EFMODY 10mg modified release capsules medication leaflet

Efmody 5 mg modified-release hard capsules

Efmody 10 mg modified-release hard capsules

Efmody 5 mg modified-release hard capsules.

Each modified-release hard capsule contains 5 mg hydrocortisone.

Efmody 10 mg modified-release hard capsules.

Each modified-release hard capsule contains 10 mg hydrocortisone.

For the full list of excipients, see section 6.1.

Modified-release hard capsules.

Efmody 5 mg modified-release hard capsules.

A capsule (approx.19 mm long) with an opaque blue cap and opaque white body printed with“CHC 5 mg” containing white to off white granules.

Efmody 10 mg modified-release hard capsules.

A capsule (approx.19 mm long) with an opaque green cap and opaque white body printed with“CHC 10 mg” containing white to off white granules.

Treatment of congenital adrenal hyperplasia (CAH) in adolescents aged 12 years and over and adults.

Treatment should be initiated by physicians experienced in the management of CAH.

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

Monitoring of the clinical response is necessary and patients should be observed closely for signs thatmight require dose adjustment, including changes in clinical status resulting from remissions orexacerbations of the disease, changes in electrolytes particularly hypokalaemia (see section 4.4) orhyponatraemia, individual responsiveness to the medicinal product, and the effect of stress (e.g.surgery, infection, trauma). As the treatment has a modified-release profile, blood tests are used tomonitor clinical response, assessment of the evening dose should be done with a morning blood testand 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 orinhibitors (see section 4.5).

Treatment in CAH

Recommended replacement doses of hydrocortisone are 10-15 mg/m2/day in adolescents aged 12years and over who have not completed growth, and 15-25 mg/day in adolescents who have completedgrowth and adult patients with CAH. In patients with some remaining endogenous cortisol productiona lower dose may be sufficient.

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

The morning dose should be taken on an empty stomach at least 1 hour before a meal and the eveningdose 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 conventional oral hydrocortisone replacement therapy to Efmody, theidentical total daily dose should be given, but the dose should be given in two doses with two thirds tothree 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 shouldbe used, and the patient monitored for response carefully.

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

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 ofhydrocortisone must be replaced with parenteral treatment (see section 4.4).

In less severe situations when parenteral administration of hydrocortisone is not required, duringperiods of physical and/or mental stress, additional immediate release hydrocortisone at the same totaldaily dose as Efmody should be given in three divided doses; Efmody should be continued as wellwith the usual regimen (i.e. a doubled daily dose of hydrocortisone) to allow for easy return to thenormal 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 orillness, the additional hydrocortisone should be carefully weaned off.

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

No clinical data on the safety and efficacy of Efmody are available in elderly patients over the age of65 years.

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

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

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.

No clinical data on the safety and efficacy of Efmody are available in adolescents aged 12 to 18 years.

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.

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

Adrenal crisis

Acute adrenal insufficiency may develop in patients with known adrenal insufficiency who are oninadequate daily doses or in situations with increased cortisol need. Therefore, patients should beadvised of the signs and symptoms of acute adrenal insufficiency and of adrenal crisis and the need toseek immediate medical attention. Sudden discontinuation of therapy with hydrocortisone riskstriggering an adrenal crisis and death.

During adrenal crisis parenteral, preferably intravenous administration of hydrocortisone in highdoses, together with sodium chloride 9 mg/ml (0.9%) solution for infusion, should be administeredaccording 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 haspreviously taken corticosteroids.

Parenteral administration of hydrocortisone is warranted during transient illness episodes such assevere infections, in particular gastroenteritis associated with vomiting and/or diarrhoea, high fever ofany aetiology or extensive physical stress, such as for instance serious accidents and surgery undergeneral anaesthesia. Where parenteral hydrocortisone is required, the patient should be treated in afacility with resuscitation facilities in case of evolving adrenal crisis.

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

Infection should not be more likely at a replacement dose of hydrocortisone, but all infections shouldbe 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 infectionshould be high and specialist advice should be sought early.

