Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Repaglinide Accord 0.5 mg tablets
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 0.5 mg of repaglinide.
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Tablet.
White to off white, round, biconvex with beveled edge, uncoated tablets, with inscription “R” on one side and plain on other side.
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone.
Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.
4.2Posology and method of administration
Posology
Repaglinide is given preprandially and is titrated individually to optimise glycaemic control. In addition to the usual
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
The recommended starting dose is 0.5 mg. One to two weeks should elapse between titration steps (as determined by blood glucose response).
If patients are transferred from another oral hypoglycaemic medicinal product, the recommended starting dose is 1 mg.
Maintenance
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Special populations
Elderly
No clinical studies have been conducted in patients >75 years of age.
Renal impairment
Repaglinide is not affected by renal disorders (see section 5.2).
Eight percent of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment. As insulin sensitivity is increased in diabetic patients with renal impairment, caution is advised when titrating these patients.
Hepatic impairment
No clinical studies have been conducted in patients with hepatic insufficiency.
Debilitated or malnourished patients
In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful dose titration is required to avoid hypoglycaemic reactions.
Patients receiving other oral hypoglycaemic medicinal products
Patients can be transferred directly from other oral hypoglycaemic medicinal products to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic medicinal products. The recommended maximum starting dose of patients transferred to repaglinide is 1 mg given before main meals.
Repaglinide can be given in combination with metformin, when the blood glucose is insufficiently controlled with metformin alone. In this case, the dosage of metformin should be maintained and repaglinide administered concomitantly. The starting dose of repaglinide is 0.5 mg, taken before main meals; titration is according to blood glucose response as for monotherapy.
Paediatric population
The safety and efficacy of repaglinide in children below 18 years have not been established. No data are available.
Method of administration
Repaglinide should be taken before main meals (i.e. preprandially).
Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal (i.e. preprandially 2, 3, or 4 meals a day). Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
In the case of concomitant use with other active substances refer to sections 4.4 and 4.5 to assess the dosage.
4.3Contraindications
•Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1.
•Diabetes mellitus type 1,
•Diabetic ketoacidosis, with or without coma.
•Severe hepatic function disorder.
•Concomitant use of gemfibrozil (see section 4.5).
4.4Special warnings and precautions for use
General
Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis.
Hypoglycaemia
Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.
Combination with insulin secretagogues
The blood
Repaglinide acts through a distinct binding site with a short action on the
Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies.
Combination with metformin
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
Acute coronary syndrome
The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1.
Concomitant use
Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.
4.5Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician:
In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of repaglinide, may be altered by substances which influence these cytochrome
Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below).
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketoconazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of the metabolism of repaglinide. Seven days
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the pharmacokinetics of repaglinide has been studied in healthy subjects.
repaglinide).
In a study conducted in healthy volunteers, the concomitant administration of repaglinide (a single dose of 0.25 mg) and ciclosporin (repeated dose at 100 mg) increased repaglinide AUC and Cmax about
In an interaction study with healthy volunteers,
4 days), a moderate inhibitor of CYP2C8 and CYP3A4, and repaglinide (single dose, 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to
In an interaction study with healthy volunteers,
Repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustment of these compounds when
The following substances may reduce the hypoglycaemic effect of repaglinide:
Oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.
When these medications are administered to or withdrawn from a patient receiving repaglinide, the patient should be observed closely for changes in glycaemic control.
When repaglinide is used together with other medicinal products that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.
Paediatric population
No interaction studies have been performed in children and adolescents.
4.6Fertility, pregnancy and lactation
Pregnancy
There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy.
There are no studies in
Fertility
Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.
4.7Effects on ability to drive and use machines
Repaglinide Accord has no direct influence on the ability to drive and use machines but may cause hypoglycaemia.
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 signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress.
Tabulated list of adverse reactions
Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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) and not known (cannot be estimated from the available data).
