Diaclide MR 30 mg Modified-release Tablets

4.2 Posology and method of administration

Switching from another oral antidiabetic agent to Diaclide MR modified-release tablets
When switching from a hypoglycaemic sulphfonylurea with a prolonged half-life, a treatment free period of a few days may be necessary to avoid an additive effect of the two products, which might cause hypoglycaemia

Patients with rRenal impairment
In patients with mild to moderate renal insufficiency the same dosing regimen can be used as in patients with normal renal function with careful patient monitoring. These data have been confirmed in clinical trials.

Patients at rRisk of hypoglycaemia
Higher risk of hypoglycemia exists in following patients:
- undernourished or malnourished,

4.3 Contraindications

• Hypersensitivity to gliclazide, other sulphfonylureas, sulphfonamides, or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Hypoglycaemia
Hypoglycaemia may occur following administration of sulphfonylureas (see section 4.8).

Poor blood glucose control
Blood glucose control in a patient receiving antidiabetic treatment may be affected by any of the following: St. John’s wort (Hypericum perforatum) preparations (see section 4.5), fever, trauma, infection or surgical intervention. In some cases, it may be necessary to administer insulin.

Dysglycaemia
Disturbances in blood glucose, including hypoglycaemia and hyperglycaemia have been reported in diabetic patients receiving concomitant treatment with fluoroquinolones, especially in elderly patients. Careful monitoring of blood glucose is therefore recommended in all patients receiving gliclazide at the same time as fluoroquinolones.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations which are not recommended
- Phenylbutazone (systemic route): increases the hypoglycaemic effect of sulphfonylureas (displaces their binding to plasma proteins and/or reduces their elimination).


Combinations requiring precautions during use

St. John’s wort (Hypericum perforatum) preparations:
Gliclazide exposure is decreased by St. John's wort (Hypericum perforatum). The importance of blood glucose monitoring should be emphasised.

The following products may cause dysglycaemia

Combinations requiring precautions during use
- Fluoroquinolones:
In case of a concomitant use of gliclazide and a fluoroquinolone, the patient should be warned of the risk of dysglycaemia and the importance of blood glucose monitoring should be emphasised.

Combination which must be taken into account

- Anticoagulant therapy (e.g. warfarin):
Sulphfonylureas may lead to potentiation of anticoagulation during concurrent treatment.

4.6 Fertility, pregnancy and lactation

Pregnancy
There is no or limited data (less than 300 pregnancy outcomes) from experience with the use of gliclazide in pregnant women during pregnancy in humans, even though there are few data with other sulphfonylureas.
In animal studies, gliclazide is not teratogenic (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of gliclazide during pregnancy.
Control of diabetes should be obtained before the time of conception to reduce the risk of congenital abnormalities linked to uncontrolled diabetes.
Oral hypoglycaemic agents are not suitable; insulin is the agent of first choice for treatment of diabetes during pregnancy. It is recommended that oral hypoglycaemic therapy is changed to insulin before a pregnancy is attempted, or as soon as pregnancy is discovered.

Breast-feeding
It is not known whether gliclazide or its metabolites are excreted in breast human milk. Given the risk of neonatal hypoglycaemia, theis medicinal product is therefore contra-indicated in breast-feeding mothers. A risk to the newborns/infants cannot be excluded.

Fertility
No effect on fertility or reproductive performance was noted in male and female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Gliclazide has no or negligible known influence on the ability to drive and use machines. However, patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machines, especially at the beginning of treatment.

4.8 Undesirable effects

Hypoglycaemia
The most frequent adverse reaction with gliclazide is hypoglycaemia.
As for other sulphfonylureas, treatment with Diaclide MR modified-release tablets can commonly cause hypoglycaemia, if meal times are irregular and, in particular, if meals are skipped.

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

Other undesirable effects

Gastrointestinal disturbances, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, and constipation have been reportedare uncommon: if these should occur, they can be avoided or minimised if gliclazide 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) and, exceptionally, drug reaction with eosinophilia and systemic symptoms (DRESS).

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

4.9 Overdose

An overdose of sulphfonylureas may cause hypoglycaemia.


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: sulfonylureassulfonamides, urea derivates
ATC code: A10BB09

Mechanism of action

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

5.3 Preclinical safety data

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 foetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans. Fertility and reproductive performance were unaffected after gliclazide administration in animal studies.

