SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Virostad Cream 50mg/g aciclovir Aciclovir Cream 50 mg/g Viralief™ Cream 50 mg/g.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1g of Cream contains 50 mg aciclovir Ph.Eur.

3. PHARMACEUTICAL FORM

Cream.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Virostad Cream 50 mg/g aciclovir/Aciclovir Cream 50 mg/g/

Viralief ^TM Cream 50 mg/g (POM packs):

The treatment of herpes simplex virus infections of the skin, including initial genital herpes and herpes labialis. For topical use within 24 hours of onset of prodromal symptoms. Do not use in the eyes.

Virostad Cream 50 mg/g aciclovir/Aciclovir Cream 50 mg/g/

Viralief™ Cream 50 mg/g (P packs):

The treatment of herpes simplex virus infections of the lips and face.

4.2. Posology and method of administration

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, followed by a further 5 days treatment if healing has not occurred.

Virostad Cream 50 mg/g aciclovir/Aciclovir Cream 50 mg/g/

Viralief™ Cream 50 mg/g only (POM packs):

Genital herpes: Medical advice should be obtained prior to treatment of genital herpes.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

The cream is not recommended for application to mucous membranes such as in the mouth, eye or vagina, as it may be irritant. Particular care should be taken to avoid accidental introduction into the eye.

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.

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

Virostad Cream 50 mg/g aciclovir/Aciclovir Cream 50 mg/g/ Viralief™ Cream 50 mg/g (P packs):

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

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 clinically significant interactions have been identified.

4.6 Fertility, pregnancy and lactation

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.

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.

The use of aciclovir should be considered only when the potential benefit outweighs the possibility of unknown risks however the systemic exposure to aciclovir from topical application of aciclovir cream is very low.

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.

Lactation

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

4.7. Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

In this section, frequencies of undesirable effects are defined as follows: very common (> 1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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. When sensitivity tests have been conducted, the reactive substances have most often been shown to be components of the cream rather than the active substance acyclovir.

Immune system disorders

Very rare: Immediate hypersensitivity including angioedema and urticaria.

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 the tube containing 500mg of aciclovir were ingested orally.

Doses of 800 mg five times daily (4 g per day), have been 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

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 treatment with aciclovir is not clear.

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 (2-14% 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 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.

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 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.

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

PEG-5-glycerol-stearate Dimeticone Ph. Eur.

Cetyl alcohol Ph. Eur. Liquid paraffin Ph. Eur. White soft paraffin B.P. Propylene glycol Ph. Eur. Purified water Ph. Eur

6.2. Incompatibilities

None.

6.3. Shelf-life

3 years.

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

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 into card boxes together with package leaflets.

Pack sizes:
Virostad Cream 50 mg/g aciclovir	Tubes of 2,5,10, 20 g (POM)
Virostad Cream 50 mg/g aciclovir	Pump dispensers of 2 g (POM)
Aciclovir Cream 50 mg/g	Tubes of 2, 5,10, 20 g (POM)
Aciclovir Cream 50 mg/g	Pump dispensers of 2 g (POM)
Viralief™ Cream 50 mg/g:	Pump dispensers of 2 g (POM)
Virostad Cream 50 mg/g aciclovir	Tubes of 2, 5, 10, 20 g (P)
Virostad Cream 50 mg/g aciclovir	Pump dispensers of 2 g (P)
Aciclovir Cream 50 mg/g	Tubes of 2, 5, 10, 20 g (P)
Aciclovir Cream 50 mg/g	Pump dispensers of 2 g (P)
Viralief™ Cream 50 mg/g	Pump dispensers of 2 g (P)

6.6. Instructions for use, handling and disposal

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

STADA Arzneimittel AG Stadastrasse 2 - 18 D-61118 BAD VILBEL

GERMANY.

8.    MARKETING AUTHORIZATION NUMBER(S)

PL: 11204/0033.

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

26^th November 1998.

10 DATE OF REVISION OF THE TEXT

26/04/2012