Treatment schedules of corticosteroids for people with CAH do not cause immunosuppression and arenot, 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. Undesirableeffects are therefore less likely when using corticosteroids as replacement therapy. High (supra-physiological) dosages of hydrocortisone can cause elevation of blood pressure, salt and waterretention, and increased excretion of potassium.

Long-term treatment with higher than physiological hydrocortisone doses can lead to clinical featuresresembling Cushing´s syndrome with increased adiposity, abdominal obesity, hypertension anddiabetes, 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-termglucocorticoid 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 ofhydrocortisone (see section 4.8). Symptoms typically emerge within a few days or weeks of startingthe treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5), althoughdose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactionsrecover 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 possiblepsychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal ofsystemic steroids, although such reactions have been reported infrequently.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids, medicaladvice 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 increasedgastrointestinal motility, i.e. chronic diarrhoea, due to the risk of impaired cortisol exposure. There areno data in patients with confirmed slow gastric emptying or decreased motility disease/disorder. Theclinical 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 andwhen reduction in dose is possible, the reduction should be gradual. Excessive weight gain withdecreased height velocity or other symptoms or signs of Cushing syndrome indicate excessiveglucocorticoid 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 closelymonitored; and if signs of early puberty or accelerated sexual maturation are present, an increase indose should be considered. Careful and regular monitoring of adolescent patients with doseadjustment 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 presentswith symptoms such as blurred vision or other visual disturbances, the patient should be considered forreferral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucomaor rare diseases such as central serous chorioretinopathy which have been reported after use ofsystemic and topical corticosteroids.

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

Precaution

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

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

Medicinal products inducing CYP3A4, requiring a potential increase in Efmody dosing, include butare 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 hydrocortisonedosing, 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 bycorticosteroids.

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

Hydrocortisone crosses the placenta. Hydrocortisone is preferentially metabolised by placental11βHSD2 to inactive cortisone reducing the fetal exposure. There are no indications that replacementtherapy 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).

Hydrocortisone is excreted in breast milk. However, the doses of hydrocortisone used for replacementtherapy probably do not clinically significantly affect the child. Hydrocortisone for replacementtherapy can be used during breast-feeding.

In both men and women who have lower fertility due to CAH, fertility may be restored shortly afterbeginning treatment with Efmody. In women, a reduction of 17-OH progesterone and androstenedionewill 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 beenreported. Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and usemachines.

In the clinical trial programme the overall most common serious adverse events were acute adrenalinsufficiency (4.2% of patients treated with Efmody), another common adverse 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%). Two serious adverse reactions of hypokalaemia (2.2%) were reported inthe long-term extension study DIUR-006 for patients that were receiving a mineralocorticoid.

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

MedDRA system organ classification Event Frequency

Endocrine disorders Adrenal insufficiency including Commonacute events

Metabolism and nutrition disorders Increased appetite Common

Decreased appetite Common

Impaired fasting glucose Common

Psychiatric disorders Insomnia Common

Abnormal dreams Common

Depressed mood Common

Sleep disorder Common

Nervous System Disorders Headache Common

Dizziness Common

Carpal tunnel syndrome Common

Paraesthesia Common

Gastrointestinal disorders Nausea Common

Abdominal pain upper Common

Skin and subcutaneous tissue disorders Acne Common

Hair growth abnormal Common

Musculoskeletal and connective tissue Arthralgia Commondisorders Muscle fatigue* Common

Myalgia Common

Pain in extremity Common

General disorders and administration site Asthenia Commonc onditions

Fatigue Very Common

Investigations Blood potassium decreased Common

Low density lipoprotein Commonincreased

Renin increased Common

Weight increased Common

*Includes muscular weakness

Adrenal insufficiency (including acute events).

Events of acute adrenal insufficiency were reported during the clinical trial programme but none wereconsidered related to Efmody. Acute adrenal insufficiency should be monitored for and treatedpromptly in patients with adrenal insufficiency (see sections 4.2 and 4.4).

