Alkindi

/ Medomie Pharma Ltd, Israel

Dosage must be individualised according to the response of the individual patient. The lowest possible dosage should be used.
Replacement therapy in primary and secondary adrenal insufficiency: Oral administration of granules according to clinical practice, in a dose to be titrated against individual clinical response. Recommended replacement doses of hydrocortisone are 8-10 mg/m²/day for patients with adrenal insufficiency 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 need an increased dose, especially in the afternoon or evening.
Pre-operatively, during serious trauma or illness in patients with known adrenal insufficiency or doubtful adrenal reserve: Pre-operatively, anaesthetists must be informed if the patient is taking corticosteroids or has previously taken corticosteroids. 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, and the normal oral daily replacement dose should be increased temporarily; the total daily dose should be increased by doubling or tripling the usual dose. Once the intercurrent illness episode is over, patients can return to the normal replacement dose. In severe situations, an increase in dose is immediately required and oral administration of hydrocortisone must be replaced with parenteral treatment. 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.
See prescribing information for full details.

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

– Hypersensitivity to the active substance or to any of the excipients.
– 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 this medicinal product 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 this product. Close monitoring of patients is recommended in the first week after switch. Healthcare professionals should inform carers and patients that extra doses of hydrocortisone should be given if symptoms of adrenal insufficiency are seen. If this is required, then an increase in the total daily dose of the medication should be considered and immediate medical advice should be sought.
Infections and immunization: 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. 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: The granules are not suitable for nasogastric administration as they may cause tube blockage.

No common adverse reactions were seen in studies. See prescribing information for full details.

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 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 hydrocortisone 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 hydrocortisone 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.
Breast-feeding:
Hydrocortisone for replacement therapy can be used during breast-feeding.
Fertility:
There are no data available for possible effects on fertility.

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

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