Aciclovir 5%W/W Cream
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aciclovir 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
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.
4.2 Posology and method of administration
Route of administration - topical
Adults and children: 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.
Aciclovir 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 comment
Contraindications
4.3
Hypersensitivity to aciclovir, valaciclovir, propylene glycol or any other ingredients of the preparation.
4.4 Special warnings and precautions
Aciclovir 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 aciclovir dosing should be considered. Such patients should be encouraged to consult a physician concerning the treatment of any infection.
Cetyl alcohol may cause local skin reactions (e.g. contact dermatitis).
Propylene glycol may cause skin irritation.
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 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 Aciclovir Cream is very low.
However, use of the cream should be considered only when the potential benefitsoutweigh the possibility of unknown risks.
In internationally accepted standard tests the systemic administration of acyclovir 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.
Teratogenicity:
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)
Lactation
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 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.
See Clinical Studies in section 5.2
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
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
• Transient burning or stinging following application of aciclovir Cream
• Itching
• Mild drying or flaking of the skin 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 and urticaria 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 untoward effects would be expected if the entire contents of a 20g tube of the cream were ingested. Doses of 800 mg five times daily (4g 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.
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.
Aciclovir is phosphorylated after entry into herpes infected cells to the active compound aciclovir triphosphate. The first step in this process is dependent on the presence of the HSV-coded thymidine kinase. Aciclovir triphosphate acts as an inhibitor of, and substrate for, the herpes-specified DNA polymerase, preventing further viral DNA synthesis without affecting normal cellular processes
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
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 only at 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.
Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice.
In a non-standard test in rats, foetal abnormalities were observed, but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Stearoyl macrogolgycerides
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 sizes: Tubes of 2g, 10g.
6.6 Instructions for use and 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
Relonchem Limited Cheshire House Gorsey Lane Widnes Cheshire WA8 0RP United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20395/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17th May 2005
10 DATE OF REVISION OF THE TEXT
13/10/2014