EFMODY Modified-release hard capsule Ref.[50004] Active ingredients: Hydrocortisone

Adrenal crisis

Acute adrenal insufficiency may develop in patients with known adrenal insufficiency or CAH who are on inadequate daily doses or in situations with increased cortisol need. 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. Sudden discontinuation of therapy with hydrocortisone risks triggering an adrenal crisis and death.

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.

Pre-operatively, during serious trauma or during intercurrent illness

Pre-operatively, anaesthetists must be informed if the patient is taking corticosteroids or has previously taken corticosteroids.

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. Where parenteral hydrocortisone is required, the patient should be treated in a facility with resuscitation facilities in case of evolving adrenal crisis.

In less severe situations when parenteral administration of hydrocortisone is not required, for instance low grade infections, moderate fever of any aetiology and stressful situations such as minor surgical procedures, there should be high awareness of the risk of developing acute adrenal insufficiency.

Infections

Infection should not be more likely at a replacement dose of hydrocortisone, but all infections should be taken seriously, and an increase in steroid dose be initiated early (see section 4.2). Patients with AI or CAH are at risk of life-threatening adrenal crisis during infection so clinical suspicion of infection should be high and specialist advice should be sought early.

Immunisation

Treatment schedules of corticosteroids for people with AI or CAH do not cause immunosuppression and are not, therefore, contraindications for administration of live vaccines.

Adverse reactions to corticosteroid replacement therapy

Most adverse reactions to corticosteroids are dose and duration of exposure related. Adverse reactions are therefore less likely when using corticosteroids as replacement therapy. High (supra-physiological) doses 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. Patients should be warned of the signs of diabetes and the need to seek medical advice if they occur.

All glucocorticoids increase calcium excretion and reduce the bone-remodelling rate. Long-term glucocorticoid replacement therapy may therefore reduce bone mineral density (see section 4.8).

Patients should be warned that potentially severe psychiatric adverse reactions; euphoria, mania, psychosis with hallucinations and delirium have been seen in adult patients at replacement doses of hydrocortisone (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids, medical advice should be sought immediately in the case of anaphylactoid symptoms (see section 4.8).

Gastric emptying and motility disorders

Hydrocortisone modified-release hard capsules 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.

Growth retardation

Corticosteroids may cause growth retardation in childhood and adolescence; this may be irreversible. Treatment should be limited to the minimum dose required to achieve desired clinical response and when reduction in dose is possible, the reduction should be gradual. Excessive weight gain with decreased height velocity or other symptoms or signs of Cushing syndrome indicate excessive glucocorticoid replacement. Children require frequent assessment to assess growth, blood pressure, and general well-being.

Accelerated sexual maturation

Adolescents with CAH may show accelerated sexual maturation. Patients should be closely monitored; and if signs of early puberty or accelerated sexual maturation are present, an increase in dose should be considered. Careful and regular monitoring of adolescent patients with dose adjustment according to the response of the individual patient is recommended.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy which have been reported after use of systemic and topical corticosteroids.

Hypokalaemia

Treatment of AI and CAH often warrants additional treatment with mineralocorticosteroids. Potassium should be monitored (see sections 4.5 and 4.8).

Precaution on fertility

In both men and women who have lower fertility due to CAH, fertility may be restored shortly after beginning treatment with Efmody, which can lead to unexpected pregnancies. Patients should be informed of the potential for restored fertility when starting treatment with Efmody, to be able to consider if a contraceptive measure is needed (see section 4.6).

Hydrocortisone is metabolised by cytochrome P450 3A4 (CYP3A4). Concomitant administration of medicinal products that are inhibitors or inducers of CYP3A4 may therefore lead to unwanted alterations in serum concentrations of hydrocortisone with the risk of adverse reactions, particularly adrenal crisis. The need for dose adjustment when such medicinal products are used can be anticipated and patients should be closely monitored.

Medicinal products inducing CYP3A4, requiring a potential increase in Efmody dosing, include but are not limited to:

• Anticonvulsants: phenytoin, carbamazepine and oxcarbazepine
• Antibiotics: rifampicin and rifabutin
• Barbiturates including phenobarbital and primidone
• Antiretroviral medicinal products: efavirenz and nevirapine
• Herbal medicinal products such as St. John's Wort

Medicinal products/substances inhibiting CYP3A4, requiring a potential decrease in hydrocortisone dosing, include but are not limited to:

• Anti-fungals: itraconazole, posaconazole, voriconazole
• Antibiotics: erythromycin and clarithromycin
• Antiretroviral medicinal products: ritonavir
• Grapefruit juice
• Liquorice

The desired actions of hypoglycaemic medicinal products including insulin are antagonised by corticosteroids.

