4.1. Therapeutic indications

Efmody is indicated in adolescents aged 12 years and over and adults for the:

• Treatment of adrenal insufficiency (AI)

• Treatment of congenital adrenal hyperplasia (CAH)

4.2. Posology and method of administration

Posology

Treatment should be initiated by physicians experienced in the management of AI and/or CAH.

As maintenance therapy the dose must be individualised according to the response of the individual patient. The lowest possible dose should be used.

Monitoring of the clinical response is necessary and patients should be observed closely for signs that might require dose adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, changes in electrolytes particularly hypokalaemia (see section 4.4) or hyponatraemia , individual responsiveness to the medicinal product, and the effect of stress (e.g. surgery, infection, trauma). As the treatment has a modified release profile when, in CAH, blood tests are used to monitor clinical response, assessment of the evening dose should be done with a morning blood test and assessment of the morning dose should be done with an early afternoon blood test.

During excessive physical and/or mental stress it may be necessary to increase the dose of Efmody, and/or add additional immediate release hydrocortisone especially in the afternoon or evening.

Dose adjustments should be considered in case of concomitant use of potent CYP3A4 inducers or inhibitors (see section 4.5).

Treatment in AI and CAH

Recommended replacement doses of hydrocortisone are 10-15 mg/m2/day (CAH) and 8‑10 mg/m2/day (other forms of AI) in adolescents aged 12 years and over who have not completed growth, and 15-25 mg/day in adolescents who have completed growth and adult patients with AI or CAH. In patients with some remaining endogenous cortisol production a lower dose may be sufficient.

At initiation the total daily dose should be split into two doses with two thirds to three quarters of the dose given in the evening at bedtime and the rest given in the morning. Patients should then be titrated based on their individual response.

The morning dose should be taken on an empty stomach at least 1 hour before a meal and the evening dose taken at bedtime at least 2 hours after the last meal of the day.

Changing from conventional oral glucocorticoid treatment to Efmody

When changing patients from other oral hydrocortisone replacement therapy to Efmody, the identical total daily dose should be given, but the dose should be given in two doses with two thirds to three quarters of the dose given in the evening at bedtime and the rest given in the morning.

When changing patients from other glucocorticoids to Efmody an appropriate conversion factor should be used, and the patient monitored for response carefully.

Conversion to Efmody might elicit symptoms of adrenal insufficiency or overreplacement during dose optimisation.

A starting dose exceeding 40 mg per day of hydrocortisone is not recommended.

During serious trauma, intercurrent illness or periods of stress

In severe situations, an increase in dose is immediately required and oral administration of hydrocortisone must be replaced with parenteral treatment (see section 4.4).

In less severe situations when parenteral administration of hydrocortisone is not required, during periods of physical and/or mental stress, additional immediate release hydrocortisone at the same total daily dose as Efmody should be given in three divided doses; Efmody should be continued as well with the usual regimen (i.e. a doubled daily dose of hydrocortisone) to allow for easy return to the normal replacement dose of Efmody once additional hydrocortisone is no longer required.

In case of long-term increases in hydrocortisone daily dose due to prolonged periods of stress or illness, the additional hydrocortisone should be carefully weaned off.

Missed doses

If a dose of Efmody is missed it is recommended that it be taken as soon as possible.

Special populations

Elderly

Limited clinical data on the safety and efficacy of Efmody are available in elderly patients (over the age of 65 years) with AI or with CAH. There are no data available in very elderly patients (over the age of 75 years).

Renal impairment

There is no need for dose adjustment in patients with mild to moderate renal impairment. In patients with severe renal impairment monitoring of the clinical response is recommended and adjustment of dose may be necessary (see section 4.4).

Hepatic impairment

There is no need for dose adjustment in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment monitoring of the clinical response is recommended and adjustment of dose may be necessary (see section 4.4).

Paediatric population

No clinical data on the safety and efficacy of Efmody are available in children aged below 12 years. Other hydrocortisone containing medicinal products are available for children below 12 years.

Adolescents

Limited clinical data on the safety and efficacy of Efmody are available in adolescents aged 12-18 years.

Two patients ≤ 18 years of age have been treated with Efmody in the clinical development programme. Their response was comparable to that of patients > 18 years of age.

Method of administration

The capsules must be given orally.

Patients should be advised to swallow the capsules with water to wash the capsules down.

The capsules should not be chewed as chewing the capsule could affect the release profile.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

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. 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.

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

Precaution

In both men and women who have lower fertility, 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).

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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

In both men and women who have lower fertility, 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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of 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 have been reported from 203 Efmody-treated patients. Unexpected therapeutic benefits and fatigue were both reported very commonly, affecting 23.6% and 14.3% of patients, respectively. The most frequently reported unexpected therapeutic benefits of Efmody included feeling more alert, reduced tiredness, better sleep, improved menstrual cyclicity, and increased bone density. Headache (6.4%), and Dizziness (5.9%) were reported commonly.

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 commonest reactions reported to Efmody in the pooled population in the clinical trial population (n = 203), and spontaneous reporting 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

MedDRA system organ classification

Event

Frequency

Blood and Lymphatic System Disorders

Increased tendency to bruise

Uncommon

Endocrine disorders

Adrenocortical insufficiency acute1

Unknown

Cushingoid

Uncommon

Gastrointestinal disorders

Abdominal pain upper

Diarrhoea

Nausea

Common

General disorders and administration site conditions

Fatigue

Therapeutic response unexpected2

Very common

Asthenia

Fat tissue increased

Common

Oedema peripheral

Swelling

Thirst

Uncommon

Infections and infestations

Paronychia

Uncommon

Injury, poisoning and procedural complications

Maternal exposure during pregnancy

Common

Investigations

Blood potassium decreased

Blood testosterone decreased

Blood testosterone increased

Low density lipoprotein increased

Renin increased

Weight increased

Common

Bone density decreased

Osteocalcin decreased

Renin decreased

Urine output decreased

Uncommon

Metabolism and nutrition disorders

Abnormal weight gain

Decreased appetite

Increased appetite

Impaired fasting glucose

Common

Blood glucose increase

Fluid retention

Hyperinsulinaemia

Hyperlipidaemia

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Muscle fatigue

Muscle weakness

Myalgia

Pain in extremity

Common

Nervous System Disorders

Carpal tunnel syndrome

Dizziness

Headache

Hypoaesthesia

Paraesthesia

Common

Somnolence

Uncommon

Psychiatric disorders

Abnormal dreams

Depressed mood

Insomnia

Irritability

Sleep disorder

Stress

Common

Reproductive System and Breast Disorders

Heavy menstrual bleed

Menstruation irregular

Uncommon

Skin and subcutaneous tissue disorders

Acne

Hirsutism

Common

Hyperhidrosis

Skin striae

Uncommon

Vascular Disorders

Hypertension

Uncommon

1frequency based on postmarketing reports

2Includes events of; feeling more alert/less tired/better sleep; improved menstrual cyclicity; increased bone density

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 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

No paediatric patients (<16 years)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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Reports of acute toxicity and/or deaths following hydrocortisone overdose are rare. No antidote is available. Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him/her unusually susceptible to ill effects from hydrocortisone. In which case, symptomatic treatment should be instituted as necessary.