SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lipsore 5% w/w cream Cymex Ultra

Essential Waitrose Cold Sore 5% w/w Cream

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1g of Cream contains 50mg aciclovir For excipients see 6.1

3.    PHARMACEUTICAL FORM

Cream

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lipsore Cream is indicated in adults and children for the treatment of herpes simplex virus infections of the lips and face (recurrent Herpes Labialis).

Immunocompromised Patients

Lipsore Cream is not recommended for use in immunocompromised patients. Such patients must be advised to consult a physician concerning the treatment of any infection.

4.2    Posology and method of administration

Route of administration - Topical

Adults and children

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

Lipsore Cream should be applied to the lesions or impending lesions as soon as possible, preferably during the earliest stages (prodrome or erythema). Treatment can also be started during the later (papule or blister) stages. Treatment should be continued for at least 4 days. If healing has not occurred, treatment may be continued for up to 10 days. If lesions are still present after 10 days, users should be advised to consult a doctor. Users should wash their hands before and after applying the cream, and avoid unnecessary rubbing of the lesions or touching them with a towel, to avoid aggravating or transferring the infection.

Use in the Elderly No special comment

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. 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.

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

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

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

The excipient propylene glycol can cause skin irritation and the excipient cetyl alcohol can cause Local skin reactions (e.g. contact dermatitis).

Ocular herpes

Lipsore Cream must not be used for treatment of ocular herpes infections. Genital Herpes

Lipsore 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 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 Pregnancy and lactation

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

Systemic exposure to aciclovir from topical application of Lipsore Cream is very low.

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 sub-cutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

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

Lactation

Limited human data show that the drug does pass into breast milk following systemic administration.

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.

However, the dosage received by a nursing infant following maternal use of Lipsore Cream would be expected to be insignificant.

Fertility

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 information on the effect of aciclovir on human female 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.

4.7. Effects on ability to drive and use machines

None known.

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 >1/1000 and <1/100, rare > 1/10,000 and <1/1000, very rare <1/10,000.

Skin and subcutaneous tissue disorders Uncommon

•    Mild drying or flaking of the skin

•    Transient burning or stinging following application of Lipsore Cream

•    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 base rather than aciclovir.

Immune system disorders Very rare

•    Immediate hypersensitivity reactions including angioedema

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 (4g per day), have been administered without adverse effects. Single intravenous doses of up to 80mg/kg have been inadvertently administered without adverse effects. Aciclovir is dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Aciclovir is an antiviral agent which is highly active in vitro against herpes simplex virus (HSV) types 1 and 2. Toxicity to mammalian host cells is low.

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 VSV 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.

In two large, double blind randomised clinical studies involving 1,385 subjects treated over 4 days for recurrent herpes labialis, aciclovir Cream was compared to vehicle cream. In these studies, time from start of treatment to healing was 4.6 days using aciclovir Cream and 5.0 days using vehicle cream (p<0.001). Duration of pain was 3.0 days after start of treatment in the aciclovir Cream group and 3.4 days in the vehicle group (p=0.002). Overall, approximately 60% of patients started treatment at an early lesion stage (prodrome or erythema) and 40% at a late stage (papule or blister). The results were similar in both groups of patients.

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 l/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 914% 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 oral aciclovir were carried out to determine bioavailability of aciclovir in human skin. The in vitro studies used human skin biopsies 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 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 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 pathological changes in the rabbit eyes.

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir does not 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 at systemic doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of orally administered aciclovir on fertility.

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Stearoyl macrogolglycerides

Dimeticone

Cetyl alcohol

Liquid paraffin

White soft paraffin

Propylene glycol

Purified water

6.2. Incompatibilities

Not applicable.

6.3. Shelf life

3 years

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. The tubes consisting of aluminium are closed with a polypropylene cap. The tubes are packed into cardboard boxes together with package leaflets.

Pack size: Tubes of 2g.

6.6. Instruction for use and handling

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

7    MARKETING AUTHORISATION HOLDER

Relonchem Limited Cheshire House, Gorsey Lane Widnes, Cheshire WA8 0RP, UK

8.    MARKETING AUTHORISATION NUMBER

PL 20395/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/10/2005

10 DATE OF REVISION OF THE TEXT

06/03/2015