Shi De

Treatment of acute herpetic keratitis (dendritic and geographic ulcers).

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:

Use of the medicinal product in children under 18 years is not recommended since no specific studies have been conducted.

Method of administration

Ocular instillation.

This medicinal product is not indicated in the treatment of cytomegalovirus (CMV) retina infections.

Efficacy in other viral types of keratoconjunctivitis has not been demonstrated.

No specific clinical studies were performed in immunodepressed subjects.

Benzalkonium chloride may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses prior to application and wait at least 15 min before reinsertion. Known to discolour soft contact lenses.

Patients should refrain from driving a vehicle or operating machines on the occurrence of any visual disturbance or other visual symptomatology.

Eye disorders

- Very common (>1/10): Transient burning or stinging sensations

- Common (>1/100, <1/10): Superficial punctate keratitis.

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. Website: www.mhra.gov.uk/yellowcard

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.

Pharmacotherapeutic group: Antiinfectives, antivirals; ATC code: S01AD09

Shi De^® 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 broad-spectrum 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 and mutagenic potential

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 Shi De.

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 Shi De, and in the mouse micronucleus assay at 50 mg/kg/iv corresponding to 15,000 times the plasma levels during ocular therapy with Shi De.

Reproduction, fertility

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 Shi De. There was impairment of reproductive performance in male mice at 60-fold the systemic exposure of Shi De patients. Impairment of reproductive performance in female mice occurred at 3000-fold the systemic exposure of patients treated with Shi De. 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 Shi De.

Ocular toxicity

Ocular use of Shi De during 28 days in rabbits, with 5 instillations per day, did not demonstrate any local or systemic toxic effect.

Not applicable.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.