ALKINDI 2mg granules packed in capsules to be opened medication leaflet

Alkindi 0.5 mg granules in capsules for opening

Alkindi 1 mg granules in capsules for opening

Alkindi 2 mg granules in capsules for opening

Alkindi 5 mg granules in capsules for opening

Alkindi 0.5 mg granules in capsules for opening

Each capsule contains 0.5 mg hydrocortisone.

Alkindi 1 mg granules in capsules for opening

Each capsule contains 1 mg hydrocortisone.

Alkindi 2 mg granules in capsules for opening

Each capsule contains 2 mg hydrocortisone.

Alkindi 5 mg granules in capsules for opening

Each capsule contains 5 mg hydrocortisone.

For the full list of excipients, see section 6.1.

Granules in capsules for opening.

The granules are white to off-white and contained in a transparent colourless (size 00el) hard capsule.

Alkindi 0.5 mg granules in capsules for opening

The capsule is printed with 'INF-0.5' in red ink.

Alkindi 1 mg granules in capsules for opening

The capsule is printed with 'INF-1.0' in blue ink.

Alkindi 2 mg granules in capsules for opening

The capsule is printed with 'INF-2.0' in green ink.

Alkindi 5 mg granules in capsules for opening

The capsule is printed with 'INF-5.0' in grey ink.

Replacement therapy of adrenal insufficiency in infants, children and adolescents (from birth to< 18 years old).

Dose must be individualised according to the response of the individual patient. The lowest possibledose 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, individual responsiveness to the medicinal product, and the effect ofstress (e.g. surgery, infection, trauma). During stress it may be necessary to increase the dosetemporarily.

Replacement therapy in primary and secondary adrenal insufficiency

Alkindi is given as replacement therapy by oral administration of granules according to clinicalpractice, in a dose to be titrated against individual clinical response.

Recommended replacement doses of hydrocortisone are 8-10 mg/m2/day for patients with adrenalinsufficiency alone and 10-15 mg/m2/day in patients with congenital adrenal hyperplasia (CAH),typically in three or four divided doses.

In patients with some remaining endogenous cortisol production a lower dose may be sufficient.

In situations when the body is exposed to excessive physical and/or mental stress, patients may needan increased dose, especially in the afternoon or evening.

Pre-operatively, during serious trauma or illness in patients with known adrenal insufficiency ordoubtful adrenal reserve

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

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, andthe normal oral daily replacement dose should be increased temporarily; the Alkindi total daily doseshould be increased by doubling or tripling the usual dose. Once the intercurrent illness episode isover, patients can return to the normal replacement dose of Alkindi.

In severe situations, an increase in dose is immediately required and oral administration ofhydrocortisone must be replaced with parenteral treatment. Parenteral administration ofhydrocortisone is warranted during transient illness episodes such as severe infections, in particulargastroenteritis associated with vomiting and/or diarrhoea, high fever of any aetiology or extensivephysical stress, such as for instance serious accidents and surgery under general anaesthesia. Whereparenteral hydrocortisone is required, the patient should be treated in a facility with resuscitationfacilities in case of evolving adrenal crisis.

Changing from conventional oral glucocorticoid treatment to Alkindi

When changing patients from conventional oral hydrocortisone replacement therapy, crushed orcompounded, to Alkindi, an identical total daily dose may be given. Alkindi is therapeuticallyequivalent to conventional oral hydrocortisone formulations. Where a patient is changed from otheroral hydrocortisone formulations to Alkindi, inaccuracy in the dosing possible with other oralhydrocortisone formulations can lead to a relative fall in hydrocortisone exposure on the same nominaldose, leading to symptoms of adrenal insufficiency or crisis (see section 4.4).

Missed or Incomplete Dose

If a full dose of Alkindi is missed, that dose should be administered as soon as possible, as well astheir next dose at the usual time, even if this means that the child receives two doses at the same time.