Immune system disorders | Allergic reactions* | Very rare | |
|
|
| |
Metabolism and nutrition | Hypoglycaemia | Common | |
disorders |
|
| |
Hypoglycaemic coma and | Not known | ||
| |||
| hypoglycaemic |
| |
| unconsciousness |
| |
|
|
| |
Eye disorders | Refraction disorder* | Very rare | |
|
|
| |
Cardiac disorders | Cardiovascular disease | Rare | |
|
|
| |
Gastrointestinal disorders | Abdominal pain, diarrhoea | Common | |
|
|
| |
| Vomiting, constipation | Very rare | |
|
|
| |
| Nausea | Not known | |
|
|
| |
|
|

Hepatobiliary disorders | Abnormal hepatic function, | Very rare |
| increased liver enzymes* |
|
|
|
|
Skin and subcutaneous tissue | Hypersensitivity* | Not known |
disorders |
|
|
* see section Description of selected adverse reactions below
Description of selected adverse reactions
Allergic reactions
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Refraction disorders
Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials.
Abnormal hepatic function, increased liver enzymes
Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes. In very rare cases, severe hepatic dysfunction has been reported.
Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no reason to suspect
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 listed in Appendix V.
4.9Overdose
Repaglinide has been given with weekly escalating doses from 4 - 20 mg four times daily in a 6 week period. No safety concerns were raised. As hypoglycaemia in this study was avoided through increased calorie intake, a relative overdose may result in an exaggerated
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Mechanism of action
Repaglinide is a
Repaglinide closes
Pharmacodynamic effects
In type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after an oral dose of repaglinide. This resulted in a blood
Clinical efficacy and safety
A
Clinical study results have shown that repaglinide is optimally dosed in relation to main meals (preprandial dosing).
Doses are usually taken within 15 minutes of the meal, but the time may vary from immediately preceding the meal to as long as 30 minutes before the meal.
One epidemiological study suggested an increased risk of acute coronary syndrome in repaglinide treated patients as compared to sulfonylurea treated patients (see sections 4.4 and 4.8).
5.2Pharmacokinetic properties
Absorption
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the active substance. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%).
No clinically relevant differences were seen in the pharmacokinetics of repaglinide, when repaglinide was administered 0, 15 or 30 minutes before a meal or in fasting state.
A high interindividual variability (60%) in repaglinide plasma concentrations has been detected in the clinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should be titrated against the clinical response, efficacy is not affected by interindividual variability.
Distribution
- Novonorm - repaglinide
- Repaglinide teva - repaglinide
- Enyglid - repaglinide
- Repaglinide krka - repaglinide
- Prandin - repaglinide
Prescription drugs listed. Substance: "Repaglinide"
Repaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent with distribution into intracellular fluid) and is highly bound to plasma proteins in humans (greater than 98%).
Elimination
Repaglinide is eliminated rapidly within 4 - 6 hours from the blood. The plasma elimination
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant
hypoglycaemic effect have been identified.
Repaglinide metabolites are excreted primarily via the bile. A small fraction (less than 8%) of the administered dose appears in the urine, primarily as metabolites. Less than 1% of repaglinide is recovered in faeces.
Special patient groups
Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2 diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepatic insufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patients with hepatic insufficiency, and 117.9 ng/ml x hr (83.8) in the elderly type 2 diabetic patients.
After a 5 day treatment of repaglinide (2 mg x 3/day) in patients with a severe impaired renal function (creatinine clearance:
Paediatric population
No data are available.
5.3Preclinical safety data
Repaglinide was shown not to be teratogenic in animal studies. Embryotoxicity, abnormal limb development in rat foetuses and new born pups, was observed in female rats exposed to high doses in the last stage of pregnancy and during the lactation period. Repaglinide was detected in the milk of animals.
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Cellulose, microcrystalline (E460)
Calcium hydrogen phosphate, anhydrous
Maize starch
Povidone
Glycerin
Magnesium stearate
Meglumine
Poloxamer 188
6.2Incompatibilities
Not applicable
6.3Shelf life
2years
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
Aluminium/aluminium blister in packs containing 30, 90, 120, 180 or 270 tablets.
HDPE bottle containing 100 tablets in packs of 1 bottle.
