DIABEN – GLIBENCLAMIDE FROM PHARCO

Glibenclamide (DIABEN ) is a hypoglycaemic agent indicated in the treatment of non- insulin dependent diabetes who respond inadequately to dietary measures alone.

DIABEN Composition

Active content

Each tablet contains Glibenclamide 5 mg.

Inactive content

Lactose monohydrate, Maize starch, Magnesium stearate, Colloidal Silicon dioxide, Talc powder.

DIABEN Mode of action

Both in healthy people and in patients with non-insulin dependent (type 2) diabetes mellitus, glibenclamide lowers blood glucose concentration by stimulating insulin release from the beta-cells of the pancreas.

This effect operates the interaction with glucose (Improvement In the responsiveness of beta-cells to the physiological glucose stimulus).

Glibenclamide is also reported as having extra-pancreatic effects: It reduces hepatic glucose production and enhances insulin binding and insulin sensitivity in peripheral tissues.

DIABEN Pharmacodynamic characteristics

After a single morning dose, the blood-glucose-lowering effect remains detectable for approx. 24 hours. During long-term therapy the hypo-glycemic effect of glibenclamide persists, while Insulin levels return to the normal range.

Glibenclamide has a mild diuretic action and increases free water clearance.

DIABEN Pharmacokinetics

Glibenclamide is rapidly and completely absorbed after oral administration.

The bioavailability of glibenclamide from tablets is approximately 70%.

Peak serum concentrations are reached after 2 to 4 hours.

Absorption of glibenclamide is not significantly influenced by food intake. The serum half-life of glibenclamide after oral administration is 2 to 5 hours, though some studies suggest that In patients with diabetes mellitus there may be a longer half-life of 8 to 10 hours.

There is no accumulation. The protein binding of glibenclamide is more than 98%, in vitro, this binding is predominantly non-ionic,

Glibenclamide is completely metabolized in the liver. The principal metabolite is 4-trans-hydroxyglibencl­amide; another is 3-cis-hydroxyglibenclamide. The metabolites of glibenclamide make some .contribution to the blood glucose lowering effect.

Excretion of the metabolites takes place via the-urine and bile roughly half by each route-and is complete after 45 to 72 hours.

In patients With Impaired renal function, there is increased excretion of metabolites In the bile, the increase be dependent on the severity of renal Impairment.

Glibenclamide crosses the placenta in only minimal amounts. Like other sulfonylureas, glibenclamide is presumably excreted into the breast milk.

DIABEN Indications

Glibenclamide is a hypoglycaemic agent indicated in the treatment of non- insulin dependent diabetes who respond inadequately to dietary measures alone.

DIABEN Dosage and administration

Dosage

In principle, the dosage of Diaben is governed by the desired blood glucose level. The dosage of glibenclamide must be the lowest possible dose which is ef­fective.

Treatment with Diaben must be initiated and monitored by a physician; The patient must take Diaben at the times and in the doses prescribed by the physician.

Mistakes

E.g. forgetting to take a dose, must never be corrected by subsequently taking a larger dose.

Measures for dealing with such mistakes in particular forgetting a dose or skipping a meal or in the event a dose cannot be taken at the prescribed time must be discussed and agreed between physician and patient beforehand.

If it is discovered that too high a Glucose or an extra dose of Diaben has been taken, a physician must be notified immediately.

Initial dose and dose titration

Usual initial dose: half to 1 tablet Diaben once daily.

It is recommended that treatment be started with the smallest possible dose.

This applies in particular to patients who are prone to hypoglycaemia or who weigh less than 50 kg.

If necessary the daily dose can be raised.

It s recommended that the dose is increased gradually i.e. in increments of no more than half tablet, and at intervals one or two weeks, and the increase be guided by regular blood glucose monitoring.

Dose range in patients with well-controlled diabetes; maximum doses

usual single dose: half to 2 tablets Diaben.

A Single dose of 2 tablets Diaben must not be exceeded .

Larger daily dose must be divided into at least two separate single doses.

Usual daily dose: 1 to 2 tablets Diaben.

Exceeding a total daily dose of 3 tablets Diaben is not recommended, because higher daily doses of up 4 tablets Diaben are more effective only In exceptional cases.

Distribution of doses

Timing and distribution of doses are to be decided by the physician , taking into consideration the patient’s current life-style.

Normally a single daily dose of Diaben is sufficient.

It is recom­mended that daily doses of up to 2 tablets Diaben to be taken before a substantial breakfast or before the first main meal and any remaining portions of the total daily dose before the evening meal.

It is very important not to skip meals after the tablets have been taken.

Dosage in young adults with type 2 diabetes mellitus

Dosage is basically the same as for older adults.

Secondary dosage adjustment

As an improvement in control of diabetes. in itself, associated with higher insulin sensitivity, glibenclamide requirements may fall as treatment proceeds.

To avoid hypoglycemia, timely dose reduction or cessation of Diaben therapy must therefore be considered.

Correction of dosage must also be considered, whenever

  1. the patient’s weight changes.
  2. the patient’s life-style changes,other factors arise, which cause an increased susceptibility to hypoglycemia or hyperglycemia.

Duration of treatment

Treatment with Diaben is normally a long-term therapy.

Changeover from other oral antidiabetics to Diaben

There is no exact dosage, relationship between Diaben and other oral anti-diabetics.

When substituting Diaben for other oral antidiabetics , it is recommended that the procedure be the same as for initial dosage, starting with daily doses of half to 1 tablet Diaben.

This applies even in cases where the patient is being switched from the maximum dose of another oral anti-diabetic.

Consideration must be given to the potency and duration of action of the previous anti-diabetic agent.

