Glibenclamide

Glibenclamide is a second-generation sulfonylurea that lowers blood glucose by stimulating the pancreas to release insulin. This depends on active beta cells, or on beta cells that glibenclamide can make active, as in some forms of neonatal diabetes. It is used as tablets for type 2 diabetes in adults, authorised nationally, and as the Amglidia oral suspension for neonatal diabetes, authorised centrally. The pharmacology below follows the EU SmPC of Amglidia and DrugBank. The use, dosing, warnings and side effects of the tablets follow the French SmPC of Daonil 5 mg (Sanofi Winthrop Industrie, ANSM).

Mechanism of Action

• Potassium channel closure: at low glucose the ATP-sensitive potassium channel of the beta cell is open and potassium leaves the cell. Glibenclamide binds the sulfonylurea receptor (SUR1) of the channel and shuts it whatever the glucose level. The membrane then depolarises, calcium channels open, and the calcium that enters triggers release of insulin granules.
• Meal-related insulin response: stimulation of insulin secretion after a meal is of major importance. Post-meal insulin and C-peptide responses stay enhanced after at least 6 months of treatment, and over many years in neonatal diabetes caused by potassium channel disorders.
• Neonatal diabetes: sulfonylureas are effective in patients with mutations in the genes coding for the beta-cell ATP-sensitive potassium channel and in chromosome 6q24-related transient neonatal diabetes. Published data report success with sulfonylurea treatment in about 90% of patients with neonatal diabetes associated with K-ATP channel mutations.
• Active concentration: the minimum concentration for the effect is considered to be 30–50 ng/mL.

Pharmacokinetics

• Absorption: rapid after oral dosing; the effect begins within about 2.5 hours and lasts up to 15 hours, although the elimination half-life is 5 to 10 hours. The effect of food on absorption of the suspension has not been investigated.
• Compared with tablets: against crushed Daonil 5 mg tablets, the Amglidia suspensions reached peak concentrations about 0.5 hours earlier (median 2.5 versus 3 hours), with a Cmax about 40% higher. Relative bioavailability was 121.6% for the 0.6 mg/mL and 114.1% for the 6 mg/mL suspension. Non-micronised tablets are not bioequivalent to micronised ones, no head-to-head data exist between the suspension and micronised tablets, and no conversion rate between micronised tablets and the suspension has been established.
• Children: in population modelling, plasma levels in children of 10–30 kg on 0.9 mg twice daily were about 30–60% lower than in adults on 1.25 mg twice daily. Levels rise with smaller body weight and exceeded adult levels only slightly, in poor metabolisers.
• Distribution: about 99% bound to plasma albumin, which may account for certain drug interactions; the binding is not easily displaced by acidic medicines.
• Metabolism: hepatic. According to DrugBank the main enzyme is CYP3A4, followed by CYP2C9 and others, producing hydroxylated metabolites, two of which are active.
• Elimination: elimination half-life 5 to 10 hours. According to DrugBank about half of the dose is excreted in urine and half in faeces, mainly as the 4-trans-hydroxy metabolite.

• Type 2 diabetes mellitus (tablets, national authorisations): in the French SmPC of Daonil 5 mg, non-insulin-dependent diabetes, together with a suitable diet, when the diet alone is not enough to restore glycaemic control. Use is reserved for adults. Other national tablet products may word the indication and the strengths differently, so the SmPC of the product in use applies.
• Neonatal diabetes mellitus (Amglidia oral suspension): treatment of neonatal diabetes mellitus in newborns, infants and children. Sulfonylureas have been shown to be effective in patients with mutations in the genes coding for the beta-cell ATP-sensitive potassium channel and in chromosome 6q24-related transient neonatal diabetes mellitus.

Tablets (Daonil 5 mg):

• Hypersensitivity to glibenclamide, to other sulfonylureas or to any of the excipients.
• Insulin-dependent diabetes, in particular juvenile diabetes, diabetic ketoacidosis and diabetic pre-coma.
• Severe renal impairment or severe hepatic impairment.
• Porphyria.
• Treatment with miconazole (see Drug Interactions).
• Breastfeeding.

