Alkindi · 4.8 Undesirable effects · 1

HOS-217673 · has-adverse-reaction-information · PDF-Seite 7

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. In clinical practice most adverse reactions have been mild and self-limiting but adrenal crisis has been observed at time of changing from other hydrocortisone products and monitoring of patients at time of switch is advised (see section 4.4). 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). 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 Description of selected adverse reactions When changing a patient from other oral hydrocortisone formulations to Alkindi, inaccuracy in the dosing possible with other oral hydrocortisone formulations can lead to a relative fall in hydrocortisone exposure on the same nominal dose, leading to symptoms of adrenal insufficiency such as 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 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. 7 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 natio

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HOS-217669 · has-contraindication-information · PDF-Seite 4

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. 4

HOS-217668 · has-indication-information · PDF-Seite 3

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

HOS-217671 · has-interaction-information · PDF-Seite 6

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 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 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

HOS-217672 · has-pregnancy-information · PDF-Seite 6

Pregnancy Hydrocortisone for replacement therapy can be used during pregnancy. 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. 6 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. Hydrocortisone is excreted in breast milk. However, the doses of hydrocortisone used for replacement therapy probably do not clinically significantly affect the child. Fertility There are no data available for possible effects of Alkindi on fertility.

HOS-217670 · has-warning-information · PDF-Seite 5

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 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. Immunisation Replacement schedules of corticosteroids for people with adrenal insufficiency do not cause immunosuppression and are not, therefore, contraindications for administration of live vaccines. Infections 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 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. Infants require frequent assessment and should be evaluated at a minim

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