Oramikron

Non insulin dependent diabetes mellitus.

Posology

Adults

The total daily dose may vary from 40-320mg. The dose should be adjusted according to the individual's response, commencing with 40-80mg daily and increasing until adequate control is achieved. A single dose should not exceed 160mg. When higher doses are required, Oramikron should be taken twice daily and according to the main meals of the day.

In obese patients or those not showing adequate response to Oramikron alone, additional therapy may be required.

Elderly

Plasma clearance of Oramikron is not altered in the elderly and steady state plasma levels can therefore be expected to be similar to those in adults under 65 years. Clinical experience in the elderly to date shows that Oramikron is effective and well tolerated. Care should be exercised however, when prescribing sulfonylureas in the elderly due to a possible age-related increased risk of hypoglycaemia.

Children

Oramikron, as with other sulfonylureas, is not indicated for the treatment of juvenile onset diabetes mellitus.

Method of administration

For oral use.

-

- Type I diabetes

- Diabetic pre-coma and coma, diabetic keto-acidosis

- Severe renal or hepatic insufficiency: in these cases the use of insulin is recommended

- Treatment with miconazole

- Lactation.

Hypoglycaemia

This treatment should be prescribed only if the patient is likely to have a regular food intake (including breakfast). It is important to have a regular carbohydrate intake due to the increased risk of hypoglycaemia if a meal is taken late, if an inadequate amount of food is consumed or if the food is low in carbohydrate. Hypoglycaemia is more likely to occur during low-calorie diets, following prolonged or strenuous exercise, alcohol intake or if a combination of hypoglycaemic agents is being used.

Hypoglycaemia may occur following administration of sulfonylureas. Some cases may be severe and prolonged. Hospitalisation may be necessary and glucose administration may need to be continued for several days.

Careful selection of patients, of the dose used, and clear patient directions are necessary to reduce the risk of hypoglycaemic episodes.

Factors which increase the risk of hypoglycaemia:

- patient refuses or (particularly in elderly subjects) is unable to co-operate

- malnutrition, irregular mealtimes, skipping meals, periods of fasting or dietary changes

- imbalance between physical exercise and carbohydrate intake

- renal insufficiency

- severe hepatic insufficiency

- overdose of Oramikron

- certain endocrine disorders: thyroid disorders, hypopituitarism and adrenal insufficiency

- concomitant administration of certain other medicines.

Renal and hepatic insufficiency

The pharmacokinetics and/or pharmacodynamics of Oramikron may be altered in patients with hepatic insufficiency or severe renal failure. A hypoglycaemic episode occurring in these patients may be prolonged, so appropriate management should be initiated.

Patient information

The risks of hypoglycaemia, together with its symptoms, treatment and conditions that predispose to its development, should be explained to the patient and to family members.

The patient should be informed of the importance of following dietary advice, of taking regular exercise, and of regular monitoring of blood glucose levels.

Poor blood glucose control

Blood glucose control in a patient receiving antidiabetic treatment may be affected by any of the following: fever, trauma, infection or surgical intervention. In some cases, it may be necessary to administer insulin.

The hypoglycaemic efficacy of any oral antidiabetic agent, including Oramikron, is attenuated over time in many patients. This may be due to progression in the severity of the diabetes, or to a reduced response to treatment. This phenomenon is known as secondary failure which is distinct from primary failure, when an active substance is ineffective as first-line treatment. Adequate dose adjustment and dietary compliance should be considered before classifying the patient as secondary failure.

Laboratory tests

Measurement of glycated haemoglobin levels (or fasting venous plasma glucose) is recommended in assessing blood glucose control. Blood glucose self-monitoring may also be useful.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

Oramikron has no known influence on the ability to drive and use machines. However, patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment.

Based on the experience with Oramikron, the following undesirable effects have to be mentioned.

Hypoglycaemia

As for other sulfonylureas, treatment with Oramikron can cause hypoglycaemia, if mealtimes are irregular and, in particular, if meals are skipped. Possible symptoms of hypoglycaemia are: headache, intense hunger, nausea, vomiting, lassitude, sleep disorders, agitation, aggression, poor concentration, reduced awareness and slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disorders, dizziness, feeling of powerlessness, loss of self-control, delirium, convulsions, shallow respiration, bradycardia, drowsiness and loss of consciousness, possibly resulting in coma and lethal outcome.

In addition, signs of adrenergic counter-regulation may be observed: sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmia.

Usually, symptoms disappear after intake of carbohydrates (sugar). However, artificial sweeteners have no effect. Experience with other sulfonylureas shows that hypoglycaemia can recur even when measures prove effective initially.

If a hypoglycaemic episode is severe or prolonged, and even if it is temporarily controlled by intake of sugar, immediate medical treatment or even hospitalisation are required.

Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea and constipation have been reported: if these should occur they can be avoided or minimised if Oramikron is taken with breakfast.

The following undesirable effects have been more rarely reported:

Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, angioedema, erythema, maculopapular rashes, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis).

Blood and lymphatic system disorders: Changes in haematology are rare. They may include anaemia, leucopenia, thrombocytopenia, granulocytopenia. These are in general reversible upon discontinuation of Oramikron.

Hepatobiliary disorders: Raised hepatic enzyme levels (ASAT, ALAT, alkaline phosphatase), hepatitis (isolated reports). Discontinue treatment if cholestatic jaundice appears.

These symptoms usually disappear after discontinuation of treatment.

Eye disorders: Transient visual disturbances may occur, especially on initiation of treatment, due to changes in blood glucose levels.

Class attribution effects

As for other sulfonylureas, the following adverse events have been observed: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulfonylurea or led to life-threatening liver failure in isolated cases.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

An overdose of sulfonylureas may cause hypoglycaemia.

Moderate symptoms of hypoglycaemia, without any loss of consciousness or neurological signs, must be corrected by carbohydrate intake, dose adjustment and/or change of diet. Strict monitoring should be continued until the doctor is sure that the patient is out of danger.

Severe hypoglycaemic reactions, with coma, convulsions or other neurological disorders are possible and must be treated as a medical emergency, requiring immediate hospitalisation.

If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid I.V. injection of 50 ml of concentrated glucose solution (20 to 30%). This should be followed by continuous infusion of a more dilute glucose solution (10%) at a rate that will maintain blood glucose levels above 1 g/l. Patients should be monitored closely and, depending on the patient's condition after this time, the doctor will decide if further monitoring is necessary.

Dialysis is of no benefit to patients due to the strong binding of Oramikron to proteins.

Pharmacotherapeuticgroup: sulfonamides, urea derivatives.

ATC code: A10BB09

Oramikron is a hypoglycaemic sulfonylurea antidiabetic active substance differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.

Oramikron reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.

In addition to these metabolic properties, Oramikron has haemovascular properties.

Effects on insulin release

In type 2 diabetics, Oramikron restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. A significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.

Haemovascular properties:

Oramikron decreases microthrombosis by two mechanisms which may be involved in complications of diabetes:

- a partial inhibition of platelet aggregation and adhesion, with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B₂),

- an action on the vascular endothelium fibrinolytic activity with an increase in tPA activity.

The drug is well absorbed and its half-life in man is approximately 10-12 hours. Oramikron is metabolised in the liver; less that 5% of the dose is excreted unchanged in the urine.

Preclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity and genotoxicity. Long term carcinogenicity studies have not been done. No teratogenic changes have been shown in animal studies, but lower fetal body weight was observed in animals receiving doses 9.4 fold higher than the maximum recommended dose in humans.

Not applicable

No special requirements.