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

Special care should be taken when calculating the dose. Before each administration, it should be verified that the correct strength and syringe are used.

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 treate this lifethreatening condition. Continuous intravenous insulin injection and intravenous infusion of physiologic sodium chloride solution remains the benchmark treatmen

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.

Diarrhea, 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.

If there is minor vomiting, an antivomiting medicinal product should be given and treatment with glibenclamide can be continued.

Biological analyses

Blood-glucose should be monitored periodically throughout treatment with glibenclamide. 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 glycosylated haemoglobin level should be measured every three months to assess the child’s metabolic equilibrium.

Renal impairment

Patients with renal impairment should be monitored periodically during treatment due to the increased risk of hypoglycaemia. Dose adjustment is required in patients with mild to moderate renal impairment (refer to section 4.2).

Hepatic impairment

Patients with hepatic impairment should be monitored periodically during treatment due to the increased risk of hypoglycaemia. Dose adjustment is required in patients with mild to moderate hepatic impairment (refer to section 4.2).

Sodium

This medicinal product contains 2.8 mg of sodium per mL oral suspension, equivalent to 0.1% of the WHO recommended daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

Benzoic acid and benzoates (sodium benzoate)

This medicinal product contains 5 mg benzoate salt in each mL oral suspension.

Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in the brain tissue).

No interaction studies have been performed for the two oral suspensions of glibenclamide (0.6 mg/mL and 6 mg/mL).

Hypoglycaemia may occur when taking other medicinal products.

Highly protein-bound medicinal products, which may also potentiate the hypoglycaemic action of glibenclamide due to glibenclamide displacement from plasma proteins, include oral anticoagulants, phenytoin, salicylates and other non-steroidal anti-inflammatory agents.

Weakening of the blood-glucose-lowering effect and, thus, raised blood-glucose levels may occur when taking other medicinal products.

Under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent. The symptoms of hypoglycaemia may also be milder or absent where hypoglycaemia develops gradually or where there is autonomic neuropathy.

In very rare cases, an intolerance to alcohol may occur. Both acute and chronic alcohol intake, or excessive alcohol ingestion by people who drink occasionally, may attenuate the hypoglycaemic effect of glibenclamide or dangerously potentiate it by delaying its metabolic inactivation. Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glibenclamide.

Glibenclamide may increase ciclosporin plasma concentration and potentially lead to its increased toxicity. Monitoring and dose adjustment of ciclosporin are therefore recommended when both medicinal products are co-administered.

Colesevelam binds to glibenclamide and reduces glibenclamide absorption from the gastrointestinal tract. No interaction was observed when glibenclamide was taken at least 4 hours before colesevelam. Therefore, glibenclamide should be administered at least 4 hours prior to colesevelam.

Summary of interactions

A summary of the interactions detailed above and further interactions are summarized in the table below.

Table 2. Summary of interactions:

General aspects

AMGLIDIA is indicated for the treatment of neonatal diabetes in newborns, infants and children.

Women of childbearing potential

Women of childbearing potential planning a pregnancy should be switched from oral glibenclamide to insulin. Glibenclamide should not be given during pregnancy.

Pregnancy

Based on a limited amount of published data, the use of glibenclamide during the first trimester does not seem to cause an increase in congenital malformations. With respect to the second and third trimester published data did not find fetotoxic effects.

Animal studies do not indicate a teratogenic potential.

Glibenclamide crosses the placenta mostly in small amounts; however, transfer is highly variable among patients.

In pregnant women insulin is recommended for blood sugar control.

Breast-feeding

Published data from 11 glibenclamide-treated mothers indicate that glibenclamide is not excreted in human milk and hypoglycaemia in the breast-fed newborns was not reported. Breast-feeding seems to be compatible, but as a precautious measure monitoring of the fully breast-fed infant’s blood sugar level is advisable.

Fertility

Clinical data are not available.

Glibenclamide has moderate influence on the ability to drive and use machines since it may increase the risk of hypoglycaemia. This may not be relevant for the target population. However, reduced alertness may also be of concern when participating in road traffic (e.g. cycling) or in play (e.g. skateboarding).

Summary of the safety profile

The most frequent adverse reactions are hypoglycaemia, transitory diarrhea and abdominal pain. The most serious adverse reaction is hypoglycaemia (see section 4.4).

Overall, the safety profile of glibenclamide is in line with the safety profile of others 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:

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 diarrhea, vomiting and abdominal pain and dyspepsia

Two children had abdominal pain (one with transient diarrhea and vomiting during the same episode) that were considered related to the medicinal product. Symptomatic measures were taken and the medicinal product continued and the situation resolved in the two cases.

One child had dyspepsia, which was considered related to the medicinal product. Symptomatic measures were taken and the situation resolved.

Neutropenia and transitory increased transaminases

One child had punctually low leucocytes level, but close to the normal range (neutrophils 1.3×10³/μL for a lower limit of normal of 1.5×10³/μL).

The same child had a transient and minimal ASAT 73 IU/L, and ALAT 42 IU/L increased (normal range below 60 and 40 respectively). These resolved subsequently.

Skin disorders

One child experienced isolated skin rash.

The following other adverse reaction has been collected from post marketing sources.

Eye disorders

One child experienced filmy vision: Visual disturbances can be due to fluid moving into and out of the eye due to high blood sugar levels.

The following adverse effects have been observed in adult patients treated with other products containing glibenclamide. These adverse effects have been not observed with AMGLIDIA but may occur:

Eye disorders:

Transient visual disturbances (blurred vision or accommodation disorder) have been reported, especially early in treatment without glycaemic variation.

Skin and subcutaneous tissue disorders:

In isolated cases photosensitivity may occur.

Skin rash, pruritus, urticaria, allergic skin reaction, bullous eruptions, exfoliative dermatitis and erythema multiforme have occasionally been reported in adults.

Immune system disorders:

Anaphylactic reaction including dyspnoea, hypotension and shock have been reported.

Blood disorders:

Blood affections have been observed, generally reversible when treatment stops.

Hypereosinophilia, leucopenia, mild or severe thrombocytopenia have been reported, which can lead to purpura. Rare cases of agranulocytosis, haemolytic anaemia, bone marrow aplasia and pancytopenia have also been reported.

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 national reporting system listed in Appendix V.

Not applicable.