Patients and/or caregivers should be instructed to contact their healthcare provider if most of thegranules in a dose are regurgitated, vomited or spat out, as a repeat dose may be required to avoidadrenal insufficiency.

The granules must be given orally and should not be chewed. The capsule shell must not be swallowedbut carefully be opened as follows:

- The capsule is held so that the printed strength is at the top, and tapped to ensure all the granulesare in the lower half of the capsule.

- The bottom of the capsule is gently squeezed.

- The top of the capsule is twisted off.

- The granules are either poured directly onto the child’s tongue, or the granules are poured onto aspoon and placed in the child’s mouth. For children who are able to take soft food, the granulesmay be sprinkled onto a spoonful of cold or room temperature soft food (such as yoghurt or fruitpuree) and given immediately.

- Whichever method is used, the capsule is tapped to ensure all the granules are removed.

Immediately after administration a drink such as water, milk, breast-milk, or formula-milk should begiven to help ensure all granules are swallowed.

If the granules are sprinkled onto a spoonful of soft food this should be given immediately (within 5minutes) and not stored for future use.

The granules must not be added to liquid as this can result in less than the full dose being given, andmay affect the taste masking which will allow the bitter taste of hydrocortisone to become apparent.

Do not administer via nasogastric tube as there is a risk of nasogastric tube blockage (see section 4.4).

Detailed pictograms on how to administer the granules are provided in the package leaflet.

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

Patients with dysphagia or premature infants where oral feeding has not been established.

Adrenal crisis

Where a child is vomiting or acutely unwell parenteral hydrocortisone should be started without delay,carers should be trained in adminstering this in an emergency.

Sudden discontinuation of therapy with hydrocortisone risks triggering an adrenal crisis and death.

Medicinal product-induced secondary adrenocortical insufficiency may result from too rapid awithdrawal of corticosteroids and may be minimised by gradual reduction of dosage. This type ofrelative insufficiency may persist for months after discontinuation of therapy; therefore, in anysituation of stress occurring during that period, corticosteroid therapy should be reinstated.

Adrenal crisis can occur when switching from conventional oral hydrocortisone formulations, crushedor compounded, to Alkindi. Close monitoring of patients is recommended in the first week afterswitch. Healthcare professionals should inform carers and patients that extra doses of Alkindi shouldbe given if symptoms of adrenal insufficiency are seen. If this is required, then an increase in the totaldaily dose of Alkindi should be considered and immediate medical advice should be sought.

Replacement schedules of corticosteroids for people with adrenal insufficiency do not causeimmunosuppression and are not, therefore, contraindications for administration of live vaccines.

Infection should not be more likely at a replacement dose of hydrocortisone, but all infections shouldbe treated seriously and stress dosing of steroid initiated early (see section 4.2). Patients with adrenalinsufficiency are at risk of life-threatening adrenal crisis during infection so clinical suspicion ofinfection should be high and specialist advice should be sought early.

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.

Corticosteroids may cause growth retardation in infancy, childhood and adolescence; this may beirreversible. Treatment should be limited to the minimum dose required to achieve desired clinicalresponse and when reduction in dose is possible, the reduction should be gradual. Excessive weightgain with decreased height velocity or other symptoms or signs of Cushing syndrome indicateexcessive glucocorticoid replacement. Infants require frequent assessment and should be evaluated at aminimum every 3 to 4 months to assess growth, blood pressure, and general well-being.

Bone mineral density may be impacted in children when higher doses of replacement steroids areused. The lowest appropriate dose of steroid according to the response of the individual patient shouldbe used.

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions; euphoria,mania, psychosis with hallucinations and delirium have been seen in adult patients at replacementdoses of hydrocortisone (see section 4.8). Symptoms typically emerge within a few days or weeks ofstarting 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. Mostreactions recover after either dose reduction or withdrawal, although specific treatment may benecessary. Patients/carers should be encouraged to seek medical advice if worrying psychologicalsymptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carersshould also be alert to possible psychiatric disturbances that may occur either during or immediatelyafter dose tapering/withdrawal of systemic steroids, although such reactions have been reportedinfrequently.

