Properties
What is it?
ACICHERPIN 5% (ACICLOVIR CREAM BP) Composition: Each gram of cream contains: Aciclovir BP . . . . . . . . . 50 mg; Cream base Indications: Treatment of herpes simplex virus infections of the lips and face (Herpes labialis). The use of this product is not recommended in immunocompromised patients. Do not use in eyes. Dosage and Administration: For topical use. Adults and Children: Treatment should be started as early as possible after the onset of infection, ideally during the prodromal period or when lesions first appear. Apply a thin layer of cream to the infected and immediately surrounding skin areas 5 times daily at 4-hour intervals during the day, not at night. Treatment should continue for 5 days, then for a further 5 days if healing has not occurred. Patients should wash their hands before and after applying the cream and avoid unnecessary pressure on or rubbing of the lesions with a towel to prevent exacerbation or transmission of infection. Use in the Elderly: No specific indications. Contraindications: Hypersensitivity to aciclovir, valaciclovir, propylene glycol or any other ingredient of the preparation. Warnings and Precautions: In patients with significantly impaired immune systems (e.g. AIDS patients or bone marrow transplant recipients) oral dosing should be considered. Such patients should be advised to consult their doctor regarding the treatment of any infection. Individuals with herpes simplex should avoid transmitting the virus, especially when active lesions are present. The cream should not be used on mucous membranes (e.g. in the mouth, eye or vagina) as local irritation may occur. Particular care should be taken to avoid contact with the eyes. The excipient propylene glycol may cause skin irritation. The excipient cetyl alcohol may cause local skin reactions (e.g. contact dermatitis). Recommended for use only on herpes simplex of the lips and face. Aciclovir cream contains a specially formulated base and must not be diluted or used as a base for mixing other medicinal products. Drug Interactions: Probenecid increases the mean elimination half-life and area under the plasma concentration-time curve of systemically administered aciclovir. Other drugs affecting renal physiology may potentially affect the pharmacokinetics of aciclovir. However, this is likely to be of minor importance with topical aciclovir. No interactions with other drugs have been described with topical aciclovir. Pregnancy and Lactation: Pregnancy: The aciclovir post-marketing pregnancy registry has recorded pregnancy outcomes in women exposed to any form of aciclovir. Based on registry data, there is no evidence of an increase in the incidence of congenital defects in subjects exposed to aciclovir compared with the general population, nor were any congenital defects unique or consequential, suggesting a common cause. Specific studies of topically applied aciclovir have not been conducted in pregnant or lactating women. Relevant plasma levels have not yet been assessed and systemic effects have not been reported. However, the use of the cream should only be considered if the potential benefit outweighs the possibility of unknown risks. Teratogenicity: In internationally accepted standard tests, systemically administered aciclovir has not produced embryo toxic or teratogenic effects in rabbits, rats or mice. In preclinical studies, effects were only observed at exposures sufficiently in excess of the maximum exposure observed in humans, suggesting little relevance for clinical use (see section 5.3). Fertility: Fetal abnormalities have been reported in non-standard tests in rats, but only after high subcutaneous doses which caused maternal toxicity. The clinical significance of these findings is unknown. Primarily reversible adverse effects on spermatogenesis in rats and dogs, along with general toxicity, were only observed at doses significantly in excess of therapeutic doses. In two-generation studies in mice, oral aciclovir had no effect on fertility. There is no experience of the effect of aciclovir tablets on female fertility in humans. As shown in men, aciclovir tablets do not have a defined effect on sperm count, morphology and motility. Breastfeeding: When 200 mg of aciclovir was given orally five times daily, aciclovir was found in breast milk at concentrations 0.6 to 4.1 times the corresponding plasma levels. These levels could potentially affect breast-fed infants at an aciclovir dose of up to 0.3 mg/kg per day. Adverse Effects: Frequency: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000), Very rare (<1/10,000). Immune system disorders: Very rare: Immediate hypersensitivity reactions including angioneurotic oedema and urticaria. Skin and subcutaneous tissue disorders: Uncommon: Transient burning or stinging following application of aciclovir cream; Mild skin dryness or peeling; Itching. Rare: Erythema; Contact dermatitis following application. When sensitivity testing was performed, the reactive substances were most often the components of the cream and not the active ingredient (aciclovir). 