella-zoster virus (VZV), aciclovir is converted into a virostatic agent. The conversion of aciclovir is catalysed by viral HSV- or VZV -thymidine kinase. Human thymidine kinase does not use aciclovir effectively as a substrate, hence the toxicity to mammalian host cells is low.

In the infected cell, aciclovir is phosphorylated by viral thymidine kinase to aciclovir monophosphate, which is further converted by cellular enzymes to aciclovir triphosphate. Aciclovir triphosphate has a greater affinity for viral DNA polymerase than host cell DNA polymerase and therefore selectively interferes with the viral enzyme causing inhibition of viral DNA replication. Aciclovir is also incorporated into viral DNA by viral DNA polymerase, which results in chain termination, as aciclovir lacks a 3'-hydroxyl group, preventing addition of nucleotides by 3'-5'- linkage.

In severely immunocompromised patients a longer or repeated treatment with aciclovir can lead to a selection of viral strains with reduced sensitivity. As a result, these patients no longer respond to treatment with aciclovir. Most of the clinical isolates with reduced sensitivity showed a relative lack of virus thymidine kinase. However strains with changed/different virus thymidine kinase or DNA polymerase were also reported. The in vitro exposition of HSV -isolates can also lead to the development of less sensitive strains. The connection between the in vitro determined sensitivity of HSV -isolates and the clinical response to treatment with aciclovir is not clear.

5.2 Pharmacokinetic properties

Absorption and plasma concentrations

Aciclovir penetrates into the skin. The intracutaneous concentration levels are higher than the minimal inhibitory concentration (MIC) in tissue at steady state.

After topical application of aciclovir, no aciclovir plasma concentrations could be determined.

As the aciclovir plasma concentrations following topical application are below the limit of detection, no pharmacokinetic studies are available on topical aciclovir. Therefore, the following data is based on the data after oral or intravenous administration

Plasma protein binding is reported to range between 9 and 33% as a function of dose. The volume of distribution at steady state in adults is 50 ± 8.7 1/1.73 m², or 0.7 1/kg.

Two metabolites could be identified in the urine of patients with normal renal function after single dosing with ¹⁴C-aciclovir: 9-carboxymethoxymethylguanine (2-4% of an administered dose) and 8-hydroxy-9-(2-hydroxyethoxymethyl) guanine (< 0.2% of a dose). Subjects with normal renal function eliminate 62-91% of an aciclovir dose unchanged and 9-14% as 9-carboxymethoxymethyl guanine via the kidneys.

Aciclovir is predominantly eliminated via the kidneys, primarily by glomerular filtration and to a lesser extent by tubular secretion.

In vitro and in vivo studies of aciclovir cream and aciclovir ointment versus aciclovir were carried out to determine the bioavailability of aciclovir in human skin. The in vitro studies used human skin biopsates, whilst the bioassays either used human skin grafts on mice or were carried out in the human eye (3 patients). The following dermal drug concentration gradient emerged for both topical and oral aciclovir: stratum corneum > epidermis > dermis. There was no difference in concentration between cream and ointment.

The upper layers of the epidermis on average showed a 48-fold higher concentration following topical application of aciclovir ointment or cream 5% than after oral dosing, but the drug concentration in the basal epidermis -the site of herpes virus infection - was 2 to 3 times lower following topical application than after dosing.

On the basis of continuous absorption the concentration increased as a function of time (higher drug concentrations being found 48 hours post topical dose than 24 hours post topical dose). Thus short dosing intervals appear rational for the topical treatment of herpes simplex virus (HSV) infections.

5.3 Preclinical safety data

For 24 days, PEG-based Aciclovir Cream 5 or 10% was applied to the shaved (intact and grazed) skin of guinea pigs. The treated area corresponded to 10% of the body surface. There were neither systemic nor local toxic symptoms. This is also confirmed by histologic studies and autopsy. According to the test carried out by Draize, who evaluated the allergic sensitising potential of a substance there were no pathologic findings.

Studies carried out in swine showed that 5% aciclovir cream in a PEG vehicle caused an only minimal (quantitative) delay in epidermal wound healing.

Rabbits had 1, 3 or 6% aciclovir cream in a white petroleum vehicle introduced directly into both eyes 5 times daily at 90-minute intervals for 3 weeks. Neither autopsy nor inspection nor histological examination revealed any changes in the rabbit eyes.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

PEG-5-glycerol-stearate Dimeticone Cetyl alcohol Liquid paraffin White soft paraffin Propylene glycol Purified water

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years unopened.

6 weeks after first opening of container.

6.4    Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5    Nature and contents of container

The cream is filled into tubes or pump dispensers. The tubes consisting of aluminium are closed with a polyethylene cap. The pump dispensers consist mainly of polyethylene and polypropylene.

The tubes and pump dispensers are packed individually into cardboard boxes together with package leaflets.

Pack sizes:

Tubes of 2g

Pump dispensers of 2g

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough

Northamptonshire NN8 6GT UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20417/0094

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/03/2009

10    DATE OF REVISION OF THE TEXT

14/09/2015