1. Name Of The Medicinal Product
VIRGAN eye gel.
2. Qualitative And Quantitative Composition
Active Ingredient.
Ganciclovir 0.15%.
3. Pharmaceutical Form
Eye gel.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of acute herpetic keratitis (dendritic and geographic ulcers).
4.2 Posology And Method Of Administration
Instil one drop of gel in the inferior conjunctival sac of the eye to be treated, 5 times a day until complete corneal re-epithelialisation. Then 3 instillations a day for 7 days after healing. The treatment does not usually exceed 21 days.
Use in the elderly:
The dosage in the elderly is the same as in adults (see above). There is no need to adjust the dosage in the elderly as in clinical trials patients up to the age of 85 years have been treated and no specific health concerns were observed.
Use in children:
VIRGAN eye gel is not recommended for use in children.
Only limited clinical trial data are available (7 children, range 2-14 years).
4.3 Contraindications
Hypersensitivity to ganciclovir or acyclovir or to any other ingredients of the product.
4.4 Special Warnings And Precautions For Use
The following special warnings and precautions for use should be borne in mind, although systemic effects after ocular instillation are very unlikely. In preclinical testing ganciclovir given systemically caused aspermatogenesis, mutagenicity, teratogenicity, carcinogenicity and suppression of female fertility. These effects in animal studies have been observed at plasma concentrations far exceeding those being seen in humans after therapeutic use of Virgan Eye Gel (see also 5.3). However, ganciclovir should be considered a potential carcinogen and teratogen in humans.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In case of any additional local ocular treatment there should be an application interval of at least 5 minutes between the two medications. VIRGAN Eye Gel should be the last medication instilled.
Although the quantities of ganciclovir passing into the general circulation after ophthalmic use are small, the risk of drug interactions cannot be ruled out.
Interactions with ganciclovir administered systemically have been observed:
Binding of ganciclovir to plasma proteins is only about 1-2% and drug interactions involving binding site displacement are not anticipated.
It is possible that drugs which inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa might have combined additive toxic effects when used concomitantly with, before or after ganciclovir. Because of the possibility of additive toxicity with co-administration of drugs such as dapsone, pentamidine, flucystosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations or other nucleoside analogues, combination with ganciclovir therapy should be used only if the potential benefits outweigh the risks.
Since both zidovudine and ganciclovir can result in neutropenia, it is recommended that these two drugs should not be given concomitantly during induction treatment with ganciclovir. Maintenance ganciclovir treatment plus zidovudine at the recommended dose resulted in severe neutropenia in most patients studied to date.
Generalised seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly.
It is also possible that probenecid, as well as other drugs which inhibit renal tubular secretion or resorption, may reduce renal clearance of ganciclovir and could increase the plasma half-life of ganciclovir.
4.6 Pregnancy And Lactation
Teratogenicity has been observed in animal studies with systemic ganciclovir. There is no experience regarding the safety of VIRGAN eye gel in human pregnancy or lactation. Administration during pregnancy and lactation is therefore not recommended, except for compelling reasons.
4.7 Effects On Ability To Drive And Use Machines
Patients should refrain from driving a vehicle or operating machines on the occurrence of any visual disturbance or other visual symptomatology.
4.8 Undesirable Effects
In some cases, adverse events which did not result in a treatment interruption were observed in relation to the use of VIRGAN eye gel: burning sensations or brief tingling sensations, superficial punctate keratitis, visual disturbance on application.
4.9 Overdose
There is practically no risk of adverse events due to accidental oral ingestion since a tube of 5g contains 7.5mg ganciclovir compared to the daily adult i.v. dose of 500-1000mg.
In the unlikely event of overdose, dialysis and hydration may be of benefit in reducing drug plasma levels.
Toxic manifestations seen in animals given very high single intravenous doses of ganciclovir (500mg/kg) included emesis, hypersalivation, anorexia, bloody diarrhoea, inactivity, cytopenia, abnormal liver function tests and BUN, testicular atrophy and death.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
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 herpetickeratitis 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.
5.3 Preclinical Safety Data
Animal data indicate that a side-effect of systemic ganciclovir is inhibition of spermatogenesis which is reversible at lower doses and irreversible at higher doses. Animal data have also indicated that permanent suppression of fertility in women may occur.
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. In rabbits, ganciclovir had no effect on developing foetuses at daily intravenous doses of 6mg/kg, but caused foetal growth retardation, embryo death, teratogenicity and/or maternal toxicity at daily doses of 20 or 60mg/kg.
Ganciclovir did not cause point mutations in bacterial or yeast cells or dominant lethality in mice, but caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. Ganciclovir was positive in these tests at thousands of times the concentration in plasma of patients undergoing therapy with VIRGAN eye gel.
Ganciclovir was carcinogenic in the mouse after daily oral doses of 20 and 1000mg/kg/day. No carcinogenic effect occurred at the dose of 1mg/kg/day.
Tumour incidence was slightly increased at plasma levels of ganciclovir approximately 50 times human levels following VIRGAN eye gel treatment.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Benzalkonium chloride
Carbomer 974P
Sorbitol
Sodium hydroxide
Purified water
6.2 Incompatibilities
None known to date.
6.3 Shelf Life
In the unopened container: 3 years.
In the opened container: 4 weeks.
6.4 Special Precautions For Storage
Do not store above 25°C.
6.5 Nature And Contents Of Container
5g tube (polyethylene-aluminium) with dropper nozzle (polyethylene) and screw cap (polyethylene) fitted with a detachable plastic base. This base allows the tube to be placed vertically, with the dropper nozzle pointing downwards, thus avoiding an accumulation of air around the opening, which would inhibit the correct formation of drops.
6.6 Special Precautions For Disposal And Other Handling
The package remains sterile until the original closure is broken. Do not use VIRGAN eye gel for more than 28 days after first opening.
7. Marketing Authorisation Holder
LABORATOIRES THEA
12RUE LOUIS-BLERIOT
Z.I. DU BREZET
63017 CLERMONT FERRAND CEDEX 2
FRANCE
8. Marketing Authorisation Number(S)
PL 20162/0006
9. Date Of First Authorisation/Renewal Of The Authorisation
21st July 2000
10. Date Of Revision Of The Text
February 2002
February 2003
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