PLENADREN Modified-release tablet Ref.[27674] Active ingredients: Hydrocortisone

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 with these conditions.

Using higher than normal doses of hydrocortisone

High (supra-physiological) dosages of hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. Long-term treatment with higher than physiological hydrocortisone doses can lead to clinical features resembling Cushing´s syndrome with increased adiposity, abdominal obesity, hypertension and diabetes, and thus result in an increased risk of cardiovascular morbidity and mortality.

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 bone-remodelling rate. Patients with adrenal insufficiency on long-term glucocorticoid replacement therapy have been found to have reduced bone mineral density.

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.

Thyroid function

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.

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.

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.

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.

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.

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).

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.

Not applicable.