ALKINDI Granule in capsule Ref.[27923] Active ingredients: Hydrocortisone

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 Alkindi risks triggering an adrenal crisis and death. Medicinal product-induced secondary adrenocortical insufficiency may result from too rapid a withdrawal of corticosteroids and may be minimised by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, corticosteroid therapy should be reinstated.

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

Infections and immunisation

Replacement schedules of corticosteroids for people with adrenal insufficiency do not cause immunosuppression 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 should be treated seriously and stress dosing of steroid initiated early (see section 4.2). Patients with adrenal insufficiency 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.

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.

Corticosteroids may cause growth retardation in infancy, childhood and adolescence; this may be irreversible. Treatment should be limited to the minimum dosage required to achieve desired clinical response and when reduction in dosage 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. Infants require frequent assessment and should be evaluated at a minimum 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 are used. The lowest appropriate dose of steroid according to the response of the individual patient should be 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 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/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers 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, 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 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.

Excretion of granules

The granules may sometimes be seen in stools since the centre of the granule is not absorbed in the gut after it has released the active substance. This does not mean the medicinal product has been ineffective 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 of medicinal products that are inhibitors or inducers of CYP3A4 may therefore lead to unwanted alterations in serum concentrations of Alkindi with the risk of adverse effects, 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 Alkindi 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

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

Pregnancy

Hydrocortisone for replacement therapy can be used during pregnancy The ability of corticosteroids to cross the placenta varies between the different types of corticosteroids, however, hydrocortisone readily crosses the placenta.

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

Breast-feeding

Hydrocortisone for replacement therapy can be used during breast-feeding.

Fertility

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

Alkindi has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

A total of 30 healthy (but dexamethasone-suppressed) adult male subjects in two phase 1 studies and 24 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.

Tabulated list of adverse reactions

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

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

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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.