Medicinal products/substances that affect the electrolyte balance may increase the risk of hypokalaemia in patients taking Efmody. These include hypokalaemic diuretics, stimulant laxatives, mineralocorticosteroids (fludrocortisone), tetracosactide (Synacthen), IV amphotericin B and liquorice.

Pregnancy

Hydrocortisone crosses the placenta. Hydrocortisone is preferentially metabolised by placental 11βHSD2 to inactive cortisone reducing the fetal exposure. There are no indications that replacement therapy with hydrocortisone in pregnant women is associated with harmful effects for the fetus. Hydrocortisone for replacement therapy can be used during pregnancy. Studies in animals have shown reproductive toxicity of corticosteroids (see section 5.3).

Breast-feeding

Hydrocortisone is excreted in human milk. However, the doses of hydrocortisone used for replacement therapy probably do not clinically significantly affect the breastfed newborn/infants. Hydrocortisone for replacement therapy can be used during breast-feeding.

Fertility

In both men and women who have lower fertility due to CAH, fertility may be In both men and women who have lower fertility due to CAH, fertility may be restored shortly after beginning treatment with Efmody. In women, a reduction of 17-OH progesterone and androstenedione will lead to a corresponding fall in progesterone and testosterone which may restore menses/fertility. (see section 4.4).

Efmody has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported (see section 4.8). Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and use machines.

Summary of the safety profile

The adverse drug reactions reported to Efmody in the clinical trial programmes for AI and CAH, and from post-marketing surveillance of CAH are discussed in this section.

In the clinical trial programmes of AI and CAH, 284 adverse reactions were reported from 203 Efmody-treated patients. Fatigue was reported very commonly, affecting 11.3% of patients. Headache (5.4%), and Dizziness (4.9%) were reported commonly. The most common adverse reactions observed in CAH only clinical trial programme are weight increased (6.9%), increased appetite (4.8%), decreased appetite (4.1%) , asthenia (4.1%), insomnia (4.1%) and carpal tunnel syndrome (2.8%). Adverse reactions may respond to dose adjustment/ dose optimisation in some individuals (see section 4.2). Two serious adverse reactions of hypokalaemia (2.2%) were reported in the long-term extension study DIUR-006 for patients that were receiving a mineralocorticoid.

Events of adrenal insufficiency, including acute events, were reported in 7.9% of clinical trial participants without causal attribution. Acute adrenal insufficiency has been reported in CAH patients as a post-marketing ADR for Efmody.

Tabulated list of adverse reactions

The adverse reactions reported for Efmody in the pooled population (n= 203) in the clinical trial programme for CAH and AI, and from post-marketing surveillance, are tabulated below. Frequencies are defined as 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), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse reactions:

¹ frequency based on postmarketing reports

Description of selected adverse reactions

Acute adrenal insufficiency should be monitored for and treated promptly in patients with adrenal insufficiency (see sections 4.2 and 4.4).

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids especially when a patient has a history of allergies to medicinal products.

Historical cohorts of adults treated from childhood for AI and CAH have been found to have reduced bone mineral density and increased fracture rates (see section 4.4) - it is unclear if these relate to hydrocortisone therapy using current replacement regimens.

Historical cohorts of adults treated from childhood for AI and CAH have been found to have raised cardiovascular risk factors and a higher risk of cerebrovascular disease than the general population - it is unclear if these relate to hydrocortisone therapy using current replacement regimens.

Paediatric population

Limited paediatric patients were included in the clinical development programme for Efmody. Hydrocortisone has been used for more than 60 years in paediatrics with a safety profile similar to that in adults. Growth retardation has been seen in children treated with hydrocortisone for CAH and can be caused by both the disorder and hydrocortisone. Accelerated sexual maturation has been seen in hydrocortisone-treated paediatric CAH patients and is associated with excess adrenal androgen production (see section 4.4).

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.

Not applicable.