Amglidia oral suspension:

• Hypersensitivity to glibenclamide, to other sulfonylureas or sulfonamides, or to any of the excipients.
• Ketoacidosis, which is treated with continuous intravenous insulin and intravenous physiological saline.
• Porphyria.
• Treatment with bosentan.
• Severe renal impairment.
• Severe hepatic impairment.

Hypoglycaemia is the most important side effect of glibenclamide in both uses. The reactions below follow the SmPC of each product.

Tablets (Daonil 5 mg)

Hypoglycaemia is the only reaction listed as very common. The SmPC groups the others by system organ class.

Very common (≥1/10)

• Metabolism and nutrition disorders: hypoglycaemia, which can be prolonged and severe and is not always easy to correct.

Common (≥1/100 to <1/10)

• Skin and subcutaneous tissue disorders: skin and mucous membrane rashes (mucocutaneous eruptions).
• Gastrointestinal disorders: nausea; diarrhoea.
• Investigations: weight gain, as with all sulfonylureas.

Uncommon (≥1/1,000 to <1/100)

• Gastrointestinal disorders: epigastric discomfort.

Not known

• Metabolism and nutrition disorders: hyponatraemia (isolated cases).
• Skin and subcutaneous tissue disorders: pruritus; maculopapular rash; bullous reactions; erythema multiforme; exfoliative dermatitis; a few cases of photosensitivity.
• Immune system disorders: hypersensitivity, allergic or pseudo-allergic reactions; isolated cases of urticaria-type reactions that can progress to life-threatening bronchospasm, dyspnoea, hypotension or shock.
• Hepatobiliary disorders: raised liver enzymes, with possible cytolytic or cholestatic hepatitis that requires treatment to be stopped and can progress to life-threatening hepatic failure.
• Blood and lymphatic system disorders (generally reversible on stopping treatment): eosinophilia; leucopenia; moderate or severe thrombocytopenia, which can show as purpura; agranulocytosis; haemolytic anaemia; bone marrow aplasia; pancytopenia.
• Investigations: occasional mild to moderate rises in blood urea and creatinine.
• Eye disorders: transient visual disturbances such as blurred vision or accommodation disorders, mainly at the start of treatment, with or without changes in blood glucose.
• General disorders: a disulfiram-like effect if alcohol is drunk with meals.
• Vasculitis: exceptionally, allergic cutaneous or visceral vasculitis, which can be life-threatening.

Reactions that need prompt medical attention include severe or prolonged hypoglycaemia (hospital care and glucose for several days may be needed), life-threatening allergic reactions, hepatitis that can progress to hepatic failure, and blood disorders such as agranulocytosis and pancytopenia. The SmPC also lists clinical expression of porphyria (hepatic or cutaneous) in patients with porphyria (see Contraindications).

Amglidia Oral Suspension (Neonatal Diabetes)

With glibenclamide (oral suspension or crushed tablets) in children with neonatal diabetes, the most frequent side effects were hypoglycaemia, transitory diarrhoea and abdominal pain, and the most serious was hypoglycaemia. The safety profile is in line with other sulfonylureas. The details below come from a small open-label study (Neogli) in which ten children were switched to the suspension for 3 months.

Very common (≥1/10): hypoglycaemia; neutropenia; transitory diarrhoea; abdominal pain; vomiting; dyspepsia; transitory increase in transaminases; skin rash.

Common (≥1/100 to <1/10): blurred vision; tooth discolouration.

• Hypoglycaemia: two cases of severe hypoglycaemia were considered related to treatment and resolved with symptomatic measures.
• Gastrointestinal events: two children had abdominal pain (one with transient diarrhoea and vomiting) and one had dyspepsia; treatment was continued and the events resolved.
• Blood count: one child had an isolated, slightly low neutrophil count (1.3 x 10³/µL, lower limit of normal 1.5 x 10³/µL).

Tablets (Daonil 5 mg)

The SmPC sorts interactions by the action needed. For most of them the patient is warned, blood-glucose self-monitoring is stepped up, and the dose of the antidiabetic may be adjusted during and after the other treatment.