Not all pack sizes may be marketed.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited,
Sage house, 319 Pinner road, Harrow, HA1 4HF
United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22 December 2011
Date of latest renewal:
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
1. NAME OF THE MEDICINAL PRODUCT
Repaglinide Accord 1 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1 mg of repaglinide.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet.
Light yellow to yellow colored, round, biconvex with beveled edge, uncoated tablets, with inscription “R” on one side and plain on other side, may have mottled appearance.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone.
Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.
4.2 Posology and method of administration
Posology
Repaglinide is given preprandially and is titrated individually to optimise glycaemic control. In addition to the usual
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
The recommended starting dose is 0.5 mg. One to two weeks should elapse between titration steps (as determined by blood glucose response).
If patients are transferred from another oral hypoglycaemic medicinal product, the recommended starting dose is 1 mg.
Maintenance
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Special populations
Elderly
No clinical studies have been conducted in patients >75 years of age.
Renal impairment
Repaglinide is not affected by renal disorders (see section 5.2).
Eight percent of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment. As insulin sensitivity is increased in diabetic patients with renal impairment, caution is advised when titrating these patients.
Hepatic impairment
No clinical studies have been conducted in patients with hepatic insufficiency.
Debilitated or malnourished patients
In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful dose titration is required to avoid hypoglycaemic reactions.
Patients receiving other oral hypoglycaemic medicinal products
Patients can be transferred directly from other oral hypoglycaemic medicinal products to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic medicinal products. The recommended maximum starting dose of patients transferred to repaglinide is 1 mg given before main meals.
Repaglinide can be given in combination with metformin, when the blood glucose is insufficiently controlled with metformin alone. In this case, the dosage of metformin should be maintained and repaglinide administered concomitantly. The starting dose of repaglinide is 0.5 mg, taken before main meals; titration is according to blood glucose response as for monotherapy.
Paediatric population
The safety and efficacy of repaglinide in children below 18 years have not been established. No data are available.
Method of administration
Repaglinide should be taken before main meals (i.e. preprandially).
Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal (i.e. preprandially 2, 3, or 4 meals a day). Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
In the case of concomitant use with other active substances refer to sections 4.4 and 4.5 to assess the dosage.
4.3 Contraindications
•Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1.
•Diabetes mellitus type 1,
•Diabetic ketoacidosis, with or without coma.
•Severe hepatic function disorder.
•Concomitant use of gemfibrozil (see section 4.5).
4.4 Special warnings and precautions for use
General
Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis.
Hypoglycaemia
Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.
Combination with insulin secretagogues
The blood
Repaglinide acts through a distinct binding site with a short action on the
Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies.
Combination with metformin
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
Acute coronary syndrome
The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1.
Concomitant use
Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.
4.5 Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician:
In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of repaglinide, may be altered by substances which influence these cytochrome
Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below).
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide:
Gemfibrozil, clarithromycin, itraconazole, ketoconazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of the metabolism of repaglinide. Seven days
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the pharmacokinetics of repaglinide has been studied in healthy subjects.
level in healthy volunteers was observed. In an interaction study in healthy volunteers,
In a study conducted in healthy volunteers, the concomitant administration of repaglinide (a single dose of 0.25 mg) and ciclosporin (repeated dose at 100 mg) increased repaglinide AUC and Cmax about
In an interaction study with healthy volunteers,
4 days), a moderate inhibitor of CYP2C8 and CYP3A4, and repaglinide (single dose, 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to
In an interaction study with healthy volunteers,
Repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustment of these compounds when
The following substances may reduce the hypoglycaemic effect of repaglinide:
Oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.
When these medications are administered to or withdrawn from a patient receiving repaglinide, the patient should be observed closely for changes in glycaemic control.
When repaglinide is used together with other medicinal products that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.
Paediatric population
No interaction studies have been performed in children and adolescents.
4.6 Fertility, pregnancy and lactation
- Palonosetron accord - Accord Healthcare Ltd
- Ibandronic acid accord - Accord Healthcare Ltd
- Ivabradine accord - Accord Healthcare Ltd
- Docetaxel accord - Accord Healthcare Ltd
Prescription drugs listed. Manufacturer: "Accord Healthcare Ltd"
Pregnancy
There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy.
