Savir Cream is indicated for the treatment of Herpes Simplex virus infections of the skin including initial and recurrent genital herpes and herpes labial.

Adults and children.

Savir Cream should be applied five times daily at approximately four hourly intervals, omitting the night time application.

Savir Cream should be applied to the lesions or impending lesions as soon as possible, preferably during the early 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 for herpes labialis and for 5 days for genital herpes. If healing has not occurred then treatment may be continued for up to an additional 5 days.

Use in the elderly: No special requirement

SAVIR 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 bone marrow transplant recipients) oral acyclovir 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 irritations (e.g. contact dermatitis).

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

No clinically significant interactions have been identified.

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.

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

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

Common

- Mild drying or flaking of the skin

Uncommon                                                                     

- 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.

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

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

No unwanted effects would be expected if the entire contents of a 2.0 g tube of the cream were ingested. 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 dialyzable.

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 several 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 the 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 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 ± 8.71ν1.73 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%-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 9%-14% as 9-carboxymethoxymethylguanine via the kidneys.

Aciclovir is predominantly eliminated via the kidneys, preliminary 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 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 corneu > epidermi >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.

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 histological studies and autopsy. According to the test carried out by Draize, who evaluated the allergic sensitizing 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.

Macrogol Cetostearyl Ether

Cetostearyl alcohol

Liquid paraffin

Propylene glycol

Sodium Lauryl Sulfate

Sodium metabisulfite

Disodium Edetate

Benzyl Alcohol

Purified water

Not applicable

Do not store above 30°C.

Aluminum tube with polyethylene screw cap.

Pack size: 15 g

Not Applicable