• Miconazole (contraindicated): by the systemic route or as an oral gel, it increases the glucose-lowering effect, with possible hypoglycaemic episodes or even coma.
• Phenylbutazone (not recommended): all forms, including local ones, increase the glucose-lowering effect of sulfonylureas by reducing their hepatic metabolism. Another, less interacting anti-inflammatory medicine is preferred.
• Alcohol (not recommended): a disulfiram-like effect (warmth, flushing, vomiting, tachycardia) and a stronger hypoglycaemic reaction through inhibition of compensatory reactions, which can favour hypoglycaemic coma. Alcoholic drinks and medicines containing alcohol are avoided.
• Danazol (not recommended): its diabetogenic effect raises blood glucose. If the combination cannot be avoided, blood and urine glucose self-monitoring is increased.
• Beta-blockers (precautions; except esmolol): all can mask palpitations and tachycardia, two symptoms of hypoglycaemia, and most non-cardioselective ones increase the frequency and severity of hypoglycaemia. Self-monitoring is increased, especially at the start.
• Fluconazole (precautions): it lengthens the half-life of the sulfonylurea, so hypoglycaemic episodes may occur. The sulfonylurea dose may need adjusting during fluconazole treatment.
• ACE inhibitors (precautions): they may increase the glucose-lowering effect in diabetic patients treated with sulfonylureas. Hypoglycaemic episodes seem exceptional.
• Clarithromycin and erythromycin (precautions): risk of hypoglycaemia, because absorption and plasma concentrations of the antidiabetic rise. The sulfonylurea dose may need adjusting during treatment.
• Chlorpromazine, a neuroleptic (precautions): at high doses (above 100 mg of chlorpromazine a day) it raises blood glucose by reducing insulin release. The antidiabetic dose may need adjusting during and after the neuroleptic.
• Glucocorticoids and tetracosactide (precautions): systemic and local routes (intra-articular, skin, rectal enema) are covered, and hydrocortisone as replacement therapy is excepted. Blood glucose rises, sometimes with ketoacidosis, because carbohydrate tolerance falls. Self-monitoring is increased, especially at the start.
• Intravenous beta-2 agonists (precautions): ritodrine, salbutamol and terbutaline raise blood glucose. Blood and urine monitoring is increased, and a switch to insulin may be needed.
• Bosentan (other interactions): its inducing effect lowers plasma glibenclamide concentrations, so efficacy may fall, and cases of hepatotoxicity have been reported with the combination. Blood glucose and liver tests are monitored, and treatment adapted as needed.
• Somatostatin analogues, octreotide and lanreotide (other interactions): risk of hypoglycaemia or hyperglycaemia, as the sulfonylurea requirement falls or rises (for example through lower endogenous glucagon secretion). Self-monitoring is increased and the dose adjusted if needed.
• Colesevelam (other interactions): given together, it lowered the AUC0-inf of glibenclamide by 32% and the Cmax by 47%. No interaction was seen when colesevelam was given four hours after glibenclamide, so glibenclamide is taken at least 4 hours before colesevelam.

Amglidia Oral Suspension

No interaction studies have been performed with Amglidia. Hypoglycaemia may occur with other medicinal products, and other medicinal products may weaken the glucose-lowering effect; Table 2 of the SmPC gives the full list.

