SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Galpharm Aciclovir 5%w/w Cream

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Aciclovir 50 mg/g.

Excipients:

Cetyl alcohol    15mg/g

Propylene glycol    150mg/g

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Cream.

White to off-white cream.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of Herpes Simplex virus infections of the lips and face (Herpes labialis).

4.2    Posology and method of administration

Route of administration - Topical 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.

Treatment should be continued for 5 days, following 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 lesions or touching with a towel, to avoid aggravating or transferring the infection.

Elderly

No special requirements

4.3 Contraindications

Hypersensitivity to Aciclovir, valaciclovir, propylene glycol or any other ingredients of the preparation.

4.4 Special warnings and precautions for use

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

People with particularly severe Herpes labialis should be encouraged to seek medical advice.

Not to be applied to mucous membranes such as inside the mouth or vagina, or on the eye. Particular care should be taken to avoid contact with the eye.

Not for use for the treatment of genital herpes or ocular herpes infections.

Not recommended for use by patients who know they are immunocompromised e.g. by HIV infection, bone marrow transplant or cancer treatment. Such individuals should be encouraged to consult a physician concerning the treatment of any infection.

Cold sore sufferers should be advised to avoid transmitting the virus, particularly when active lesions are present.

The excipient propylene glycol can cause skin irritations and the excipients cetyl alcohol can cause local skin reactions.

Ocular herpes

Galpharm Aciclovir 5% w/w Cream must not be used for treatment of ocular herpes infections.

Genital herpes

Galpharm Aciclovir 5% w/w Cream must not be used for treatment of genital herpes.

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 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 lactation

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.

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

Foetal abnormalities were observed in non-standard tests in rats, but only following such high subcutaneous 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.

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 0.3 mg/kg/day.

A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of aciclovir 5% w/w cream. The birth defects described amongst aciclovir 5% w/w cream exposed subjects have not shown any uniqueness or consistent pattern to suggest a common

cause.

The use of aciclovir 5% w/w cream should be considered only when the potential benefits outweigh the possibility of unknown risks however the systemic exposure to aciclovir from topical application of aciclovir cream is very low.

Limited human data show that the drug does pass into breast milk following systemic administration. However, the dosage received by a nursing infant following maternal use of aciclovir 5% w/w cream would be expected to be insignificant.

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 medicinal product has no influence on the ability to drive or operate machinery.

4.8 Undesirable effects

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

Skin and subcutaneous tissue disorders

Common

-    Mild drying or flaking of the skin Uncommon

-    Itching Rare

-    Erythema

-    Contact dermatitis following application. Where sensitivity tests have been conducted, the reactive substance have most often been shown to be components of the cream base rather than aciclovir.

Immune system disorders

Very rare

- Immediate hypersensitivity reactions including angioedema.

After application of the cream, transient burning or stinging of the treated skin areas may occur.

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.

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 unwanted effects would be expected if the entire contents of a 2.0g tube of the cream were ingested. Doses of 800 mg five times daily (4 g per day), have administered without adverse effects. Single intravenous doses of up to 80 mg/kg have been inadvertently administered without adverse effects. Aciclovir is dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: D06 BB03

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 (VSV), 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 DNS 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 the 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 concentration 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± 8.7v1.73 m , or 0.7 I/kg.

Two metabolites could be identified in the urine of patients with normal renal function after single dosing with ¹⁴C-Aciclovir:    9-

carboxymethoxymethylguanine (2-14% 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 914% as 9-carboxymethoxymethylguanine 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 oral 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 layer 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 oral 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 special treatment of herpes simplex virus (HSV) infections.

Clinical Studies

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.

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 pathogenic 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 petrolatum 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 pathological changes in the rabbit eyes.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Arlatone 983S Dimeticone Cetyl alcohol Liquid paraffin White soft paraffin Propylene glycol (E1520)

Purified water

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years (unopened)

6 weeks (open)

6.4    Special precautions for storage

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

6.5    Nature and contents of container

Aluminium tube with polyethylene screw cap.

Pack size: 2g

6.6    Special precautions for disposal

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7.    MARKETING AUTHORISATION HOLDER

Galpharm Healthcare Limited

Wrafton

Braunton

Devon

EX33 2DL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16028/0136

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/06/2010

10    DATE OF REVISION OF THE TEXT

04/05/2016