- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Plenadren 5 mg
Plenadren 20 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Plenadren 5 mg
Plenadren 20 mg
For the full list of excipients, see section 6.1.
Plenadren 5 mg
The tablets are round (diameter 8 mm), convex and pink.
Plenadren 20 mg
The tablets are round (diameter 8 mm), convex and white.
Treatment of adrenal insufficiency in adults.
4.2Posology and method of administration
Plenadren is given as maintenance therapy. Oral replacement doses must be individualised according to the clinical response. A common maintenance dose is 20 – 30 mg per day, given once daily in the morning. In patients with some remaining endogenous cortisol production a lower dose may be sufficient. 40 mg is the highest maintenance dose studied. The lowest possible maintenance dosage should be used. In situations when the body is exposed to excessive physical and/or mental stress, patients may need additional substitution of immediate release hydrocortisone tablets especially in the afternoon/evening, see also section ‘Use in intercurrent illness’ where other ways of temporarily increasing the dose of hydrocortisone is described.
Changing from conventional oral glucocorticoid treatment to Plenadren
When changing patients from conventional oral hydrocortisone replacement therapy given three times daily to Plenadren, an identical total daily dose may be given. Due to a lower bioavailability of the daily dose of Plenadren compared to that of conventional hydrocortisone tablets given three times daily (see section 5.2) clinical response needs to be monitored and further dose individualisation may be required. Changing patients from hydrocortisone tablets given twice daily, cortisone acetate or synthetic glucocorticoids to Plenadren has not been studied, but changing to a hydrocortisone equivalent daily dose of Plenadren is recommended in these instances; further dose individualisation may be required.
Use in intercurrent illness
During intercurrent illness, there should be high awareness of the risk of developing acute adrenal insufficiency.
In severe situations, an increase in dose is immediately required and oral administration of hydrocortisone must be replaced with parenteral, preferably intravenous treatment. Intravenous administration of hydrocortisone is warranted during transient illness episodes such as severe infections, in particular gastroenteritis associated with vomiting and/or diarrhoea, high fever of any aetiology or extensive physical stress, such as for instance serious accidents and surgery under general anaesthesia, see section 4.4.
In less severe situations when intravenous administration of hydrocortisone is not required, for instance low grade infections, fever of any aetiology and stressful situations such as minor surgical procedures, the normal oral daily replacement dose must be increased temporarily; the total daily dose should be increased by administering the maintenance dose twice or thrice daily with 8 ± 2 hours intervals (an increase in number of administrations, not increasing the morning dose). This regimen has been documented in over 300 intercurrent illness episodes within the clinical study programme. At the discretion of the treating physician, immediate release hydrocortisone tablets can be given instead of Plenadren or may be added to treatment. Increasing the dose of hydrocortisone at one dose occasion increases the total plasma exposure of cortisol less than proportional, see section 5.2. Once the intercurrent illness episode is over, patients can return to the normal maintenance dose.
In case of
There is no need for dosage adjustment in patients with mild to moderate renal impairment. In patients with severe renal impairment monitoring of the clinical response is recommended and dose adjustment may be required, see section 5.2.
There is no need for dose adjustment in mild to moderate hepatic impairment. In case of severe hepatic impairment, the functional liver mass decreases and thus the metabolising capacity for hydrocortisone. Therefore, monitoring of the clinical response is recommended and dose adjustment may be required, see section 5.2.
The safety and efficacy of Plenadren in children/adolescents aged below 18 years have not yet been established. No data are available.
Method of administration
Patients should be instructed to take Plenadren orally with a glass of water on awakening at least
30 minutes before food intake, preferably in an upright position and between 6.00 am and 8.00 am in the morning. It should be swallowed whole; tablets should not be divided, chewed or crushed. If more than one daily administration is required the morning dose should be given as instructed, additional doses given later during the day can be given with or without food.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4Special warnings and precautions for use
Acute adrenal insufficiency
Acute adrenal insufficiency may develop in patients with known adrenal insufficiency who are
on inadequate daily doses or in situations with increased cortisol need. Events have been reported in patients treated with Plenadren. Adrenal crisis can develop in patients with acute adrenal insufficiency. Therefore, patients should be advised of the signs and symptoms of acute adrenal insufficiency and of adrenal crisis and the need to seek immediate medical attention.
During adrenal crisis parenteral, preferably intravenous administration of hydrocortisone in high doses, together with sodium chloride 9 mg/ml (0.9%) solution for infusion, should be administered according to current treatment guidelines.
During transient illnesses such as low grade infection, fever of any aetiology, stressful situations such as minor surgical procedures, the daily replacement dose must be increased temporarily, see section 4.2, ‘Use in intercurrent illness’. The patient must be carefully informed how to act in these situations and also advised to immediately seek medical attention should an acute deterioration occur; especially in cases of gastroenteritis, vomiting and/or diarrhoea leading to fluid and salt loss, as well as to inadequate absorption of oral hydrocortisone.
Patients with adrenal insufficiency and concomitant retroviral infection, such as HIV, need careful dose adjustment due to potential interaction with antiretroviral medicinal products and increased hydrocortisone dose due to the infection.