There are no studies in
Fertility
Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.
4.7 Effects on ability to drive and use machines
Repaglinide Accord has no direct influence on the ability to drive and use machines but may cause hypoglycaemia.
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 signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress.
Tabulated list of adverse reactions
Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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) and not known (cannot be estimated from the available data).
Immune system disorders | Allergic reactions* | Very rare | |
|
|
| |
Metabolism and nutrition | Hypoglycaemia | Common | |
disorders |
|
| |
Hypoglycaemic coma and | Not known | ||
| |||
| hypoglycaemic |
| |
| unconsciousness |
| |
|
|
| |
Eye disorders | Refraction disorder* | Very rare | |
|
|
| |
Cardiac disorders | Cardiovascular disease | Rare | |
|
|
| |
Gastrointestinal disorders | Abdominal pain, diarrhoea | Common | |
|
|
| |
| Vomiting, constipation | Very rare | |
|
|
| |
| Nausea | Not known | |
|
|
|

Hepatobiliary disorders | Abnormal hepatic function, | Very rare |
| increased liver enzymes* |
|
|
|
|
Skin and subcutaneous | Hypersensitivity* | Not known |
tissue disorders |
|
|
* see section Description of selected adverse reactions below
Description of selected adverse reactions
Allergic reactions
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Refraction disorders
Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials.
Abnormal hepatic function, increased liver enzymes
Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes. In very rare cases, severe hepatic dysfunction has been reported.
Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no reason to suspect
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 listed in Appendix V.
4.9 Overdose
Repaglinide has been given with weekly escalating doses from 4 - 20 mg four times daily in a 6 week period. No safety concerns were raised. As hypoglycaemia in this study was avoided through increased calorie intake, a relative overdose may result in an exaggerated
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Mechanism of action
Repaglinide is a
Repaglinide closes
Pharmacodynamic effects
In type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after an oral dose of repaglinide. This resulted in a blood
Clinical efficacy and safety
A
Doses are usually taken within 15 minutes of the meal, but the time may vary from immediately preceding the meal to as long as 30 minutes before the meal.
One epidemiological study suggested an increased risk of acute coronary syndrome in repaglinide treated patients as compared to sulfonylurea treated patients (see sections 4.4 and 4.8).
5.2 Pharmacokinetic properties
Absorption
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the active substance. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly. Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%).
No clinically relevant differences were seen in the pharmacokinetics of repaglinide, when repaglinide was administered 0, 15 or 30 minutes before a meal or in fasting state.
A high interindividual variability (60%) in repaglinide plasma concentrations has been detected in the clinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should be titrated against the clinical response, efficacy is not affected by interindividual variability.
Distribution
Repaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent with distribution into intracellular fluid), and is highly bound to plasma proteins in humans (greater than 98%).
Elimination
Repaglinide is eliminated rapidly within 4 - 6 hours from the blood. The plasma elimination
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified.
Repaglinide metabolites are excreted primarily via the bile. A small fraction (less than 8%) of the administered dose appears in the urine, primarily as metabolites. Less than 1% of repaglinide is recovered in faeces.
Special patient groups
Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2 diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepatic insufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patients with hepatic insufficiency, and 117.9 ng/ml x hr (83.8) in the elderly type 2 diabetic patients.
After a 5 day treatment of repaglinide (2 mg x 3/day) in patients with a severe impaired renal function (creatinine clearance:
Paediatric population
No data are available.
5.3 Preclinical safety data
Repaglinide was shown not to be teratogenic in animal studies. Embryotoxicity, abnormal limb development in rat foetuses and new born pups, was observed in female rats exposed to high doses in the last stage of pregnancy and during the lactation period. Repaglinide was detected in the milk of animals.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose, microcrystalline (E460)
Calcium hydrogen phosphate, anhydrous
Maize starch
Povidone
Glycerin
Magnesium stearate
Meglumine
Poloxamer 188
Iron oxide, yellow (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/aluminium blister in packs containing 30, 90, 120, 180 or 270 tablets.
