None known
Not applicable.
Not applicable
There are no non-clinical data of relevance to the prescriber that are not already covered in other sections of the SmPC.
The use of prednisolone in ophthalmology is well-established. Little specific toxicology work has been reported, however, the breadth of clinical experience confirms its suitability as a topical ophthalmic agent.
Subchronic/chronic toxicity
Light and electron microscopic changes in the Langerhans' islet cells of rats were observed following daily intraperitoneal administration of 33 mg/kg bw over 7 to 14 days in rats. In rabbits, experimental liver damage could be produced by administering 2 to 3 mg/kg bw/day for 2 to 4 weeks. Histotoxic effects (myonecroses) were reported following several weeks of administration of 0.5 to 5 mg/kg bw in guinea pigs and 4 mg/kg bw in dogs.
Mutagenic and tumour-forming potential
The toxicity observed in animal studies with prednisone was associated with exaggerated pharmacological activity. No genotoxic effects of prednisone have been observed in conventional genotoxicity tests.
Reproductive toxicity
In animal reproduction studies, glucocorticoids such as prednisone have been shown to induce malformations (cleft palate, skeletal malformations). With parenteral administration, minor anomalies of skull, jaw and tongue were found in rats. Intrauterine growth retardation was observed.
Similar effects are considered unlikely to occur in patients at therapeutic doses.
Pred-Fortee is rapidly and apparently almost completely absorbed after oral administration; it reaches peak plasma concentrations after 1-3 hours. There is however wide inter-subject variation suggesting impaired absorption in some individuals. Plasma half-life is about 3 hours in adults and somewhat less in children. Its initial absorption, but not its overall bioavailability, is affected by food. Pred-Fortee has a biological half-life lasting several hours, making it suitable for alternate-day administration regimens.
Although peak plasma Pred-Fortee levels are somewhat lower after administration of Pred-Fortee and absorption is delayed, total absorption and bioavailability are the same as after plain Pred-Fortee. Pred-Fortee shows dose dependent pharmacokinetics, with an increase in dose leading to an increase in volume of distribution and plasma clearance. The degree of plasma protein binding determines the distribution and clearance of free, pharmacologically active drug. Reduced doses are necessary in patients with hypoalbuminaemia.
Pred-Fortee is metabolised primarily in the liver to a biologically inactive compound. Liver disease prolongs the half-life of Pred-Fortee and, if the patient has hypoalbuminaemia, also increases the proportion of unbound drug and may thereby increase adverse effects.
Pred-Fortee is excreted in the urine as free and conjugated metabolites, together with small amounts of unchanged Pred-Fortee.
Significant differences in the pharmacokinetics of Pred-Fortee amongst menopausal women have been described. The postmenopausal women had reduced unbound clearance (30%), reduced total clearance and increased half-life of Pred-Fortee.
The pharmacokinetic profile of RAYOS has an approximately 4-hour lag time from that of immediate-release prednisone formulations. While the pharmacokinetic profile of RAYOS when given with food differs in terms of lag time from IR prednisone, its absorption, distribution, and elimination processes are comparable.
AbsorptionPrednisone is released from RAYOS when taken with food approximately 4 hours after oral ingestion. This causes a delay in the time until peak plasma concentrations (Tmax) are achieved. Median Tmax of RAYOS in 27 healthy male subjects was 6.0 - 6.5 hours compared to 2.0 hours for an immediate-release (IR) formulation. Subsequently, prednisone was absorbed at the same rate as the IR formulation. Peak plasma concentrations (Cmax) and exposure, as indicated by AUC0-last and AUC0-∞, were comparable for both prednisone IR and RAYOS administered 2.5 hours after a light meal or with normal meal (Figure 1).