• Bosentan: contraindicated (it raises liver enzymes and disturbs glucose control).
• Protein-bound medicines: oral anticoagulants, phenytoin, salicylates and other non-steroidal anti-inflammatory medicines are highly protein-bound and may potentiate the effect by displacing glibenclamide from plasma proteins.
• Increased glucose-lowering effect (hypoglycaemia risk): ACE inhibitors, anabolic steroids and male sex hormones, beta-blockers, biguanides, chloramphenicol, clarithromycin, coumarin derivatives, cyclophosphamide, ifosfamide and phosphamides, disopyramide, fenfluramine, fibrates, fluoxetine, heparin, insulin and other oral antidiabetics, long-acting sulfonamides, co-trimoxazole, MAO inhibitors, miconazole, quinolone antibiotics, tetracyclines, probenecid, salicylates, oxypentifylline, oxyphenbutazone and tritoqualine.
• Weakened glucose-lowering effect (raised blood glucose): acetazolamide, adrenaline and other sympathomimetics, barbiturates, calcium channel blockers, cimetidine, corticosteroids, diazoxide, diuretics, glucagon, isoniazid, large doses of laxatives, high-dose nicotinic acid, oestrogens, progestogens, phenothiazine derivatives, phenytoin, rifampicin and thyroid hormones.
• Beta-blockers, clonidine, guanethidine and reserpine: signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent, and symptoms may be milder or absent when hypoglycaemia develops gradually or with autonomic neuropathy. H2-receptor antagonists, clonidine and reserpine may potentiate or weaken the effect.
• Alcohol: acute or chronic intake may weaken the effect or dangerously potentiate it by delaying metabolic inactivation. Intolerance to alcohol and disulfiram-like reactions occur very rarely. Alcohol should be avoided.
• Ciclosporin: glibenclamide may raise ciclosporin plasma concentrations and its toxicity. Monitor and adjust the ciclosporin dose.
• Colesevelam: it binds glibenclamide and reduces absorption. No interaction was seen when glibenclamide was taken at least 4 hours before colesevelam, so give glibenclamide at least 4 hours before it.
• Milk: no interaction study with milk has been done, so the suspension is given 15 minutes before a milk feed.

Tablets (type 2 diabetes): taken by mouth by adults only, with the dose fitted to each patient, as for any glucose-lowering medicine. Doses are taken before breakfast and before the main meals. In a transient loss of glycaemic control, a short course may be enough for a patient who is usually well controlled by diet.

Amglidia (neonatal diabetes): treatment must be started by a physician experienced in treating patients with very early-onset diabetes. The suspension is ready for use. It is given directly into the child’s mouth with the graduated oral syringe supplied in the carton, and the bottle need not be shaken. It is given 15 minutes before a milk feed. Giving it through a feeding tube should be avoided.

Tablets: Starting Dose and Titration

• Starting dose (under 65 years): half a tablet (2.5 mg) a day, taken before breakfast.
• Titration: the dose is usually raised in steps of half a tablet according to the glycaemic response, with the doses divided before the 2 or 3 main meals. Several days at least should separate each step.
• Maintenance: the maximum is 3 tablets (15 mg) a day, divided into 2 or 3 doses before the main meals.
• Not interchangeable with Amglidia: the tablets and the oral suspension are separate products for different conditions. The suspension gave higher exposure than crushed Daonil tablets, and no conversion rate between micronised tablets and the suspension has been established.

Tablets: Special Populations

• Aged 65 and over: the starting and maintenance doses are adapted with caution to lower the risk of hypoglycaemia. Treatment starts with the smallest dose available and is raised gradually if needed.
• Undernourished patients, marked deterioration of general condition, irregular calorie intake, renal or hepatic impairment: start at the lowest dose and keep strictly to the dose steps, to avoid hypoglycaemic reactions. Severe renal or hepatic impairment is a contraindication.
• Switching from another oral antidiabetic: as with any sulfonylurea, glibenclamide can take over from an antidiabetic treatment without a transition period. When changing from a sulfonylurea with a longer half-life, such as chlorpropamide, the patient is followed closely for several weeks, because the effects may overlap and cause hypoglycaemia.
• Children: the tablets are reserved for adults.

Amglidia: Dosing Safety and Choice of Strength

• Dosing errors from confusing milligrams (mg) with millilitres (mL) must be avoided. The prescriber states the dose in mL and the strength to be used, and the strength and syringe are checked before each administration.
• The syringe (1 mL or 5 mL) is chosen from the volume per dose; the 5 mL syringe is used for volumes above 1 mL, and the volume nearest to the calculated one is given.
• Because of the sodium benzoate content, the daily dose must not exceed 1 mL/kg/day, so the 0.6 mg/mL suspension is not used above 0.6 mg/kg/day.
• The 0.6 mg/mL strength is also not recommended above these doses by body weight: up to 10 kg, 0.6 mg/kg/day; 11–12 kg, 0.5; 13–15 kg, 0.4; 16–20 kg, 0.3. In every other case the 6 mg/mL strength is preferred.