A break from medication may be required to avoid any summation of effects entailing a risk of hypoglycaemia.

Administration

Diaben tablets must be swallowed without chewing with sufficient amounts of liquid, e.g. with roughly half to one glass.

DIABEN Contraindications

Diaben must not be used

  1. In patients with insulin-dependent (type 1) diabetes mellitus (for example diabetics with a history of ke­toacidosis ).
  2. In treatment of diabetic ketoacidosis.
  3. In treatment of diabetic pre-coma or coma.
  4. In patients with serious renal dysfunction.
  5. In patients with serious hepatic dysfunction.
  6. In patients hypersensitive to any of the excipients of Diaben.
  7. In pregnant women.
  8. In breast-feeding women.

Warnings & Precautions

Patients with rare hereditary problems of galactose intolterance, the Lapp lactose deficiency or glucose galactose mal-absorption should not take this medicine.

Care is necessary in the following patients

  • Elderly, debilitated or malnourished patients who are particu­larly susceptible to the hypoglycaemic effects of sulphonyl ureas.
  • During excessive exercise as hypoglycaemia may be provoked.
  • Patients with mild to moderate renal impairment. In long-term clinical trials with renal insufficiency have been treated satisfactorily using glibenclamide at reduced doses with careful patient monitoring.
  • Patients with adrenal or pituitary insufficiency.

Driving a vehicle or performing other hazardous tasks

Alertness and reactions may be impaired by hypo or hyper glycemic episodes, especially when beginning or after altering treatment, or when Diaben is not taken regularly. This may, for example, affect the ability to drive or operate machinery.

Food Interactions

No information currently deemed necessary.

Drug interactions

Bosentan

An increased incidence of elevated liver enzymes was observed in patients receiving glibenclamide concomitantly with bosentan.

Both glibenclamide and bosentan Inhibit the bile salt export pump, leading to intracellular accumulation of cytotoxic bile salts. Therefore, this combination should not be used.

DIABEN Side Effects

Blood disorders

Potentially life-threatening changes in the blood picture may occur. They may include-rarely-mild to severe, thrombocy1openia (e.g. presenting as purpura),isolated cases leucopenia, agranulocy1osis and (e.g. due to myelosupression) pancythopenia, haemolytic anaemia, erythrocytopenia ,granulocytopenia.

Immune system disorders

Hypersensitivity including dyspnoea and swelling of the lips, face, throat or tongue.

Endocrine disorders

Infrequently a syndrome of inappropriate secretion of anti-diuretic hormone may be induced which may give rise to reduced serum sodium levels.

Metabolism and nutritional disorders

Hypoglycaemia, sometimes prolonged and even life-threatening, may occur as a result of the blood glucose lowering action of glibenclamide.

Possible symptoms of hypoglyceamia include headache, ravenous hunger, nausea, vomiting, lassnude, sleepiness, disordered sleep, restlessness, impaired concentration, alertness and reactions, depression. confusion, speech disorders, aphasia, visual disorders, tremor, sensory distur­bances. dizziness. loss of self control, delirium, cerebral convulsions and loss of consciousness up to and including coma. shallow respiration and bradycardia.

Signs of adrenergic counter-regulation may be present such as swealing, clammy skin, anxiety, tachycardia, hypertension . paleitafions, angina pectoris and cardiac arrhythmias.

The picture of severe hypoglycaemic attack may resemble that of a stroke. The symptoms of hypoglycaemia a nearly always subside when hypoglycaemia is corrected.

Eye disorders

Temporary visual impairment.

Gastrointestinal disorders

Gastrointestinal symptoms such as nausea. vomiting, sensations of pressure or fullness , epigastrium, abdominal pain, diarrhoea may occur.

Hepatobiliary disorders

In isolated cases, there may be elevation of liver enzyme levels and even impair­ment of liver function (e.g. with cholestatic jaundice and hepatitis which can regress after Withdrawal of Glibenclamlde, though that may lead to life-threatening liver failure).

Skin and subcutaneous tissue disorders

Occasionally, allergic or pseudoallergic reactions may occur, e.g. In the form of itching or rashes.in isolated cases, photosensitivity may occur, and mild reactions in the form of urticaria may develop into serious and even life-threatening reactions.

Hypersensitivity reactions can occur, they consist mainly of allergic skin reactions which progress rarely erythema multiforme, Stevens-Johnson syndrome, erythema nodosum and exfoliative dermatitis, fever and jaundice.

Overdosage

Signs and symptoms

Acute overdose as well as long-term treatment with too high dose of glibenclamide may lead to severe, protracted, life-threatening hypoglycemia,

Management

As soon as an overdosage of Diaben has been discovered, a physician must be notified Without delay. The patient must immediately take sugar, if possible in the form of glucose, unless a physician has already undertaken responsibility for treating the overdose.

Careful monitoring is essential until the physician is confident that the patient is out of danger.

It must be remembered that hypoglycemia and its clinical signs may recur after initial recovery.

Admission to hospital may sometimes be necessary-even as precautionary measure.

In particular, significant overdoses and severe reactions with signs such as loss of consciousness or other serious neurological dis­orders are medical emergencies and require immediate treatment and admission of hospital.

If, for example, the patient is unconscious, an intravenous injection of concentrated glucose solution is indicated (for adults starting With 40 ml of 20 % solution, for example).

Alternatively in adults, administration of glucagons, e.g in doses of 0.5 to 1 mg i.v., s.c. or i.m. may be considered.

In particular when treating hypoglycemia in infants and young children , the dose of glucose given must be carefully adjusted in view of the possibility of producing dangerous hyper-glycemia , and must be controlled by close monitoring of blood your health and its consumption contrary to glucose.

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