AMGLIDIA Oral suspension Ref.[7818] Active ingredients: Glibenclamide

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. As a consequence, AMGLIDIA 0.6 mg/mL should not be used for posology higher than 0.6 mg/kg/day.

To limit exposure to sodium benzoate and with respect to the mode of delivery (1 mL and 5 mL oral syringes), it is not recommended to use the AMGLIDIA 0.6 mg/mL strength for posologies higher than the ones described below:

Table 1. Maximum recommended posology:

In any other cases, AMGLIDIA 6 mg/mL should be preferred.

AMGLIDIA therapy should be initiated at 0.2 mg/kg per day in two divided doses before feeding (including bottle feeding) and increased by 0.2 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 5 mL) 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.

Inpatient treatment introduction

Start AMGLIDIA at a dose of 0.2 mg/kg/day, in two administration. Give basal and bolus insulin as usual on Day 1. On Day 2, if administered sub-cutaneously, basal insulin can be removed. If on insulin pump, reduce basal rate of insulin pump by 50% and reduce further in accordance with capillary blood-glucose measurements. Throughout the transfer period, administer bolus insulin or insulin pump boluses with meals as required to maintain reasonable glycemic control. From Day 2 until the end of the titration phase, if capillary blood glucose is ≥7 mmol/L, increase AMGLIDIA by 0.2 mg/kg/day. If capillary blood glucose is <7 mmol/L, do not increase AMGLIDIA and reduce pre-meal insulin boluses 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. This may be done as an outpatient.

Patients can be discharged when no longer requiring insulin treatment, when stable on a combination of AMGLIDIA and insulin or when stable on insulin alone.

Outpatient treatment introduction

AMGLIDIA should be introduced at a dose of 0.2 mg/kg/day in two administrations and the dose should be progressively increased each week by 0.2 mg/kg/day.

As the dose is increased, it is usually possible to reduce and then stop the insulin dose.

From week 2 onward, if capillary blood glucose is ≥7 mmol/L increase AMGLIDIA by 0.2 mg/kg/day and reduce insulin. If capillary blood glucose is <7 mmol/L reduce insulin.

If blood-glucose value increases after insulin reduction, AMGLIDIA should be increased by 0.2 mg/kg/day. Insulin reduction should be done using the pre-meal glucose.

The same protocol should be repeated every week until insulin independence is achieved. As soon as insulin is discontinued, the dose of AMGLIDIA is adjusted according to capillary blood glucose.

If at the end of a 5 to 6-week period, there is no evidence of a response with insulin doses similar to those at starting, administration of doses up to 2 mg/kg/day for a week may be tried (in rare cases, it has taken 4 months to wean off insulin completely).

If there is a clear reduction in insulin requirement at this dose of 2 mg/kg/day (reduction in insulin to at least 60% of pre-AMGLIDIA dose), then it is worth continuing a higher dose of AMGLIDIA over a prolonged period of time in selected cases.

Dosage adjustments and long-term management

As shown in the literature and in the clinical studies performed with AMGLIDIA, the average daily dose is expected to be around 0.2 to 0.5 mg/kg/day in most of the patients suffering from neonatal diabetes. Higher doses have occasionally been observed and doses up to 2.8 mg/kg/day have been successfully given without adverse reactions, according to literature. In case of a partial response on lower doses, as shown by reduced insulin requirements, a further dose increase up to 2.8 mg/kg/day may be tried in selected cases.

In some children glycemic control can be better achieved when glibenclamide is administered 3 times or 4 times daily.

If no improvement is seen (unchanged insulin dose, similar glycaemic control and no improvement in neurology), AMGLIDIA should be discontinued.

During titration period patients' capillary blood-glucose concentration should continue to be monitored four times a day and at bedtime, as insulin requirements may continue to fall, or AMGLIDIA may need to be titrated. Once steady state is reached, capillary blood glucose does no longer need to be daily monitored except in clinical situations at risk of metabolic unbalance (see below). In all cases, HbA1c must be monitored every three months.

Sometimes, blood-glucose concentration will fall even though the patient is on a fixed dose of AMGLIDIA. Therefore, to avoid hypoglycaemia, consideration should be given to reducing the dose of AMGLIDIA or stopping treatment.

Reduction of AMGLIDIA dose should be anticipated by the treating physician and certainly if the glucose values are going below 4 mmol/L (72 mg/dL).

