None known.
Acute toxicity:
In mice and rats, the LD50 for Dexafort (Dexamethasone) after a single oral dose is 16 g/kg body and over 3 g/kg body weight, respectively, within the first 7 days. Following a single subcutaneous dose, the LD50 in mice is more than 700 mg/kg body weight and in rats about 120 mg/kg body weight, within the first 7 days.
Over a period of 21 days, these values become lower, which is interpreted as a consequence of serious infectious diseases caused by the hormone-induced immunosuppression.
Chronic toxicity:
There are no data on chronic toxicity in humans and animals. Corticoid-induced intoxications are not known. In longer-term treatment with doses above 1.5 mg/day, pronounced undesirable effects can be expected.
Mutagenic and tumorigenic potential:
The available study findings for glucocorticoids show no evidence of clinically relevant genotoxic properties.
Reproductive toxicity:
In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intrauterine growth can be delayed. All these effects were seen at high dosages.
Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the maximum dose for human indicating little relevance to clinical use.
No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application.
Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in rabbits following delivery of the implant to the posterior segment of the eye.
Repeat dose topical ocular safety studies with dexamethasone in rabbits have shown systemic corticosteroid effects. Such effects are considered to be unlikely when Dexafort (Dexamethasone) is used as recommended.
Dexamethasone was clastogenic in the in vitro human lymphocyte assay and in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional carcinogenicity studies with Dexafort (Dexamethasone) have not been performed.
Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development.
There are no other preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.
Absorption and distribution
After oral administration, Dexafort (Dexamethasone) is rapidly and almost completely absorbed in the stomach and small intestine. Its bioavailability is 80-90%. Maximum blood levels are reached between 60 and 120 minutes. The binding of Dexafort (Dexamethasone) to plasma albumins is dose-dependent. At very high doses, the largest portion circulates freely in the blood. In hypoalbuminaemia the proportion of the unbound (active) corticoid rises.
Biotransformation
The average (serum) elimination half-life of Dexafort (Dexamethasone) in adults is 250 minutes (+ 80 minutes). Due to its long biological half-life of more than 36 hours, daily continuous administration of Dexafort (Dexamethasone) can lead to accumulation and overdosing.
Elimination
The elimination is largely renal in the form of free Dexafort (Dexamethasone) alcohol. Dexafort (Dexamethasone) is partly metabolised, the metabolites are excreted as glucuronates or sulfates, also mainly by the kidneys.
Renal and hepatic impairment
Renal function impairment has no relevant effect on the clearance of Dexafort (Dexamethasone). However, the elimination half-life is prolonged in severe liver disease.
Plasma concentrations were obtained from a subset of 21 patients in the two RVO, 6-month efficacy studies prior to dosing and on days 7, 30, 60 and 90 following intravitreal injection of a single intravitreal implant containing 350 µg or 700 µg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the 350 µg dose group and 86% for the 700 µg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.094 ng/mL was observed in one subject from the 700 µg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
Plasma concentrations were obtained from a subgroup of patients in the two DME pivotal studies prior to dosing and on days 1, 7, and 21, and months 1.5 and 3 following intravitreal injection of a single intravitreal implant containing 350 µg or 700 µg dexamethasone. One hundred percent of the plasma dexamethasone concentration values for the 350 µg dose group and 90% for the 700 µg dose group were below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of 0.102 ng/mL was observed in 1 subject from the 700 µg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
In a 6-month monkey study following a single intravitreal injection of OZURDEX the dexamethasone vitreous humour Cmax was 100 ng/mL at day 42 post-injection and 5.57 ng/mL at day 91. Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order of dexamethasone concentration was retina > iris > ciliary body > vitreous humour > aqueous humour > plasma.
In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were observed. This is consistent with results from rabbit and monkey ocular metabolism studies.
Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in bile and urine.
The OZURDEX matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis, then further degrades into carbon dioxide and water.
Dexamethasone is absorbed rapidly after oral administration with a half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects. In plasma dexamethasone protein binding is less than for most other corticosteroids. Corticosteroids diffuse into tissue fluids and cerebrospinal fluid but transplacental diffusion in significant amounts has not been demonstrated. Corticosteroids are metabilised in the liver the kidney and excrete in the urine. Metabolism is similar to other corticosteroids. Intraocular penetration occurs in significant amounts and contributes to the effectiveness of dexamethasone in anterior segment inflammatory disease.
No special requirements for disposal.
OZURDEX is for single use only.
Each applicator can only be used for the treatment of a single eye.
If the seal of the foil pouch containing the applicator is damaged, the applicator must not be used. Once the foil pouch is opened the applicator should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Do not touch dropper tip to any surface as this may contaminate the contents.
If the drop of medication is not retained in the eye upon dosing for any reason then instill another drop.
