Plenadren · 4.8 Undesirable effects · 1

HOS-155181 · has-adverse-reaction-information · PDF-Seite 6

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. There was an initial increase in the frequency of adverse reactions in about one in five patients, observed up to eight weeks after first changing from conventional hydrocortisone tablets given three times daily to once daily modified-release tablets. However, these adverse reactions (abdominal pain, diarrhoea, nausea and fatigue) are mild or moderate, transient, of short duration but may require dose adjustment or additional concomitant medicinal products, see section 4.2. 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 Pruritus disorders Rash Musculoskeletal and connective Arthralgia tissue disorders General disorders and administration Fatigue site conditions 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.

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HOS-155177 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 3

HOS-155176 · has-indication-information · PDF-Seite 2

Treatment of adrenal insufficiency in adults.

HOS-155179 · has-interaction-information · PDF-Seite 5

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 half-life and thus reduce circulating levels and increase fluctuations of cortisol (due to shorter terminal half-life). This may require dose adjustment of hydrocortisone. 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 long-term prophylactic treatment with any of the antibiotics, adjustment of the hydrocortisone dosage should be considered. The effect of corticosteroids may be reduced for 3-4 days after treatment with mifepristone. The clinical response needs to be monitored in patients given medicinal products affecting gastric emptying and motility, see section 4.4.

HOS-155180 · has-pregnancy-information · PDF-Seite 5

Pregnancy 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. Breast-feeding Hydrocortisone is excreted in breast milk. Plenadren can be used during breast-feeding. Doses of hydrocortisone used for replacement therapy are unlikely to have any clinically significant impact on the child. Infants of mothers taking high doses of systemic glucocorticoids for prolonged periods may be at risk of adrenal suppression. 5 Fertility 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.

HOS-155178 · has-warning-information · PDF-Seite 4

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. Concomitant infections 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 Modified-release tablets are not recommended in patients with increased gastrointestinal motility, i.e., chronic diarrhoea, due to the risk of impaired cortisol exposure. There are no data in patients with confirmed slow gastric emptying or decreased motility disease/disorder. The clinical response should be monitored in patients w

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