Scientific reports do not support immunosuppressive effects of hydrocortisone in doses that have been used for replacement therapy in patients with adrenal insufficiency. Therefore, there is no reason to believe that replacement doses of hydrocortisone will exacerbate any systemic infection or worsen the outcome of such an infection. Moreover, there is no reason to believe that doses of hydrocortisone used for replacement therapy in adrenal insufficiency may reduce the response to vaccines and increase the risk of generalised infection with live vaccines.
Gastric emptying and motility disorders
Using higher than normal doses of hydrocortisone
Old age and low body mass index are known risk factors for common adverse reactions of pharmacological doses of glucocorticoids such as osteoporosis, thinning of skin, diabetes mellitus, hypertension and increased susceptibility to infections.
All glucocorticoids increase calcium excretion and reduce the
Prolonged use of high doses of glucocorticoids may produce posterior subcapsular cataracts, and glaucoma with possible damage to the optic nerves. Such effects have not been reported in patients receiving replacement therapy with glucocorticoids in doses used in adrenal insufficiency.
Psychiatric adverse reactions may occur with systemic glucocorticoids. This may occur during commencement of treatment and during dose adjustments. Risks may be higher when high doses are given. Most reactions resolve after dose reduction, although specific treatment may be necessary.
Patients with adrenal insufficiency should be monitored for thyroid dysfunction as both hypothyroidism and hyperthyroidism may markedly influence the exposure of administered hydrocortisone.
Treatment of primary adrenal insufficiency often warrants addition of a mineralocorticoid.
4.5Interaction with other medicinal products and other forms of interaction
Hydrocortisone interactions listed below have been reported after therapeutic doses of glucocorticoids.
Potent CYP 3A4 inducers such as phenytoin, rifabutin, carbamazepine, barbiturates, rifampicin, St John’s wort and less potent inducers such as the antiretroviral medicinal products efavirenz and nevirapine can enhance the metabolic clearance of cortisol, decrease terminal
Potent CYP 3A4 inhibitors such as ketoconazole, itraconazole, posaconazole, voriconazole erythromycin, telithromycin, clarithromycin, ritonavir and grapefruit juice can inhibit the metabolism of hydrocortisone, and thus increase blood levels. During
The effect of corticosteroids may be reduced for
The clinical response needs to be monitored in patients given medicinal products affecting gastric emptying and motility, see section 4.4.
4.6Fertility, pregnancy and lactation
Plenadren can be used during pregnancy. There is no indication that hydrocortisone replacement therapy in pregnant women with adrenal insufficiency is associated with adverse outcome of the mother and/or the foetus. Untreated adrenal insufficiency during pregnancy is associated with poor outcome of both the mother and the foetus, therefore it is important to continue treatment during pregnancy.
Reproductive studies in animals have shown that glucocorticoids can cause foetal abnormalities and reproductive toxicity, see section 5.3.
The dose of hydrocortisone should be carefully monitored during pregnancy in women with adrenal insufficiency. Dosing according to individual clinical response is recommended.
Hydrocortisone is excreted in breast milk. Plenadren can be used during
Patients with adrenal insufficiency have been shown to have reduced parity, which is most likely due to the underlying disease, but there is no indication that hydrocortisone in doses for replacement therapy will affect fertility.
4.7Effects on ability to drive and use machines
Plenadren has minor influence on the ability to drive and use machines. Fatigue and episodes of
Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and use machines.
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
Tabulated list of adverse reactions
A total of 80 patients (173
Very common (≥1/10); Common (≥1/100 to <1/10).
MedDRA System Organ Class
Frequency of adverse reactions
Nervous system disorders
Upper abdominal pain
Skin and subcutaneous tissue
Musculoskeletal and connective tissue
General disorders and administration
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).
Induction of glucose intolerance or diabetes mellitus.
Metabolism and nutrition disorders
Sodium and water retention and oedema tendency, hypertension, hypokalemia.
Euphoria and psychosis, insomnia.
Increased intraocular pressure and cataract.
Dyspepsia and deterioration of existing gastric ulcer.
Skin and subcutaneous tissue disorders
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 national reporting system listed in Appendix V.
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.
Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids. ATC code: H02AB09.
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.
The pivotal study was a randomised,
Compared to conventional tablets given three times daily, once daily
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.
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
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.
In plasma, cortisol is bound to
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
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.
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.
No pharmacokinetic data are available in children or adolescents.
5.3Preclinical safety data
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.
6.1List of excipients
Pregelatinised starch (maize)
Colloidal, anhydrous silica
Plenadren 5 mg
Titanium dioxide (E171)
Iron oxide red (E172)
Iron oxide yellow (E172)
Iron oxide black (E172)
Plenadren 20 mg
Titanium dioxide (E171)
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
HDPE bottles with PP screw cap containing 50
Multipacks containing 100 (2x50), 150 (3x50) and 300 (6x50)
6.6Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Shire Services BVBA
Rue Montoyer 47
B - 1000 Brussels
8.MARKETING AUTHORISATION NUMBER(S)
Plenadren 5 mg
Plenadren 20 mg
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 3rd November 2011
Date of latest renewal: 8th August 2016
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.