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroidsespecially 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 bonemineral density and increased fracture rates (see section 4.4) - it is unclear if these relate tohydrocortisone therapy using current replacement regimens.

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

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 thatin adults. Growth retardation has been seen in children treated with hydrocortisone for CAH and canbe caused by both the disorder and hydrocortisone. Accelerated sexual maturation has been seen inhydrocortisone-treated paediatric CAH patients and is associated with excess adrenal androgenproduction (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Corticosteroids for systemic use; glucocorticoids. ATC code: H02AB09.

Hydrocortisone is a glucocorticoid. Glucocorticoids have multiple effects in multiple tissues throughactions on the intracellular steroid receptors.

Hydrocortisone is a glucocorticoid and the synthetic form of endogenously produced cortisol.

Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readilyabsorbed from the gastro-intestinal tract. Cortisol is the principal corticosteroid secreted by the adrenalcortex. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are alsoused for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoidscause profound and varied metabolic effects. In addition, they modify the body’s immune responses todiverse stimuli.

A study in 122 participants with genetically diagnosed 21-hydroxylase deficiency randomised to

Efmody or continuation of standard care with blinded titration of dose and regular overnight profilesfailed to meet its primary endpoint of superiority in change from baseline to 24 weeks of the mean ofthe 24-hour standard deviation score (SDS) profile for 17-hydroxyprogesterone 17-OHP. The 17-OHP

SDS was lower in the Efmody cohort than standard therapy at 4 and 12 weeks. At 24 weeks the 17-

OHP SDS was lower in the morning period (07:00 hrs to 15:00 hrs) but not in the evening or overnight(see also Figure 1 for the geometric mean 24-hour profile of 17-OHP after 24 weeks intensivetreatment). A reduction in the 17-OHP area under the curve occurred in both groups, with greaterreduction in the Efmody cohort. The percentage of patients with controlled 09:00 hrs 17-OHP(<36nmol/l) was 50% at baseline and at 24 weeks was 91% in the Efmody cohort and 71% in thestandard therapy cohort. Efmody patients suffered no adrenal crises (compared to 3 in the control arm)and had fewer sick day episodes where increased dosing due to stress was required (26 vs 36 in thecontrol arm) despite reporting more episodes of intercurrent infective or gastro-intestinal illness.

Glucocorticoid daily dose, measured as a hydrocortisone equivalent dose, increased in most subjectsduring the study (see Table 2).

Table 2. Glucocorticoid daily dose changes during the phase 3 study DIUR-005

Dose Hydrocortisone modified- Standard glucocorticoid grouprelease hard capsules group

Baseline 24 weeks Baseline 24 weeks

All(hydrocortisone dose equivalents)

Median daily dose (mg) 25.0 30.0 25.0 31.3

On hydrocortisone at baseline

Median daily dose (mg) 20.0 25.0 23.75 25.0

On prednis(ol)one at baseline

Median daily dose (mg) 30 27.5 26.6 32.8

On dexamethasone at baseline

Median daily dose (mg) 30 30 40 40

Figure 1. End of study geometric mean 24-hour profile of 17-OHP after 24 weeks intensive treatmentwith either Efmody (closed circles) or standard therapy (open circles).

Standard GC 24 weeks Efmody 24 weeks

A safety extension study of 91 patients with titration by investigators (DIUR-006) was characterisedby dose reductions with median daily dose of Efmody at 18 months interim analysis (n=50) being20 mg (from a median baseline daily dose of 30 mg) with 17-OHP levels remaining in the clinicallydetermined optimal range and androstenedione at or below the reference range for normal individual.

In the safety assessment of clinical studies, differences between the treatment arms in treatment related

AEs were reported (by preferred term [PT]). The most notable differences between the Efmody andstandard glucocorticoid therapy pools, respectively, were observed for headache (7.5% vs 1.6%),increased appetite (5.8% vs 3.3%), weight increase (including abnormal weight gain) (9.2% vs1.6%),decreased appetite (5.0% vs 0%) and nausea (4.2% vs 1.6%).