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

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.

Excretion of granules

The granules may sometimes be seen in stools since the centre of the granule is not absorbed in the gutafter it has released the active substance. This does not mean the medicinal product has beenineffective and the patient should not take another dose for this reason.

Nasogastric tube feeding

Alkindi granules are not suitable for nasogastric administration as they may cause tube blockage.

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 Alkindi with the risk of adverse reactions, particularly adrenalcrisis. The need for dose adjustment when such medicinal products are used can be anticipated andpatients should be closely monitored.

Medicinal products inducing CYP3A4, requiring a potential increase in Alkindi 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

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

- Anti-fungals: itraconazole, posaconazole, voriconazole

- Antibiotics: erythromycin and clarithromycin

- Antiretroviral medicinal products: ritonavir

- Grapefruit juice

- Liquorice

Hydrocortisone for replacement therapy can be used during pregnancy. Hydrocortisone ispreferentially metabolised by placental 11βHSD2 to inactive cortisone reducing the fetal exposure.

There are no indications that replacement therapy with hydrocortisone in pregnant women isassociated with adverse consequences for the fetus.

Studies in animals have shown reproductive toxicity of corticosteroids (see section 5.3)

Hydrocortisone for replacement therapy can be used during breast-feeding. Hydrocortisone is excretedin breast milk. However, the doses of hydrocortisone used for replacement therapy probably do notclinically significantly affect the child.

There are no data available for possible effects of Alkindi on fertility.

Alkindi has no or negligible influence on the ability to perform skilled tasks (e.g. riding a bicycle) orusing machines.

A total of 30 healthy (but dexamethasone-suppressed) adult male subjects in two phase 1 studies and24 paediatric patients with adrenal insufficiency in two phase 3 studies have been treated with Alkindi.

There were no adverse reactions and no episodes of adrenal crisis seen in any of the studies.

In clinical practice most adverse reactions have been mild and self-limiting but adrenal crisis has beenobserved at time of changing from other hydrocortisone products and monitoring of patients at time ofswitch is advised (see section 4.4).

The following adverse reactions have been reported in the scientific literature in adult patients forother hydrocortisone medicinal products when given as adrenal insufficiency replacement therapywith frequency not known (cannot be estimated from the available data).

Table 1 - Adverse reactions

MedDRA system organ class Frequency: not known

Psychiatric disorders Psychosis with hallucinations and delirium

Mania

Euphoria

Gastrointestinal disorders Gastritis

Nausea

Renal and urinary disorders Hypokalaemic alkalosis

When changing a patient from other oral hydrocortisone formulations to Alkindi, inaccuracy in thedosing possible with other oral hydrocortisone formulations can lead to a relative fall inhydrocortisone exposure on the same nominal dose, leading to symptoms of adrenal insufficiency suchas tiredness, excessive sleeping, poor feeding, or adrenal crisis (see section 4.4).

Historical cohorts of adults treated from childhood for CAH have been found to have reduced bonemineral density and increased fracture rates and growth retardation (see section 4.4). It is unclear ifthese relate to hydrocortisone therapy using current replacement regimens.

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.

The biological half-life of hydrocortisone is about 100 minutes.

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

Hydrocortisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, bothnaturally-occurring and synthetic, which are readily absorbed from the gastro-intestinal tract.

Hydrocortisone is believed to be the principal corticosteroid secreted by the adrenal cortex.

Naturally-occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retainingproperties, are used as replacement therapy in adrenocortical deficiency states. They are also used fortheir potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids causeprofound and varied metabolic effects. In addition they modify the body’s immune responses todiverse stimuli.