Amglidia: Starting Dose and Titration

• Start at 0.2 mg/kg per day in two divided doses before feeding (including bottle feeding), and increase by 0.2 mg/kg/day until insulin independence is reached. The child is closely monitored during titration.
• Hospital introduction: on day 1 start 0.2 mg/kg/day in two doses, with basal and bolus insulin as before. On day 2, subcutaneous basal insulin can be stopped; with an insulin pump, cut the basal rate by 50% and reduce further according to capillary blood glucose. From day 2, if capillary blood glucose is at least 7 mmol/L, increase by 0.2 mg/kg/day; if it is below 7 mmol/L, do not increase and reduce pre-meal insulin boluses by 50%. Pre-lunch and pre-evening-meal values are a better marker of response than pre-breakfast values. Repeat daily until insulin independence, then adjust to capillary glucose. If the child is still on insulin at day 6, keep the dose for at least 4 weeks, which may be done as an outpatient.
• Outpatient introduction: start at 0.2 mg/kg/day in two doses and raise it each week by 0.2 mg/kg/day, reducing and then stopping insulin as the dose rises. From week 2, if capillary glucose is at least 7 mmol/L increase by 0.2 mg/kg/day and reduce insulin; if it is below 7 mmol/L reduce insulin. If glucose rises after an insulin reduction, increase by 0.2 mg/kg/day. Repeat weekly until insulin independence.
• No early response: if there is no response after 5 to 6 weeks at insulin doses similar to those at the start, doses up to 2 mg/kg/day for a week may be tried (in rare cases weaning off insulin has taken 4 months). If insulin needs fall clearly at that dose, a higher dose may be continued over a prolonged period in selected cases.

Amglidia: Dose Adjustment and Long-Term Management

• Usual dose: the average daily dose is expected to be about 0.2 to 0.5 mg/kg/day in most patients. Higher doses are occasionally needed, and up to 2.8 mg/kg/day has been given in published reports without adverse reactions. With a partial response on lower doses, an increase up to 2.8 mg/kg/day may be tried in selected cases.
• More frequent dosing: some children have better control with 3 or 4 doses a day.
• No improvement: stop if there is no improvement (unchanged insulin dose, similar glycaemic control and no improvement in neurology).
• Monitoring: during titration, capillary blood glucose is checked four times a day and at bedtime; HbA1c is checked every three months. Once steady state is reached, daily checks are no longer needed except where metabolic imbalance is a risk.
• Falling glucose: glucose may fall on a fixed dose. To avoid hypoglycaemia, consider reducing the dose or stopping, certainly if values go below 4 mmol/L (72 mg/dL).
• Intercurrent illness: dose changes may be needed with infections, trauma, shock or anaesthesia. Insulin replaces glibenclamide for major surgery, and in exceptional stress (trauma, surgery, febrile infection) a temporary switch to insulin may be needed.
• Very high glucose: values above 20 mmol/L (360 mg/dL) may occur and sometimes settle on the usual dose. Close monitoring is required, and euglycaemia must be restored (for example by a third daily dose or insulin).

Amglidia: Special Populations

• Renal or hepatic impairment: in mild to moderate impairment start at the lowest dose levels and follow closely to avoid hypoglycaemia. Severe impairment is a contraindication.
• Patients at risk: in malnourished children, those with a marked change in general condition or irregular calorie intake, and those with impaired renal or hepatic function, start at the lowest dose levels.
• Elderly: not applicable, as the medicinal product is indicated for children.

Amglidia: Missed Dose

A missed dose carries a risk of hyperglycaemia. Check blood glucose at once and give the dose as soon as possible. If blood glucose exceeds 16.5 mmol/L, check for ketonuria or ketonaemia; if ketone bodies are present, give an insulin injection rapidly and contact the attending specialist.