It may be necessary to adjust the dosage of AMGLIDIA in patients suffering from intercurrent infections, trauma, shock or anaesthesia:

• For major surgery, insulin therapy should replace AMGLIDIA;
• Hepatic or renal dysfunction may require a reduction in dosage;
• In exceptional situations of stress (e.g. trauma, surgery, febrile infections), blood-glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.

Patients occasionally may have very high glucose values, i.e. >20 mmol/L (>360 mg/dL). In some cases these high glucose values seem to settle with the normal dose of AMGLIDIA. However, close monitoring of blood-glucose is required in all cases (please also refer to recommendations given under the heading “dose omission” further below) and adequate measures to restore euglycaemia (e.g. application of a third daily AMGLIDIA dose or insulin) must be taken.

Bioequivalence with tablets

AMGLIDIA is not bioequivalent with (crushed) tablets containing the same amount of glibenclamide. Available data are described in section 5.2.

Missed dose

If a dose is forgotten, there is a risk of hyperglycaemia. Blood-glucose level must be checked immediately and AMGLIDIA taken as soon as possible. If the blood-glucose level exceeds 16.5 mmol/L, the presence of ketonuria or ketonaemia must also be checked. If ketone bodies are present, an insulin injection must be given rapidly to restore the metabolic situation. The attending specialist should then be contacted.

Special populations

Renal impairment

Dose adjustment is required in patients with mild to moderate renal impairment. In those patients, treatment should be started at the lowest dose levels and should be strictly followed, to avoid hypoglycaemic reactions (see section 4.4). For severe renal impairment see section 4.3.

Hepatic impairment

Dose adjustment is required in patients with mild to moderate hepatic impairment. In those patients, treatment should be started at the lowest dose levels and should be strictly followed, to avoid hypoglycaemic reactions (see section 4.4). For severe hepatic impairment see section 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.

At risk patients

In malnourished patients or those displaying a marked change in their general condition, or whose calorie intake is irregular, and in patients with impaired renal or hepatic function, treatment should be started at the lowest dose levels and should be strictly followed, to avoid hypoglycaemic reactions (see section 4.4).

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.

For instructions of the medicinal product before administration, see section 6.6.

Overdose of sulphonamides can result in hypoglycaemia.

The symptoms of moderate hypoglycaemia, without loss of consciousness or neurological signs, must be completely corrected by taking sugar, adjusting the dose and/or changing dietary behaviour. Close monitoring of blood-glucose by the patient’s family must be continued until the family and the physician, if he/she had to be contacted, are certain that the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and are medical emergencies requiring immediate treatment as soon as the cause is diagnosed or suspected before immediately admitting the patient to hospital.

If a hypoglycaemic coma is diagnosed or suspected, the patient should quickly receive an intravenous injection of concentrated glucose solution (0.5 g/kg body weight as a 30% glucose solution). This must be followed by continuous infusion of more dilute glucose solution (10%) at the rate needed to maintain blood-glucose above 100 mg/dL (100 mg/dL = 5.5 mmol/L). Patients must be closely monitored for at least 48 hours and, depending on the patient’s condition at this time, the physician will decide if additional monitoring is necessary.

Plasma clearance of glibenclamide may be prolonged in patients suffering from liver disease. Due to strong binding of glibenclamide to proteins, dialysis is of no benefit to the patient.

3 years.

After first opening:

30 days.

Keep the bottle tightly closed.

Keep the bottle in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Brown glass bottle (type III) with a child-resistant closure (polypropylene screw cap with polyethylene capsule inside) in a carton containing a 1 mL or 5 ml graduated oral syringe of LDPE and polypropylene depending on the presentation prescribed and an adaptor (LDPE) to be plugged on the bottle after opening for the syringe.

The 1 mL oral syringe is thin and small while the 5 mL syringe is thick and long.

Pack sizes:

One bottle of 30 ml suspension and one oral syringe of 1 mL packed in an individual bag and one syringe adaptor.

One bottle of 30 ml suspension and one oral syringe of 5 mL packed in an individual bag and one syringe adaptor.

At the first use, the bottle should be opened by unscrewing the child-resistant closure while pressing downwards. The adaptor should be inserted firmly into the bottle while holding the bottle the right way up. The screw cap should then bereplaced on the bottle with the adaptor and not removed during the 30-day use. The screw cap should be retightened in order to push the adaptor well into the bottle.

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