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«1 1. NAME OF THE MEDICINAL PRODUCT Plenadren 5 mg modified-release tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each modified-release tablet ...»

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1

1. NAME OF THE MEDICINAL PRODUCT

Plenadren 5 mg modified-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each modified-release tablet contains hydrocortisone 5 mg.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Modified-release tablet.

The tablets are round (diameter 8 mm), convex and pink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications Treatment of adrenal insufficiency in adults.

4.2 Posology and method of administration Posology 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 of Plenadren 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 of Plenadren 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 treatment. Parenteral 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 parenteral administration of hydrocortisone is not required, for instance low grade infections, fever of any aetiology and stressful situations such as minor surgical procedures, 2 the normal oral daily replacement dose must be increased temporarily; the Plenadren 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 Plenadren. 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 of Plenadren.

Special populations Elderly In case of age-related low body weight, monitoring of the clinical response is recommended and dose adjustment to a lower dose may be required, see also section 5.2.

Renal impairment 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.

Hepatic impairment 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.

Paediatric population The safety and efficacy of Plenadren in children/adolescents aged below 18 years have not yet been established. No data are available, see section 5.2.

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 6.00am and 8.00am 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.





4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use Concomittant infections During acute adrenal insufficiency parenteral administration of hydrocortisone in high doses, together with sodium chloride 9 mg/ml (0.9%) solution for injection, must be given.

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.

3 Patients with concomitant adrenal insufficiency and 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, these patients should be given other hydrocortisone formulations. 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.

4.5 Interaction 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 half-life and thus reduce 4 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 erythromycine, telithromycin, chlarithromycin, 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 also section 4.4.

4.6 Fertility, pregnancy and lactation 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.

Breastfeeding Hydrocortisone is excreted in breast milk. Plenadren can be used during breastfeeding. Doses of hydrocortisone used for replacement therapy are unlikely to have any clinical 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.

4.7 Effects on ability to drive and use machines Plenadren has minor influence on the ability to drive and use machines. Fatigue and episodes of shortlasting vertigo have been reported.

Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and use machines.

4.8 Undesirable effects 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 modifiedrelease 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 5 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 also 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 Plenadren in clinical studies.

Adverse reactions from a controlled study of three months duration are listed below by system organ

class and frequency as follows:

Very common (1/10); common (1/100 to 1/10); uncommon (1/1,000 to 1/100); rare (1/10,000 to 1/1,000); very rare (1/10,000), not known (cannot be estimated from the available data).

Infections and infestations Common: Gastroenteritis, upper respiratory tract infection, viral infection.

Nervous system disorders Common: Sedation, vertigo.

Eye disorders Common: Dry eye.

Gastrointestinal disorders Common: Oesophagitis, nausea, upper abdominal pain, tooth erosion.

Skin and subcutaneous tissue disorders Common: Pruritic rash.

Musculoskeletal and connective tissue disorders Common: Joint swelling.

General disorders and administration site conditions Very common: Fatigue.

Investigations Common: HDL decrease, weight increase.



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