Azulix

Azulix is indicated for the treatment of type 2 diabetes mellitus, when diet, physical exercise and weight reduction alone are not adequate.

For oral administration.

The basis for successful treatment of diabetes is a good diet, regular physical activity, as well as routine checks of blood and urine. Tablets or insulin cannot compensate if the patient does not keep to the recommended diet.

Posology

The dosage is determined by the results of blood and urinary glucose determinations.

The starting dose is 1 mg Azulix per day. If good control is achieved, this dosage should be used for maintenance therapy.

For the different dosage regimens appropriate strengths are available.

If control is unsatisfactory, the dosage should be increased, based on the glycaemic control, in a stepwise manner with an interval of about 1 to 2 weeks between each step, to 2, 3, or 4 mg Azulix per day.

A dosage of more than 4 mg Azulix per day gives better results only in exceptional cases.

The maximum recommended dose is 6 mg Azulix per day.

In patients not adequately controlled with the maximum daily dose of metformin, concomitant Azulix therapy can be initiated. While maintaining the metformin dose, the Azulix therapy is started with a low dose, and is then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The combination therapy should be initiated under close medical supervision.

In patients not adequately controlled with the maximum daily dose of Azulix, concomitant insulin therapy can be initiated if necessary. While maintaining the Azulix dose, insulin treatment is started at a low dose and titrated up depending on the desired level of metabolic control. The combination therapy should be initiated under close medical supervision.

Normally a single daily dose of Azulix is sufficient. It is recommended that this dose be taken shortly before or during a substantial breakfast or - if none is taken - shortly before or during the first main meal. If a dose is forgotten, this should not be corrected by increasing the next dose.

If a patient has a hypoglycaemic reaction on 1 mg Azulix daily, this indicates that they can be controlled by diet alone.

In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity, Azulix requirements may fall. To avoid hypoglycaemia timely dose reduction or cessation of therapy must therefore be considered. Change in dosage may also be necessary if there are changes in weight or life style of the patient, or other factors that increase the risk of hypo- or hyperglycaemia.

Switch over from other oral hypoglycaemic agents to Azulix

A switch over from other oral hypoglycaemic agents to Azulix can generally be done. For the switch over to Azulix the strength and the half-life of the previous medicinal product has to be taken into account. In some cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days is advisable in order to minimise the risk of hypoglycaemic reactions due to the additive effect.

The recommended starting dose is 1 mg Azulix per day. Based on the response the Azulix dosage may be increased stepwise, as indicated earlier.

Switch over from insulin to Azulix

In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to Azulix may be indicated. The changeover should be undertaken under close medical supervision.

Special Populations

Patients with renal or hepatic impairment

Paediatric population

There are no data available on the use of Azulix in patients under 8 years of age. For children aged 8 to 17 years, there are limited data on Azulix as monotherapy.

The available data on safety and efficacy are insufficient in the paediatric population and therefore such use is not recommended.

Method of administration

Tablets should be swallowed without chewing with some liquid.

- insulin dependent diabetes

- diabetic coma

- ketoacidosis

- severe renal or hepatic function disorders.

In case of severe renal or hepatic function disorders, a change over to insulin is required.

Azulix must be taken shortly before or during a meal.

When meals are taken at irregular hours or skipped altogether, treatment with ”Azulix Tablets” may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include: headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness and reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms can almost always be promptly controlled by immediate intake carbohydrates (sugar). Artificial sweeteners have no effect.

It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur.

Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, require immediate medical treatment and occasionally hospitalisation.

Factors favouring hypoglycaemia include:

- unwillingness or (more commonly in older patients) incapacity of the patient to cooperate

- undernutrition, irregular mealtimes or missed meals or periods of fasting

- alterations in diet

- imbalance between physical exertion and carbohydrate intake

- consumption of alcohol, especially in combination with skipped meals

- impaired renal function

- serious liver dysfunction

- overdosage with Azulix Tablets

- certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter regulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency)

- concurrent administration of certain other medicinal products

Treatment with Azulix tablets requires regular monitoring of glucose levels in blood and urine. In addition determination of the proportion of glycosylated haemoglobin is recommended.

Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with Azulix tablets

In stress-situations (e.g. accidents, acute operations, infections with fever etc) a temporary switch to insulin may be indicated.

No experience has been gained concerning the use of Azulix tablets in patients with severe impairment of liver function or dialysis patients. In patients with severe impairment of renal or liver function change over to insulin is indicated.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anaemia. Since Azulix belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

Azulix Tablets contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No studies on the effects on the ability to drive and use machines have been performed.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.

The following adverse reactions from clinical investigations were based on experience with Azulix and other sulfonylureas, were listed below by system organ class and in order of decreasing incidence (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).

Blood and lymphatic system disorders

Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are in general reversible upon discontinuation of medication.

Not known: severe thrombocytopenia with platelet count less than 10,000/µl and thrombocytopenic purpura.

Immune system disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnoea, fall in blood pressure and sometimes shock.

Not known: cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible.

Metabolism and nutrition disorders

Rare: hypoglycaemia.

These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct.).

Eye disorders

Not known: visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood glucose levels.

Gastrointestinal disorders

Very rare: nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which seldom lead to discontinuation of therapy.

Hepato-biliary disorders

Very rare: hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis and hepatic failure.

Not known: hepatic enzymes increased.

Skin and subcutaneous tissue disorders

Not known: hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria and photosensitivity.

Investigations

Very rare: blood sodium decrease.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and convulsions.

Management

Treatment primarily consists of preventing absorption by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdosage hospitalisation in an intensive care department is indicated. Start the administration of glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment should be symptomatic.

In particular when treating hypoglycaemia due to accidental intake of Azulix in infants and young children, the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous hyperglycaemia. Blood glucose should be closely monitored.

Azulix is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may be used in non-insulin dependent (type 2) diabetes mellitus.

Azulix acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, Azulix seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

Insulin release:

Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane. Closing the potassium channel induces depolarisation of the beta cell and results -by opening of calcium channels - in an increased influx of calcium into the cell. This leads to insulin release through exocytosis.

Azulix binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfonylureas binding site.

Extrapancreatic activity

The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.

The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Azulix increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.

Azulix increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C, which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.

Azulix inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6-bisphosphate, which in its turn inhibits the gluconeogenesis.

General

In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of Azulix is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under Azulix.

There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose.

Although the hydroxy metabolite of Azulix caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect

Combination therapy with metformin

Improved metabolic control for concomitant Azulix therapy compared to metformin alone in patients not adequately controlled with the maximum daily dosage of metformin has been shown in one study.

Combination therapy with insulin

Data for combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of Azulix, concomitant insulin therapy can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.

Special populations

Paediatric population:An active controlled clinical trial (Azulix up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2 diabetes.

Both Azulix and metformin exhibited a significant decrease from baseline in HbA_1c (Azulix -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, Azulix did not achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA_1c. The difference between treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority margin.

Following Azulix treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.

Absorption

The bioavailability of Azulix after oral administration is complete. Food intake has no relevant influence on absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours after oral intake (mean 0.3 μg/ml during multiple dosing of 4 mg/daily) and there is a linear relationship between dose and both Cmax and AUC (area under the time concentration curve).

Distribution

Azulix has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).

In animals, Azulix is excreted in milk. Azulix is transferred to the placenta. Passage of the blood-brain barrier is low.

Biotransformation and elimination

Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

After a single dose of radiolabelled Azulix, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of Azulix, the terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours respectively.

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra individual variability was very low. There was no relevant accumulation.

Special populations

Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for Azulix clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding.

Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed in such patients.

Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.

Paediatric population

A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of Azulix in 30 paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed mean AUC_(0-last) , Cmax and t_1/2 similar to that previously observed in adults.

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human exposure as to indicate little relevance to clinical use, or were due to the pharmacodynamic action (hypoglycaemia) of the compound. This finding is based on conventional safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed were considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in offspring.

Not applicable.

No special requirements for disposal.

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