Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: LABORATOIRES THEA, 12 RUE LOUIS-BLERIOT, Z.I. DU BREZET, 63017 CLERMONT, FERRAND CEDEX 2, FRANCE
Pharmacotherapeutic group: Antiinfectives, antivirals;
ATC code: S01AD09
VIRGAN is a formulation of 0.15% ganciclovir in a transparent aqueous gel with a hydrophilic polymer base.
Ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl)guanine or DHPG, is a broadspectrum virustatic agent which inhibits the replication of viruses, including viruses of the herpes group, both in vivo and in vitro: herpes simplex types 1 and 2 (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes zoster (HZV).
The mean effective dose (ED50) in vitro of ganciclovir on ocular clinical isolates of the herpes simplex virus is on average 0.23 μg/ml (0.06-0.50). Ganciclovir inhibits in vitro the replication of various adenovirus serotypes. The ED50 is 1.8 to 4.0 μg/ml for Ad 8 and Ad 19, those most frequently seen in ophthalmology.
Herpetic viruses induce one or more cellular kinases in the host cells, which phosphorylise the ganciclovir into its triphosphate derivative. This phosphorylation is carried out mainly in infected cells, as the concentrations of ganciclovir-triphosphate in non-infected cells are 10 times lower.
Ganciclovir-triphosphate works as an antiviral agent by inhibiting the synthesis of viral DNA in two ways: competitive inhibition of viral DNA-polymerases and direct incorporation into viral DNA which has the effect of stopping its elongation.
Studies of ocular pharmacokinetics in rabbits have shown a rapid and relevant penetration of ganciclovir into the cornea and the anterior segment of the eye, allowing concentrations higher than the effective antiviral concentrations over several hours. In fact, after instillation of one drop of ganciclovir gel, the concentrations (Cmax) of ganciclovir measured in the cornea (17μg/g), the conjunctiva (160μg/g), the aqueous humour (1μg/g) and the iris/ciliary body (4μg/g), are higher than the inhibitory concentrations for herpes simplex viruses 1 and 2 (< 0.5μg/ml) over more than 4 hours.
The repeated instillation 4 times a day for 12 days in rabbits with herpetic keratitis does not result in an accumulation of ganciclovir in the plasma.
In man, after daily ocular instillations repeated 5 times a day for 11 to 15 days in the course of treatment of superficial herpetic keratitis, plasma levels determined by means of a precise analytical method (quantification limit: 0.005μg/ml) are very low: on average 0.013μg/ml (0-0.037) which is 640 times lower than levels following a one hour iv infusion of 5mg/kg (Cmax = 8.0 μg/ml). The oral bioavailability of ganciclovir is approximately 6% when taken with food. Ganciclovir has a half life of 2.9 hours, the systemic clearance is 3.64 ml/min/kg and the major route of excretion of ganciclovir is via glomerular filtration of unchanged drug.
Carcinogenic effects in animals were only seen following long term systemic exposure (20 mg/kg orally) with 50-fold the systemic exposure of patients treated with VIRGAN.
Ganciclovir was only positive in three of five different types of genotoxicity assay. Positive results were obtained in the most sensitive assay (mouse lymphoma) at 7,500-fold the systemic exposure in patients treated with VIRGAN, and in the mouse micronucleus assay at 50 mg/kg/iv corresponding to 15,000 times the plasma levels during ocular therapy with VIRGAN.
Intravenous and oral studies with ganciclovir in animals resulted in testicular and ovarian suppression with consequential effects on fertility. Toxicity to the male reproductive system occurred following the systemic exposure of 12-fold in dogs and 19-fold in mice of the systemic exposure of patients treated with VIRGAN. There was impairment of reproductive performance in male mice at 60-fold the systemic exposure of VIRGAN patients. Impairment of reproductive performance in female mice occurred at 3000-fold the systemic exposure of patients treated with VIRGAN. Ganciclovir had no effect on developing mouse foetuses at daily intravenous doses of 36mg/kg, but caused maternal/foetal toxicity and embryo death at daily doses of 108mg/kg. Teratogenic effects in rabbits occurred at 100-fold the systemic exposure in patients treated with VIRGAN.
Ocular use of VIRGAN during 28 days in rabbits, with 5 instillations per day, did not demonstrate any local or systemic toxic effect.
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