10. DATE OF REVISION OF THE TEXT

FebruaryMay 20157

Section 1:
Diaclide MR 30 mg Modified release Tablets

Section 2:
Excipient with known effect:
Each modified-release tablet contains 73.5 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Section 4.2:
Special populations
Elderly
Diaclide MR modified-release tablets should be prescribed using the same dosing regimen recommended for patients under 65 years of age.

Patients with renal impairment
In patients with mild to moderate renal insufficiency the same dosing regimen can be used as in patients with normal renal function with careful patient monitoring. These data have been confirmed in clinical trials.

Patients at risk of hypoglycaemia
.......

Paediatric population
The safety and efficacy of Diaclide MR modified-release tablets in children and adolescents have not been established.No data are available.

Section 4.3:
• Hypersensitivity to gliclazide, other sulphonylureas, sulphonamides, or to any of the excipients listed in section 6.1

Section 4.4

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

Patient information
The risks of hypoglycaemia, together with its symptoms (see section 4.8), treatment, and conditions that predispose to its development, should be explained to the patient and to family members.

Excipients
Diaclide MR modified-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Section 4.5:
Combinations requiring precautions for use
Potentiation of the blood glucose lowering effect and thus, in some instances, hypoglycaemia may occur when one of the following medicinal products is taken: other antidiabetic agents (insulins, acarbose, metformin, thiazolidinediones, dipeptidyl
peptidase-4 inhibitors, GLP-1 receptor agonists), beta-blockers, fluconazole, angiotensin converting enzyme inhibitors (captopril, enalapril), H2-receptor antagonists, MAOIs, sulfonamides, clarithromycin and nonsteroidal anti-inflammatory agents.

Section 4.6:

LactationBreast-feeding


Section 4.7:

Gliclazide has no known influence on the ability to drive and use machines. However, patients should be made aware of the symptoms of hypoglycaemia and should be careful if driving or operating machines, especially at the beginning of treatment.


Section 4.8:
Based on the experience with gliclazide, and other sulphonylureas the following undesirable
effects have to be mentionedbeen reported.

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 gliclazide.
- Hepatobiliary disorders: Raised hepatic enzyme levels (AST, ALT, 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 sulphonylureas, the following adverse events have been observed: cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia,
elevated liver enzyme levels and even impairment of liver function (e.g. with cholestasis and jaundice) and hepatitis which regressed after withdrawal of the sulphonylurea 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.

Section 5.2:

Absorption
Plasma levels increase progressively during the first 6 hours, reaching a plateau, which is
maintained from the sixth to the twelfth hour after administration.
Intra-individual variability is low.
Gliclazide is completely absorbed. Food intake does not affect the rate or degree of
absorption.

Distribution
The relationship between the dose administered ranging up to 120 mg and the area under the
concentration time curve is linear.
Plasma protein binding is approximately 95%. The volume of distribution is around 30 litres.

A single daily intake of Diaclide MR modified-release tablets maintains effective
gliclazide plasma concentrations over 24 hours.

Biotransformation
Gliclazide is mainly metabolised in the liver and excreted in the urine: less than 1% of the
unchanged form is found in the urine. No active metabolites have been detected in plasma.

Elimination
The elimination half-life of gliclazide varies between 12 and 20 hours.
The volume of distribution is around 30 litres.

Linearity/non-linearity
The relationship between the dose administered ranging up to 120 mg and the area under the
concentration time curve is linear.

Special populations
Elderly
No clinically significant changes in pharmacokinetic parameters have been observed in
elderly patients.
A single daily dose of Diaclide MR modified-release tablets maintains effective gliclazide
plasma concentrations over 24 hours.

Section 6.1:
Hypromellose (4000 mPas, 100 mPas)

Section 6.4:
This medicinal product does not require any special storage conditions. Store in the original
packaging.

Section 6.5:
Diaclide MR is available in clear, transparent PVC/Aluminium blisters (10, 14 or 15
tablets/blister) in boxes of 10, 14, 20, 28, 30, 56, 60, 84, 90, 100, 120 or 180 tablets and in
tablet containers (HDPE with a tamper evident PP screw-cap) of 90, 120 or 180 tablets.

Section 10: Revision date changed to April 2011

None provided