AMGLIDIA

Glibenclamide suspension therapy should be initiated by a physician experienced in the treatment of patients with very early onset diabetes. Prescription instructions Care should be taken when prescribing and administering AMGLIDIA to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL).

It should be ensured that the proper dose and strength are communicated and dispensed. Posology To avoid exceeding sodium benzoate acceptable daily dose, AMGLIDIA daily dose should not exceed 1 mL/kg/day. 6 mg/kg/day. 3 In any other cases, AMGLIDIA 6 mg/mL should be preferred.

2 mg/kg/day until insulin independence is achieved. Since AMGLIDIA is administered with an oral syringe graduated in mL, the calculated daily dose should be expressed in mL by the physician explicitly stating the strength to be used.

The syringe will be chosen (1 mL or 5mL) based on the volume in mL to be administered for each dose, as prescribed by the physician. The 5 mL syringe has to be used for volumes greater than 1 mL. The nearest volume to the calculated one should be used.

Patients should be closely monitored by their treating physician during the titration phase. 2 mg/kg/day, in two administrations. Basal and bolus insulin should be administered on Day 1. On Day 2, if administered sub- cutaneously, basal insulin can be removed.

If on insulin pump, basal rate of insulin pump should be reduced by 50% and should be further reduced in accordance with capillary blood-glucose measurements. Throughout the transfer period, bolus insulin or insulin pump boluses should be administered with meals as required to maintain reasonable glycemic control.

2 mg/kg/day. If capillary blood glucose is < 7 mmol/L, AMGLIDIA should not be increased and pre-meal insulin boluses should be reduced by 50%. Pre-breakfast glucose may be very slow to fall. Pre-lunch or pre-evening meal glucose values fall more rapidly and are generally a better marker of response to AMGLIDIA.

The same protocol should be repeated every day until insulin independence is achieved. As soon as insulin is discontinued, the dose of AMGLIDIA is adjusted according to capillary blood glucose. For patients still under insulin at day 6, the dose of AMGLIDIA should be maintained for at least 4 weeks.

Summary of the safety profile:

The most frequent adverse reactions are hypoglycaemia, transitory diarrhoea and abdominal pain. 4). Overall, the safety profile of glibenclamide is in line with the safety profile of other sulfonylureas. Tabulated list of adverse reactions Adverse reactions reported with glibenclamide (oral suspension or crushed tablets) in children, in the frame of treatment of neonatal diabetes are listed below by system organ class and frequency grouping.

Frequencies are defined as:

Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3:

Adverse reactions MedDRA system organ class Adverse reactions Very common Common Blood and lymphatic system disorders Neutropenia Eye disorders Vision blurred Metabolism and nutrition disorders Hypoglycaemia Gastrointestinal disorders Transitory diarrhoea Abdominal pain Vomiting Dyspepsia Tooth discolouration Investigations Transitory increased transaminases Skin disorders Skin rash Description of selected adverse reactions The following adverse reactions have been observed in a clinical study (Neogli study) and during the extension phase.

This was a phase II, single-centre, prospective, open-label, non-randomised study. After enrolment, patients continued taking their usual doses of glibenclamide tablets for 1 month. Ten patients were switched to glibenclamide oral suspension and treatment with oral suspension continued for 3 months.

Hypoglycaemia Two cases of severe hypoglycaemia were observed, which were considered related to the medicinal product. Symptomatic measures were taken and the situation resolved in the two cases. Transitory diarrhoea, vomiting and abdominal pain and dyspepsia Two children had abdominal pain (one with transient diarrhoea and vomiting during the same episode) that were considered related to the medicinal product.

Special care should be taken when calculating the dose. 2). Glibenclamide should not be used in patients with insulin-dependent type 1 diabetes mellitus with evidence of auto-immune destruction of beta cells. Patients with G6PD enzyme deficiency In patients carrying a G6PD enzyme deficiency, cases of acute haemolytic anaemia have been reported with glibenclamide.

It should therefore not be prescribed for these patients, and the use of an alternative treatment is strongly recommended, if available. If there is no alternative, the decision for each patient must consider the danger of haemolysis and the potential benefit expected from the treatment.

If it is necessary to prescribe this medicinal product, screening should be conducted for the occurrence of any haemolysis. Ketoacidosis Neonatal diabetes is a life-threatening and chronically debilitating condition due to hyperglycemia, which includes symptoms such like thirst, frequent urination, and dehydration.

In severe cases this is associated with ketoacidosis which can led to death. Glibenclamide should not be used to treat this life-threatening condition. Continuous intravenous insulin injection and intravenous infusion of physiologic sodium chloride solution remains the benchmark treatment.

Hypoglycaemia Hypoglycaemia can occur under treatment with hypoglycaemic sulphonamides. This can sometimes be severe and prolonged. Hospitalisation may then prove necessary and glucose may have to be administered for several days. Diarrhoea, nausea and vomiting In some patients, there may be an initial diarrhoea when the dose of glibenclamide suspension is increased but it settles if the dose is maintained.

In case of nausea glycaemia seems to be maintained and insulin does not need to be re- introduced until the patient is able to take the glibenclamide suspension. If there is major vomiting, a fast-acting insulin should be used to treat the patient until vomiting stops.

3. Hepatic impairment Dose adjustment is required in patients with mild to moderate hepatic impairment. 4). 3. Elderly Safety and efficacy of AMGLIDIA in elderly patients have not been established since the medicinal product is indicated in the paediatric population.

4). Method of administration This medicinal product is administered orally as a “ready for-use” oral suspension using a graduated oral syringe. It is administered directly into the child's mouth. The bottle does not need to be shaken before administration.

Since no interaction study between glibenclamide and milk has been performed, and despite absence of food effect on glibenclamide absorption, recommendation is given to administer the suspension 15 minutes before child’s milk feeding.

Only the oral syringe included in the outer carton should be used. Depending on the volume to be administered orally, there are two types of oral syringes, graduated up to 1 mL or up to 5 mL. Each syringe is included in a specific pack size.

The appropriate syringe (1 mL or 5 mL), included in a specific AMGLIDIA pack size, will be prescribed by the physician based on the volume to be administered for each dose. The two syringes, respectively included in two different pack sizes for each strength, are clearly distinguishable: 1 mL oral syringe is thin and small while 5 mL syringe is thick and long.

The dose to be administered is obtained by drawing the plunger back as far as the scale marking for the dose determined for each child. The dose in mL per administration and the number of administrations per day have to carefully follow the medical prescription.

Administration through a feeding tube should be avoided. 6. 1; − in patients with ketoacidosis, continuous intravenous insulin injection and intravenous infusion of physiologic sodium chloride solution remains the benchmark treatment.