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. Overdose: Overdose is unlikely if the cream is used topically as indicated. No data are available on overdose of aciclovir cream. No adverse effects are expected from swallowing the entire contents of a 20g tube of cream. Doses of 800 mg five times daily (4 g daily) have been used without adverse effects. Accidental ingestion of single intravenous doses up to 80 mg/kg has not been associated with adverse effects. However, accidental, repeated overdose of oral aciclovir over several days has resulted in gastrointestinal effects (nausea and vomiting) and neurological effects (headache and confusion). Aciclovir is dialysable. Pharmacological Action: Pharmacodynamic Properties: Aciclovir is a pharmacologically inactive substance. Following penetration into cells infected with herpes simplex virus type I and II (HSV 1 & HSV II) or varicella zoster virus (VZV), aciclovir is converted to a virostatic agent. The conversion of aciclovir is catalysed by viral HSV- or VZV-thymidine kinase. Human thymidine kinase does not efficiently utilise aciclovir as a substrate, hence toxicity to mammalian host cells is low. Within the infected cell, aciclovir is phosphorylated by viral thymidine kinase to aciclovir monophosphate, which is then converted by cellular enzymes to aciclovir triphosphate. Aciclovir triphosphate has a much stronger affinity for viral DNA polymerase than for host cell DNA polymerase and thus selectively affects the viral enzyme, leading to inhibition of viral DNA replication. Aciclovir is also incorporated into viral DNA by viral DNA polymerase, leading to chain termination because aciclovir lacks a 3'-hydroxyl group, which prevents the addition of nucleotides by 3'-5' linkage. In patients with significantly impaired immune systems, prolonged or repeated treatment with aciclovir may result in the selection of viral strains with reduced sensitivity. Consequently, such patients may no longer respond to aciclovir treatment. Most clinical isolates with reduced sensitivity have shown a relative deficiency of viral thymidine kinase. However, strains with altered/different viral thymidine kinase or DNA polymerase have also been reported. In vitro exposure of HSV isolates may also lead to the development of less sensitive strains. The correlation between in vitro sensitivity of HSV isolates and clinical response to aciclovir treatment is uncertain. Pharmacokinetics: Absorption and Plasma Concentrations: Aciclovir penetrates the skin. Skin concentration levels are higher than the minimum inhibitory concentration (MIC) in tissue at steady state. Plasma concentrations of aciclovir cannot be determined after topical application of aciclovir. As plasma concentrations of aciclovir are below the limit of detection with topical use, no pharmacokinetic studies of topical aciclovir have been conducted. Accordingly, the following data are based on data observed with oral or intravenous administration. Plasma protein binding ranges from 9 to 33% depending on the dose. The volume of distribution at steady state in adults is 50 ± 8.7 L/1.73 m2, or 0.7 L/kg. Two metabolites may be detected in the urine of patients with normal renal function after a single dose of 14C-aciclovir: 9-carboxymethoxymethylguanine (2-4% of dose) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine ( <0.2% of dose). In subjects with normal renal function, 62-91% of the aciclovir dose is excreted unchanged by the kidneys and 9-14% as 9-carboxymethoxymethylguanine. Aciclovir is primarily excreted by the kidneys, mainly by glomerular filtration and to a lesser extent by tubular secretion. In vitro and in vivo studies of aciclovir cream and aciclovir ointment and aciclovir have been conducted to determine the bioavailability of aciclovir in human skin. In vitro studies used human skin biopsies, while bioassays were performed on human skin grafts in mice or human eyes (3 patients). The concentration gradient of the preparation in the skin after topical and oral administration of aciclovir was: stratum corneum > epidermis > dermis. No difference was observed in the concentration between cream and ointment. For the upper layers of the epidermis, the concentration was on average 48 times higher after topical application of aciclovir ointment or cream 5% than after oral administration, but the concentration of the preparation in the basal epidermis - the site of herpes virus infection - was 2-3 times lower after topical application than after oral administration. Based on continuous absorption, the concentration increased with time (higher concentration of the preparation was observed locally 48 hours after dosing than 24 hours after dosing). Thus, short dosing intervals are rational for the topical treatment of infections caused by herpes simplex virus (HSV). Storage Conditions: Store at a temperature not exceeding 25°C. Dosage Form: Aluminium tube containing 5 grams of cream, packed in a cardboard box with an insert. Keep out of reach of children. Dispensing Regime: Pharmaceutical product group - III, available without prescription.