Hypoglycaemia

Hypoglycaemia can occur with sulfonylureas. It can be severe and prolonged, and hospitalisation and glucose for several days may be needed.

• Tablets: the risk appears higher with glibenclamide. Signs of adrenergic counter-regulation can appear: sweating, clammy skin, anxiety, tachycardia, high blood pressure, palpitations, angina pectoris and cardiac arrhythmia. A severe hypoglycaemic attack can look like a stroke. Symptoms usually go away after carbohydrate (sugar) is taken or once the hypoglycaemia is corrected.
• Avoiding episodes: careful selection of the patient and of the dose, and proper information of the patient, are needed. The tablets are prescribed only if the patient is likely to eat regularly, in particular to have breakfast.

Risk Factors for Hypoglycaemia (Tablets)

• Refusal or inability of the patient to cooperate, particularly in older people.
• Undernutrition, poor general condition, irregular carbohydrate intake or a low-calorie diet.
• An imbalance between physical exercise and carbohydrate intake.
• Renal or hepatic impairment: the pharmacokinetics or pharmacodynamics of glibenclamide may change, and hypoglycaemia may be severe and prolonged, so appropriate management must be in place.
• Uncompensated endocrine disorders that affect carbohydrate metabolism or the counter-regulation of hypoglycaemia, such as adrenal insufficiency and hypopituitarism.
• Age 65 or over, a risk factor in patients treated with sulfonylureas; hypoglycaemia can be hard to recognise in older people.
• Alcohol.
• Combinations of medicines that increase the glucose-lowering effect (see Drug Interactions). Hypoglycaemia can be hard to recognise in patients taking beta-blockers, and is more likely when several glucose-lowering agents are combined.

In these situations the starting and maintenance doses are adapted with caution.

Loss of Glycaemic Control and Secondary Failure (Tablets)

• Fever, trauma, infection or surgery can upset the control of diabetes. It may then be necessary to stop the tablets and give insulin.
• The effect of any oral glucose-lowering medicine, glibenclamide included, can fade over time in some patients, through progression of the diabetes or a weaker response. This is called secondary failure, as opposed to primary failure, where the medicine is ineffective from the start. Dose adjustment and adherence to the diet are considered before a patient is classed as a secondary failure.

Cardiovascular Mortality (Tablets)

Epidemiological studies suggest that glibenclamide is associated with a higher risk of cardiovascular death than metformin or gliclazide. This was seen particularly in patients with coronary artery disease.

Monitoring and Patient Information (Tablets)

• Blood glucose and urine glucose are monitored periodically. Measuring glycosylated haemoglobin can be useful.
• The patient and family are told about the risks of hypoglycaemia, its symptoms and treatment, and the conditions that predispose to it, as well as primary and secondary failure.
• The patient is informed of the potential risks and benefits of the treatment and of other treatments, and of the importance of keeping to the diet, following a regular exercise programme and regularly monitoring urine and/or blood glucose.

G6PD Deficiency

Cases of acute haemolysis (haemolytic anaemia) have been reported with glibenclamide in patients with G6PD deficiency. The tablet SmPC does not recommend prescribing it to them, and the Amglidia SmPC says it should not be prescribed. An alternative treatment is strongly recommended if one exists. If there is none, the danger of haemolysis is weighed against the expected benefit, and the patient is screened for haemolysis.

Lactose (Tablets)

The tablets contain lactose. They are not advised in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption (rare hereditary diseases).

Ketoacidosis and Type 1 Diabetes (Amglidia)

Neonatal diabetes is a life-threatening and chronically debilitating condition. In severe cases it is associated with ketoacidosis, which can lead to death. Glibenclamide must not be used to treat ketoacidosis: continuous intravenous insulin and intravenous physiological saline remain the standard treatment. It should not be used in insulin-dependent type 1 diabetes with evidence of autoimmune destruction of beta cells.

Dosing Errors (Amglidia)

Take special care when calculating the dose, and check the strength and syringe before each administration.