HDPE bottle containing 100 tablets in packs of 1 bottle.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited,
Sage house, 319 Pinner road, Harrow, HA1 4HF
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22 December 2011
Date of latest renewal:
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
1. NAME OF THE MEDICINAL PRODUCT
Repaglinide Accord 2 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg of repaglinide.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet.
Peach colored, round, biconvex with beveled edge, uncoated tablets, with inscription “R” on one side and plain on other side, may have mottled appearance.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone.
Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.
4.2 Posology and method of administration
Posology
Repaglinide is given preprandially and is titrated individually to optimise glycaemic control. In addition to the usual
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
The recommended starting dose is 0.5 mg. One to two weeks should elapse between titration steps (as determined by blood glucose response).
If patients are transferred from another oral hypoglycaemic medicinal product, the recommended starting dose is 1 mg.
Maintenance
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Special populations
Elderly
No clinical studies have been conducted in patients >75 years of age.
Renal impairment
Repaglinide is not affected by renal disorders (see section 5.2).
Eight percent of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment. As insulin sensitivity is increased in diabetic patients with renal impairment, caution is advised when titrating these patients.
Hepatic impairment
No clinical studies have been conducted in patients with hepatic insufficiency.
Debilitated or malnourished patients
In debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful dose titration is required to avoid hypoglycaemic reactions.
Patients receiving other oral hypoglycaemic medicinal products
Patients can be transferred directly from other oral hypoglycaemic medicinal products to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic medicinal products. The recommended maximum starting dose of patients transferred to repaglinide is 1 mg given before main meals.
Repaglinide can be given in combination with metformin, when the blood glucose is insufficiently controlled with metformin alone. In this case, the dosage of metformin should be maintained and repaglinide administered concomitantly. The starting dose of repaglinide is 0.5 mg, taken before main meals; titration is according to blood glucose response as for monotherapy.
Paediatric population
The safety and efficacy of repaglinide in children below 18 years have not been established. No data are available.
Method of administration
Repaglinide should be taken before main meals (i.e. preprandially).
Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal (i.e. preprandially 2, 3, or 4 meals a day). Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
In the case of concomitant use with other active substances refer to sections 4.4 and 4.5 to assess the dosage.
4.3 Contraindications
•Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1.
- Novonorm - A10BX02
- Prandin - A10BX02
- Enyglid - A10BX02
- Repaglinide teva - A10BX02
- Repaglinide krka - A10BX02
Prescription drugs listed. ATC Code: "A10BX02"
•Diabetes mellitus type 1,
•Diabetic ketoacidosis, with or without coma.
•Severe hepatic function disorder.
•Concomitant use of gemfibrozil (see section 4.5).
4.4 Special warnings and precautions for use
General
Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction.
When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis.
Hypoglycaemia
Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.
Combination with insulin secretagogues
The blood
Repaglinide acts through a distinct binding site with a short action on the
Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies.
Combination with metformin
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
Acute coronary syndrome
The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1.
Concomitant use
Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.
4.5 Interaction with other medicinal products and other forms of interaction
A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician:
In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of repaglinide, may be altered by substances which influence these cytochrome
Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below).
The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketoconazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of the metabolism of repaglinide. Seven days
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the pharmacokinetics of repaglinide has been studied in healthy subjects.
repaglinide).
In a study conducted in healthy volunteers, the concomitant administration of repaglinide (a single dose of 0.25 mg) and ciclosporin (repeated dose at 100 mg) increased repaglinide AUC and Cmax about
In an interaction study with healthy volunteers,
In an interaction study with healthy volunteers,
Repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustment of these compounds when
The following substances may reduce the hypoglycaemic effect of repaglinide:
Oral contraceptives, rifampicin, barbiturates, carbamazepine, thiazides, corticosteroids, danazol, thyroid hormones and sympathomimetics.
When these medications are administered to or withdrawn from a patient receiving repaglinide, the patient should be observed closely for changes in glycaemic control.
When repaglinide is used together with other medicinal products that are mainly secreted by the bile, like repaglinide, any potential interaction should be considered.
Paediatric population
No interaction studies have been performed in children and adolescents.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy.
