Reports of acute toxicity and/or deaths following hydrocortisone overdose are rare. No antidote is available. Symptoms may range from excitement/arousal to mania or psychosis. Signs include high blood pressure, elevated plasma glucose levels and hypokalaemia. Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him/her unusually susceptible to ill effects from hydrocortisone. In which case, symptomatic treatment should be instituted as necessary.
3 years
Not applicable
Tablet core
Hypromellose
Microcrystalline cellulose
Pregelatinised starch (maize)
Colloidal, anhydrous silica
Magnesium stearate
Plenadren 5 mg modified-release tablets
Tablet coating
Macrogol (3350)
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Iron oxide red (E172)
Iron oxide yellow (E172)
Iron oxide black (E172)
Plenadren 20 mg modified-release tablets
Tablet coating
Macrogol (3350)
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Summary of the safety profile
Hydrocortisone is given as replacement therapy aimed at restoring normal cortisol levels. The adverse reaction profile in the treatment of adrenal insufficiency is therefore not comparable to that in other conditions requiring much higher doses of oral or parenteral glucocorticoids.
Overall, the frequency and type of adverse reactions were similar for Plenadren once daily modified-release tablets and hydrocortisone tablets given three times daily in a 12-week study. Fatigue has been reported as very common.
Tabulated list of adverse reactions
A total of 80 patients (173 patient-years of data) have been treated with modified-release hydrocortisone in clinical studies. Adverse reactions from these studies and from postmarketing surveillance are listed below by system organ class and frequency as follows:
Very common (>1/10); Common (>1/100 to <1/10).
|
MedDRA System Organ Class |
Frequency of adverse reactions | |
|
Very common |
Common | |
|
Nervous system disorders |
Vertigo Headache | |
|
Gastrointestinal disorders |
Diarrhoea |
Upper abdominal pain Nausea |
|
Skin and subcutaneous tissue disorders |
Pruritus Rash | |
|
Musculoskeletal and connective tissue disorders |
Arthralgia | |
|
General disorders and administration site conditions |
Fatigue | |
In addition the following adverse reactions have been reported for other hydrocortisone medicinal products given for indications other than adrenal insufficiency replacement therapy in higher doses (frequencies not known).
Immune system disorders
Activation of infection (tuberculosis, fungal and viral infections including herpes).
Endocrine disorders
Induction of glucose intolerance or diabetes mellitus.
Metabolism and nutrition disorders
Sodium and water retention and oedema tendency, hypertension, hypokalemia.
Psychiatric disorders
Euphoria and psychosis, insomnia.
Eye disorders
Increased intraocular pressure and cataract.
Gastrointestinal disorders
Dyspepsia and deterioration of existing gastric ulcer.
Skin and subcutaneous tissue disorders
Cushing-like symptoms, stria, ecchymoses, acne and hirsutism, impaired wound healing.
Musculoskeletal and connective tissue disorders
Osteoporosis with spontaneous fractures.
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 United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
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.
Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids. ATC code: H02AB09.
Pharmacodynamic action
Hydrocortisone is a glucocorticoid and the synthetic form of endogenously produced cortisol. Glucocorticoids are important steroids for intermediary metabolism, immune function, musculoskeletal and connective tissue and the brain. Cortisol is the principal glucocorticoid secreted by the adrenal cortex.
Naturally-occurring glucocorticoids (hydrocortisone and cortisol), which also have salt-retaining properties, are used as replacement therapy in adrenal insufficiency. They are also used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition they modify the body's immune responses to diverse stimuli.
Clinical efficacy
The pivotal study was a randomised, two-period 12-week crossover multi-centre trial in 64 patients with primary adrenal insufficiency, 11 of whom had concomitant diabetes mellitus and 11 had hypertension. The study compared modified-release tablets given once daily with conventional tablets given three times daily using the same daily dose of hydrocortisone (20 to 40 mg).
Compared to conventional tablets given three times daily, once daily modified-release tablets resulted in an increased cortisol exposure during the first four hours after intake in the morning but reduced exposure in the late afternoon/evening and over the 24-hour period (Figure 1).
Figure 1. Observed mean serum cortisol concentration versus clock time following single and multiple dosing in primary adrenal insufficiency patients (n=62) after oral administration of Plenadren given once daily and hydrocortisone thrice daily.
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 Plenadren 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.
10/2016
Shire Services BVBA
Rue Montoyer 47
B - 1000 Brussels
Belgium
This medicinal product does not require any special storage conditions.
HDPE bottles with PP screw cap containing 50 modified-release tablets.
Carton containing 1 bottle of 50 modified-release tablets.
Multipacks containing 100 (2x50), 150 (3x50) and 300 (6x50) modified-release tablets.
Not all pack sizes may be marketed.
Plenadren 5 mg modified-release tablets
EU/1/11/715/001
EU/1/11/715/003
EU/1/11/715/004
EU/1/11/715/005
Plenadren 20 mg modified-release tablets
EU/1/11/715/002
EU/1/11/715/006
EU/1/11/715/007
EU/1/11/715/008
Plenadren has minor influence on the ability to drive and use machines. Fatigue and episodes of short-lasting vertigo have been reported.
Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and use machines.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Date of first authorisation: 3rd November 2011
Date of latest renewal: 8th August 2016