Following a single oral administration in fasted dexamethasone-suppressed healthy adults, the rate ofabsorption of hydrocortisone from Efmody 20 mg was delayed and reduced compared to immediaterelease hydrocortisone tablets 20 mg, as reflected by a lower Cmax and a significantly longer Tmax for

Efmody (median Tmax for serum cortisol of 4.5 hours and 0.88 hours for Efmody and hydrocortisonetablets respectively). Efmody appeared to be more bioavailable relative to immediate releasehydrocortisone tablets, with overall exposure to serum cortisol and derived free cortisol approximately19% and 13% higher respectively for Efmody.

In the same population, food (high fat meal started 30 minutes before dosing) was found to delay andreduce the rate of absorption of hydrocortisone from Efmody 20 mg, as reflected by a longer Tmax17-OHP nmol/l(median Tmax for serum cortisol of 6.75 hours and 4.5 hours for fed and fasted subjects respectively)and lower Cmax (reduced by approximately 20% in fed subjects). Overall exposure appeared similar infed and fasted subjects (90% confidence intervals for the fed/fasted ratio of the geometric least squaremean of AUC0-t and AUC0-inf were within 80-125%). This effect is therefore not considered clinicallysignificant.

Distribution90% or more of circulating hydrocortisone is reversibly bound to protein.

The binding is accounted for by two protein fractions. One, corticosteroid-binding globulin is aglycoprotein; the other is albumin.

Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded formssuch as tetrahydrocortisone and tetrahydrocortisol which are excreted in the urine, mainly conjugatedas glucuronides, together with a very small proportion of unchanged hydrocortisone. Hydrocortisone isboth metabolised by and a regulator of CYP3A4.

In the fasted dexamethasone-suppressed healthy adult population described above, terminalelimination half-life values were similar for Efmody and hydrocortisone tablets (geometric mean t1/2for serum cortisol of 1.38 hours and 1.40 hours respectively). Clearance appeared higher forhydrocortisone tablets relative to Efmody (geometric mean CL/F for serum cortisol of 22.24 L/h and18.48 L/h respectively).

Paediatrics

The pharmacokinetics of Efmody have not been studied in the paediatric population.

Other populations

No studies have been conducted in patients with hepatic or renal impairment.

Administration of corticosteroids to pregnant animals can cause abnormalities of fetal developmentincluding cleft palate, intrauterine growth retardation and effects on brain growth and development.

Granules

Microcrystalline cellulose

Povidone

Methacrylic acid-methyl methacrylate copolymer (1:2)

Methacrylic acid-methyl methacrylate copolymer (1:1)

Talc

Dibutyl sebacate

Capsule

Gelatin

Efmody 5 mg modified-release hard capsules (white/blue)

Titanium dioxide (E171)

Indigotine (E132)

Efmody 10 mg modified-release hard capsules (white/green)

Titanium dioxide (E171)

Indigotine (E132)

Yellow iron oxide (E172)

Shellac

Black iron oxide (E172)

Potassium hydroxide

Not applicable

3 years

Store in the original package.

Keep the bottle tightly closed in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

The capsules are provided in high-density polyethylene bottles with child resistant, tamper-evidentpolypropylene screw cap with integrated desiccant. Each bottle contains 50 modified-release hardcapsules.

Carton containing 1 bottle of 50 modified-release hard capsules.

Carton containing 2 bottles of 50 modified-release hard capsules (100 capsules).

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Neurocrine Netherlands B.V.

Van Heuven Goedhartlaan 935 A,1181LD Amstelveen,

The Netherlandsdiurnalinfo@neurocrine.com

Efmody 5 mg modified-release hard capsules EU/1/21/1549/001 (50 capsules)

Efmody 10 mg modified-release hard capsules EU/1/21/1549/002 (50 capsules)

Efmody 5 mg modified-release hard capsules EU/1/21/1549/004 (100 (2x50) capsules)

Efmody 10 mg modified-release hard capsules EU/1/21/1549/005 (100 (2x50) capsules)

Date of first authorisation: 27 May 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu