None known.
Not applicable.
Not applicable
None known.
There are no preclinical safety data of relevance to the consumer.
Carcinogenesis:
Hydrocortisone did not increase tumor incidences in male and female rats during a 2-year carcinogenicity study.
Mutagenesis:
Corticosteroids, a class of steroid hormones that includes hydrocortisone, are consistently negative in the bacterial mutagenicity assay. Hydrocortisone and dexamethasone induced chromosome aberrations in human lymphocytes in vitro and in mice in vivo. However, the biological relevance of these findings is not clear since hydrocortisone did not increase tumor incidences in male and female rats during a 2-year carcinogenicity study. Fludrocortisone (9α-fluorohydrocortisone, structurally similar to hydrocortisone) was negative in the human lymphocyte chromosome aberration assay.
Reproductive toxicity:
Corticosteroids have been shown to reduce fertility when administered to rats. Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to 20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation. With hydrocortisone, cleft palate was observed when administered to pregnant mice and hamsters during organogenesis
Animal experiments have shown that prenatal exposure to very high doses of glucocorticoids can induce malformations (cleft palate, skeletal malformations). Animal studies have also shown that prenatal exposure to high doses of glucocorticoids (but lower than teratogenic doses) may be associated with increased risk of intrauterine growth retardation, cardiovascular disease in adulthood and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour.
None stated.
Not applicable.
The pharmacokinetics of hydrocortisone in healthy male subjects demonstrated nonlinear kinetics when a single intravenous dose of hydrocortisone sodium succinate higher than 20 mg was administered, and the corresponding pharmacokinetic parameters of hydrocortisone are presented in Table 2
Table 2. Mean (SD) hydrocortisone pharmacokinetic parameters following single intravenous doses
| Healthy Male Adults (21-29 years; N = 6) | ||||
| Dose (mg) | 5 | 10 | 20 | 40 |
| Total Exposure (AUC0-∞; ng·h/mL) | 410 (80) | 790 (100) | 1480 (310) | 2290 (260) |
| Clearance (CL; mL/min/m2) | 209 (42) | 218 (23) | 239 (44) | 294 (34) |
| Volume of Distribution at Steady State (Vdss; L) | 20.7 (7.3) | 20.8 (4.3) | 26.0 (4.1) | 37.5 (5.8) |
| Elimination Half-life (t1/2; hr) | 1.3 (0.3) | 1.3 (0.2) | 1.7 (0.2) | 1.9 (0.1) |
AUC0-∞ = Area under the curve from time zero to infinity.
Absorption
Following administration of 5, 10, 20, and 40 mg single intravenous doses of hydrocortisone sodium succinate in healthy male subjects, mean peak values obtained at 10 minutes after dosing were 312, 573, 1095, and 1854 ng/mL, respectively. Hydrocortisone sodium succinate is rapidly absorbed when administered intramuscularly.
Distribution
Hydrocortisone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. The volume of distribution at steady state for hydrocortisone ranged from approximately 20 to 40 L (Table 2). Hydrocortisone binds to the glycoprotein transcortin (i.e., corticosteroid binding globulin) and albumin. The plasma protein binding of hydrocortisone in humans is approximately 92%.
Metabolism
Hydrocortisone (i.e., cortisol) is metabolized by 11β-HSD2 to cortisone, and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol, and 5α-tetrahydrocortisol. Cortisone can be converted to cortisol through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Hydrocortisone is also metabolized by CYP3A4 to 6β-hydroxycortisol (6β-OHF), and 6β-OHF varied from 2.8% to 31.7% of the total metabolites produced, demonstrating large inter-individual variability.
Excretion
Excretion of the administered dose is nearly complete within 12 hours. When hydrocortisone sodium succinate is administered intramuscularly, it is excreted in a pattern similar to that observed after intravenous injection.
Absorption
Following oral administration, hydrocortisone is rapidly and well absorbed from the gastrointestinal tract and the absorption has been reported to be more than 95% for an oral 20 mg dose (tablets). Hydrocortisone is a class II active substance according to the biopharmaceutical classification system (BCS) with a high intestinal permeability and a low dissolution rate, especially at higher doses. The modified-release tablet has an outer coating layer that provides an immediate release of the drug and an extended release core. The immediate-release part provides a rapid onset of absorption and the extended release part provides a more extended plasma profile of cortisol. The bioavailability (AUC0-24h) is 20% lower with the modified-release tablet compared to the same daily dose of hydrocortisone given as conventional tablets three times daily. When the oral dose is increased the total plasma exposure of cortisol increased less than proportional. The exposure increased three-fold when the dose of hydrocortisone modified-release increased from 5 mg to 20 mg.
The absorption rate of hydrocortisone was reduced after food intake resulting in a delay in the time to maximal concentration in plasma from on average less than 1 hour to over 2.5 hours. On the other hand, the extent of absorption and bioavailability was approximately 30% higher for the 20 mg tablet after food intake compared to fasting and there was no absorption failure or dose dumping.
Distribution
In plasma, cortisol is bound to corticosteroid-binding globulin (CBG, also called transcortin) and albumin. The binding is about 90%.
Elimination
The terminal half-life has been reported to be about 1.5 hours following intravenous and oral dosing of hydrocortisone tablets. The terminal half-life of cortisol following administration of Hycort was about 3 hours and formulation release controlled. This terminal half-life is similar to the pharmacokinetics of endogenous cortisol that also is secretion-controlled.
Hydrocortisone (cortisol) is a lipophilic drug that is eliminated completely via metabolism with a low clearance and accordingly low intestinal and hepatic extraction ratios.
Hydrocortisone is eliminated completely by metabolism by 11ßHSD type 1 and type 2 enzymes and CYP 3A4 in the liver and in peripheral tissue. CYP 3A4 is involved in the clearance of cortisol by the formation of 6β-hydroxycortisol which is excreted in urine. The transport of cortisol across membranes is expected to be mediated mainly by passive diffusion and therefore renal and biliary clearances are negligible.
Special populations
Renal impairment
A small amount of cortisol is excreted in the urine unchanged (<0.5% of the daily production), meaning that cortisol is eliminated completely by metabolism. Since severe renal impairment may affect medicinal products completely eliminated via metabolism, dose adjustment may be needed.
Hepatic impairment
No study has been performed in patients with hepatic impairment, however data in the literature for hydrocortisone support that no dose adjustment is required in mild to moderate hepatic impairment. In case of severe hepatic impairment, the functional liver mass decreases and thus the metabolising capacity for hydrocortisone. This may require dose individualisation.
Paediatric population
No pharmacokinetic data are available in children or adolescents.
The topically applied steroid acts locally and so pharmacokinetics are not relevant to its activity.
None.
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
SEE LEAFLET.
1 Shake the canister vigorously before each use.
2 Fill applicator so that the foam fills about ¼ of the applicator body. Only a short press is needed to do this.
3 Wait until foam has stopped expanding.
4 Repeat step 2 until the foam expands to just reach the “Fill†line. This normally takes 2-4 short press/waits.
5 Stand with one leg raised on a chair, or lie down on your left side. Insert gently into back passage and push plunger fully into the applicator.