Diarrhoea, Nausea and Vomiting (Amglidia)

• An initial diarrhoea may follow a dose increase but settles if the dose is maintained.
• With nausea, glycaemia seems to be maintained and insulin need not be restarted until the child can take the suspension.
• With major vomiting, a fast-acting insulin is used until it stops. With minor vomiting, an antiemetic is given and glibenclamide can continue.

Monitoring (Amglidia)

Blood glucose is monitored periodically. If it exceeds 16.5 mmol/L, check for ketones and give insulin rapidly if they are present. Glycosylated haemoglobin is measured every three months. Children with renal or hepatic impairment need periodic monitoring because of the higher risk of hypoglycaemia.

Sodium and Benzoate (Amglidia)

Each mL contains 2.8 mg of sodium (0.1% of the WHO-recommended daily intake of 2 g for an adult), relevant for patients on a controlled sodium diet. Each mL also contains 5 mg of benzoate. Benzoate displaces bilirubin from albumin, which may increase neonatal jaundice and could develop into kernicterus (bilirubin deposits in brain tissue).

Pregnancy, Breastfeeding and Fertility

The two SmPCs word these points differently, so each is given on its own. The SmPC of the product in use applies.

• Tablets, pregnancy: poorly controlled diabetes, gestational or permanent, increases congenital malformations and perinatal mortality, so control should be as good as possible around conception. Sulfonylureas are teratogenic in animals at high doses, and there are currently no relevant or sufficient clinical data to assess a possible malformative or foetotoxic effect of glibenclamide in pregnancy. Rebalancing the diabetes in pregnancy requires insulin, whatever the type of diabetes. A patient on an oral treatment is switched to insulin as soon as a pregnancy is planned, or when a pregnancy exposed to the medicine is found by chance. This alone is not a reason to advise termination, but it calls for caution and targeted prenatal monitoring. Monitoring of the newborn’s blood glucose is recommended.
• Tablets, breastfeeding: contraindicated, because there are no data on passage into breast milk and there is a risk of neonatal hypoglycaemia.
• Tablets, fertility: the SmPC lists fertility as not applicable.
• Amglidia, pregnancy: women of childbearing potential planning a pregnancy should be switched from oral glibenclamide to insulin, and glibenclamide should not be given during pregnancy. Limited published data show no increase in congenital malformations with first-trimester use and no foetotoxic effects in the second and third trimesters, and animal studies do not indicate teratogenic potential. Glibenclamide crosses the placenta mostly in small amounts, with high variability. Insulin is recommended in pregnant women.
• Amglidia, breastfeeding: published data from 11 treated mothers indicate that glibenclamide is not excreted in human milk, and hypoglycaemia was not reported in breast-fed newborns. Breastfeeding seems compatible, but monitoring the blood sugar of a fully breast-fed infant is advisable.
• Amglidia, fertility: no clinical data are available.

Effect on Driving

Glibenclamide has a moderate influence on the ability to drive and use machines because it may increase the risk of hypoglycaemia, which reduces alertness. The Amglidia SmPC adds that this may not be relevant for its target population, but that reduced alertness can matter in road traffic (for example cycling) or in play (for example skateboarding). For the tablets, the SmPC of the national product applies.

Tablets (Daonil 5 mg): store at a temperature not exceeding 25 °C.

Amglidia oral suspension: keep the bottle in the outer carton to protect it from light; no temperature limit is stated. After first opening, keep the bottle tightly closed and use the suspension within 30 days. The bottle is brown glass with a child-resistant closure; each carton holds a 30 mL bottle, an adaptor and either a 1 mL or a 5 mL graduated oral syringe.

• Tablets (Daonil 5 mg): 2 years.
• Amglidia oral suspension: 3 years unopened; 30 days after first opening.

Prescription only (Rx). Glibenclamide tablets are taken by the patient and are supplied to the patient or the treating clinic on prescription, under national rules. Amglidia is started by a physician experienced in treating very early-onset diabetes. It is given to the child with the oral syringe supplied, so it is supplied to the family or to the treating clinic on prescription.