Figure 1: Mean Plasma Levels of Prednisone After a Single Dose of 5 mg Prednisone Administered as a 5 mg RAYOS Tablet or a 5 mg Immediate-Release (IR) Tablet
A: 5 mg IR tablet under fasting conditions, administered at 2 am, B: 5 mg RAYOS, administered 2.5 hours after a light evening meal, and C: 5 mg RAYOS administered immediately after dinner
In a study with 24 healthy subjects, oral absorption of prednisone from RAYOS was significantly affected by the intake of food. Under standard fasting conditions, both the maximum plasma concentration (Cmax) and the bioavailability of RAYOS were significantly lower than under fed conditions, shortly after intake of a high fat meal.
RAYOS at dose levels of 1 mg, 2 mg, and 5 mg showed dose-proportionality in terms of peak and systemic exposure (Cmax, AUC0-∞, and AUC0-last) for the parent drug prednisone as well as for the active metabolite prednisolone.
MetabolismPrednisone is completely converted to the active metabolite prednisolone, which is further metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The exposure of prednisolone is 4-6 fold higher than that of prednisone.
ExcretionThe terminal half-life of both prednisone and prednisolone from the administration of RAYOS was 2-3 hours, which is comparable to that from the IR formulation.
The oral availability, distribution and excretion of prednisolone is well documented. A figure of 82 ± 13% has been quoted as the oral availability and 1.4 ± 0.3ml/min/kg as the clearance rate. A half life of 2.1 - 4.0 hours has been calculated.
With regard to ocular pharmacokinetics, Pred-Forte is a highly water soluble compound and is almost lipid insoluble. Therefore, theoretically it should not penetrate the intact corneal epithelium. Nevertheless, 30 minutes after instillation of a drop of 1% drug, corneal concentrations of 10µg/g and aqueous levels of 0.5µg/g have been attained. When a 0.5% solution was instilled in rabbit eyes every 15 minutes for an hour, an aqueous concentration of 2.5µg/ml was measured. Considerable variance exists in the intraocular penetration of prednisolone depending on whether the cornea is normal or abraded.
Absorption
It can be seen that only low levels of prednisolone will be absorbed systemically, particularly where the cornea is intact.
Any prednisolone which is absorbed will be highly protein-bound in common with other corticosteroids.
The pharmacokinetic profile of Pred-Forte has an approximately 4-hour lag time from that of immediate-release prednisone formulations. While the pharmacokinetic profile of Pred-Forte when given with food differs in terms of lag time from IR prednisone, its absorption, distribution, and elimination processes are comparable.
AbsorptionPrednisone is released from Pred-Forte when taken with food approximately 4 hours after oral ingestion. This causes a delay in the time until peak plasma concentrations (Tmax) are achieved. Median Tmax of Pred-Forte in 27 healthy male subjects was 6.0 - 6.5 hours compared to 2.0 hours for an immediate-release (IR) formulation. Subsequently, prednisone was absorbed at the same rate as the IR formulation. Peak plasma concentrations (Cmax) and exposure, as indicated by AUC0-last and AUC0-∞, were comparable for both prednisone IR and Pred-Forte administered 2.5 hours after a light meal or with normal meal (Figure 1).
Figure 1: Mean Plasma Levels of Prednisone After a Single Dose of 5 mg Prednisone Administered as a 5 mg Pred-Forte Tablet or a 5 mg Immediate-Release (IR) Tablet
A: 5 mg IR tablet under fasting conditions, administered at 2 am, B: 5 mg Pred-Forte, administered 2.5 hours after a light evening meal, and C: 5 mg Pred-Forte administered immediately after dinner
In a study with 24 healthy subjects, oral absorption of prednisone from Pred-Forte was significantly affected by the intake of food. Under standard fasting conditions, both the maximum plasma concentration (Cmax) and the bioavailability of Pred-Forte were significantly lower than under fed conditions, shortly after intake of a high fat meal.
Pred-Forte at dose levels of 1 mg, 2 mg, and 5 mg showed dose-proportionality in terms of peak and systemic exposure (Cmax, AUC0-∞, and AUC0-last) for the parent drug prednisone as well as for the active metabolite prednisolone.