The pivotal study was an open-label single-dose single-centre trial in 24 paediatric patients aged lessthan 6 years requiring replacement therapy for adrenal insufficiency due to CAH, primary adrenalfailure or hypopituitarism. The study consisted of three consecutive cohorts, the first including12 patients aged 2 to less than 6 years, the second including 6 patients aged 28 days to less than2 years, and the third including 6 neonates aged from birth to less than 28 days.

Of these 24 patients, 23 had a diagnosis of CAH and 1 had a diagnosis of hypopituitarism includinghypothyroidism. 1 patient had renal hypoplasia, 1 patient atopic dermatitis and 1 patient had rhinitis.

The study used a single dose of Alkindi granules equivalent to the previous morning’s dose of eachpatient’s usual glucocorticoid treatment. The Alkindi dose range administered was 1 mg - 4 mg.

Parents/carers (and where possible children) assessed the palatability of Alkindi after administrationusing a 5-item Likert scale.

As this was a single-dose study, the primary efficacy assessment was serum cortisol at 60 minutes. Inall 24 patients Alkindi was found to increase cortisol values from baseline as expected: medianbaseline cortisol 14.1 nmol/l (range 14.1 - 104.5), median Cmax 535.2 nmol/l (range 346.2 - 1445.1).

Alkindi was positively assessed in terms of palatability. Among parents and carers asked about theirchild’s experience of taking the medication (n=23), 82.6% agreed/strongly agreed that their childfound swallowing Alkindi easy; 65.2% agreed/strongly agreed that their child showed a positivereaction after Alkindi administration; 95.5% would be happy to give their child Alkindi in the future;and 95.5% said that they would prefer Alkindi for their child’s treatment over their usualhydrocortisone formulation. Six of the 12 children in Cohort 1 (age range 2.6 to 4.7 years) respondedto an adjusted palatability questionnaire. ≥50% subjects reported that the taste, feel in mouth and easeof swallowing were very good and that they were likely to take the medicinal product again. 68.8% ofhealthy adult volunteers have described the taste as neutral.

Following oral administration, hydrocortisone is rapidly absorbed from the gastro-intestinal tract andthe oral Alkindi 4x5 mg was approximately 87% bioavailable when compared to intravenoushydrocortisone in dexamethasone-suppressed healthy adult male volunteers.

The coadministration of Alkindi with soft food (yoghurt and fruit puree) has been studied in vitro withno significant effect on dissolution seen.

An in vivo study in healthy volunteers showed no significant difference in overall exposure when

Alkindi was dosed fed or fasted.

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.

The terminal half-life of hydrocortisone is about 1.5 hours following intravenous and oral dosing ofhydrocortisone tablets and Alkindi in dexamethasone-suppressed healthy adult male volunteers.

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

Hypromellose

Magnesium stearate

Ethyl cellulose

Capsule

Hypromellose

Shellac

Concentrated ammonia solution

Alkindi 0.5 mg capsules (red ink)

Red iron oxide (E172)

Potassium hydroxide

Alkindi 1 mg capsules (blue ink)

Indigotine (E132)

Alkindi 2 mg capsules (green ink)

Indigotine (E132)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Alkindi 5 mg capsules (grey ink)

Titanium dioxide (E171)

Black iron oxide (E172)

Potassium hydroxide

Not applicable

3 years.

After first opening: 60 days.

Do not store above 30°C. Store in the original bottle in order to protect from light.

The capsules are provided in high-density polyethylene bottles with polypropylene closure withintegrated desiccant.

Pack size:1 bottle containing 50 capsules

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

Neurocrine Netherlands B.V.

Van Heuven Goedhartlaan 935 A1181LD Amstelveen

The Netherlandsdiurnalinfo@neurocrine.com

EU/1/17/1260/001

EU/1/17/1260/002

EU/1/17/1260/003

EU/1/17/1260/004

Date of first authorisation: 09 February 2018

Date of latest renewal: 09 November 2022

Detailed information on this medicine is available on the European Medicines Agency web site:http://www.ema.europa.eu