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

Adrenal crisis

Acute adrenal insufficiency may develop in patients with known adrenal insufficiency 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 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 CAH do not cause immunosuppression and are not, therefore, contraindications for administration of live vaccines.

Undesirable effects of corticosteroid replacement therapy

Most undesirable effects of corticosteroids are dose and duration of exposure related. Undesirable effects are therefore less likely when using corticosteroids as replacement therapy.

Impaired glucose tolerance and diabetes are associated with treatment with glucocorticoids. 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

Modified-release formulations, such as Efmody 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.

Treatment of CAH often warrants additional treatment with mineralocorticosteroids.

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.

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 adverse consequences 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 breast milk. However, the doses of hydrocortisone used for replacement therapy probably do not clinically significantly affect the child. Hydrocortisone for replacement therapy can be used during breast-feeding.

Fertility

There are no data available for possible effects of Efmody on fertility. There are no indications that hydrocortisone in doses used for substitution therapy affect fertility.

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

Summary of safety profile

In the clinical trial programme the overall most common serious adverse events were acute adrenal insufficiency (4.2% of patients treated with Efmody), another common reaction, in relation to Efmody was fatigue (11.7% of patients), headache (7.5%), increased appetite (5.8%), dizziness (5.8%) and increased weight (5.8%).

Tabulated list of adverse reactions

The commonest reactions reported to Efmody in the pooled population in the clinical trial programme, are tabulated below. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100).

Table 1. Tabulated summary of adverse reactions seen in clinical trial programme:

^* Includes muscular weakness

Description of selected adverse reactions

Adrenal insufficiency (including acute events).

Events of acute adrenal insufficiency were reported during the clinical trial programme but none were considered related to Efmody. Acute adrenal insufficiency should be monitored for and treated promptly in patients with adrenal insufficiency (see section 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 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 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

No 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.