MetabolismPrednisone is completely converted to the active metabolite prednisolone, which is further metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The exposure of prednisolone is 4-6 fold higher than that of prednisone.
ExcretionThe terminal half-life of both prednisone and prednisolone from the administration of Pred-Forte was 2-3 hours, which is comparable to that from the IR formulation.
Absorption
Lodotra are prednisone-containing modified-release tablets. Prednisone is released between 4 - 6 hours following intake of Lodotra. Subsequently, prednisone is rapidly and almost completely absorbed.
Distribution
Peak serum levels are reached approximately 6 - 9 hours after intake.
Biotransformation
More than 80 % of the prednisone is converted to prednisolone by first-pass hepatic metabolism. The ratio of prednisone to prednisolone is approximately 1:6 to 1:10. Prednisone itself exerts negligible pharmacologic effects. Prednisolone is the active metabolite. The compounds are reversibly bound to plasma proteins with high affinity for transcortin (corticosteroid binding globulin, CBG) and low affinity for plasma albumin.
In the low dose range (up to 5 mg), approximately 6% of free prednisolone is present. Metabolic elimination is dose linear in this range. In the dose range above 10 mg, the binding capacity of transcortin is increasingly exhausted and more free prednisolone is present. This may result in a faster metabolic elimination.
Elimination
Prednisolone is primarily eliminated by hepatic metabolism, to approximately 70 % by glucoronidation and to approximately 30 % by sulphatation. There is also conversion to 11ß,17ß-dihydroxyandrosta-1,4-dien-3-one and to 1,4-pregnadien-20-ol. The metabolites exhibit no hormonal activity and undergo primarily renal elimination. Negligible amounts of prednisone and prednisolone are found unchanged in the urine. The plasma elimination half-life of prednis(ol)one is approximately 3 hours. In patients with severe hepatic dysfunction the half-life may be prolonged and a dose reduction should be considered. The duration of the biological effects of prednis(ol)one exceeds the duration of the presence in the serum.
Bioavailability
A bioavailability study in 27 healthy subjects conducted in 2003 revealed the following results in comparison with a prednisone immediate-release tablet:
| Parameter | Lodotra 5 mg: 2.5 hours after a light meal | Lodotra 5 mg: Immediately after a meal | Reference preparation 5 mg fasted |
| Maximum plasma concentration (Cmax): ng/ml | 20.2 (18.5; 21.9) | 21.8 (20.0; 23.7) | 20.7 (19.0; 22.5) |
| Time of maximum plasma concentration (tmax): h | 6.0 (4.5; 10.0) | 6.5 (4.5; 9.0) | 2.0 (1.0; 4.0) |
| Duration of the delay of drug release (tlag): h | 4.0 (3.5; 5.0) | 3.5 (2.0; 5.5) | 0.0 (0.0; 0.5) |
| Area under the concentration-time curve (AUC 0-∞): ng x h/ml | 110 (101; 119) | 123 (114; 133) | 109 (101; 118) |
Values are least-square geometric means and range
Figure: Mean plasma levels of prednisone after a single dose of 5 mg prednisone administered as Lodotra 5 mg or an immediate-release tablet. 5 mg immediate-release tablet (A: fasted, intake at 2 am), Lodotra 5 mg (B: 2.5 hours after a light evening meal) and Lodotra 5 mg (C: immediately after a full evening meal).
The plasma concentration profiles of Lodotra are very similar to an immediate-release tablet, with the important difference that the Lodotra profile is delayed with 4 - 6 hours after drug intake. Lower plasma concentrations have been observed in 6-7% of doses.
Dose proportionality was demonstrated for Lodotra 1 mg, 2 mg and 5 mg based on AUC and Cmax.
Not available
Each Minims unit should be discarded after a single use.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Not applicable.