There are no studies in
Fertility
Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.
4.7 Effects on ability to drive and use machines
Repaglinide Accord has no direct influence on the ability to drive and use machines but may cause hypoglycaemia.
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 signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress.
Tabulated list of adverse reactions
Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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) and not known (cannot be estimated from the available data).
Immune system disorders | Allergic reactions* | Very rare | |
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Metabolism and nutrition | Hypoglycaemia | Common | |
disorders |
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Hypoglycaemic coma and | Not known | ||
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| hypoglycaemic unconsciousness |
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Eye disorders | Refraction disorder* | Very rare | |
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Cardiac disorders | Cardiovascular disease | Rare | |
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Gastrointestinal disorders | Abdominal pain, diarrhoea | Common | |
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| Vomiting, constipation | Very rare | |
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| Nausea | Not known | |
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Hepatobiliary disorders | Abnormal hepatic function, | Very rare |
| increased liver enzymes* |
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Skin and subcutaneous | Hypersensitivity* | Not known |
tissue disorders |
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* see section Description of selected adverse reactions below |
|
Description of selected adverse reactions
Allergic reactions
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis.
Refraction disorders
Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials.
Abnormal hepatic function, increased liver enzymes
Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes. In very rare cases, severe hepatic dysfunction has been reported.
Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no reason to suspect
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 listed in Appendix V.
4.9 Overdose
Repaglinide has been given with weekly escalating doses from 4 - 20 mg four times daily in a 6 week period. No safety concerns were raised. As hypoglycaemia in this study was avoided through increased calorie intake, a relative overdose may result in an exaggerated
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Mechanism of action
Repaglinide is a
Repaglinide closes
Pharmacodynamic effects
In type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after an oral dose of repaglinide. This resulted in a blood
Clinical efficacy and safety
A
Clinical study results have shown that repaglinide is optimally dosed in relation to main meals (preprandial dosing).
Doses are usually taken within 15 minutes of the meal, but the time may vary from immediately preceding the meal to as long as 30 minutes before the meal.
One epidemiological study suggested an increased risk of acute coronary syndrome in repaglinide treated patients as compared to sulfonylurea treated patients (see sections 4.4 and 4.8).
5.2 Pharmacokinetic properties
Absorption
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the plasma concentration of the active substance. The peak plasma level occurs within one hour post administration. After reaching a maximum, the plasma level decreases rapidly.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (CV 11%).
No clinically relevant differences were seen in the pharmacokinetics of repaglinide, when repaglinide was administered 0, 15 or 30 minutes before a meal or in fasting state.
A high interindividual variability (60%) in repaglinide plasma concentrations has been detected in the clinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should be titrated against the clinical response, efficacy is not affected by interindividual variability.
Distribution
Repaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent with distribution into intracellular fluid), and is highly bound to plasma proteins in humans (greater than 98%).
Elimination
Repaglinide is eliminated rapidly within 4 - 6 hours from the blood. The plasma elimination
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant hypoglycaemic effect have been identified.
Repaglinide metabolites are excreted primarily via the bile. A small fraction (less than 8%) of the administered dose appears in the urine, primarily as metabolites. Less than 1% of repaglinide is recovered in faeces.
Special patient groups
Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2 diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepatic insufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patients with hepatic insufficiency, and 117.9 ng/ml x hr (83.8) in the elderly type 2 diabetic patients.
After a 5 day treatment of repaglinide (2 mg x 3/day) in patients with a severe impaired renal function (creatinine clearance:
Paediatric population
No data are available.
5.3 Preclinical safety data
Repaglinide was shown not to be teratogenic in animal studies. Embryotoxicity, abnormal limb development in rat foetuses and new born pups, was observed in female rats exposed to high doses in the last stage of pregnancy and during the lactation period. Repaglinide was detected in the milk of animals.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose, microcrystalline (E460)
Calcium hydrogen phosphate, anhydrous
Maize starch
Povidone
Glycerin
Magnesium stearate
Meglumine
Poloxamer 188
Iron oxide, red (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/aluminium blister in packs containing 30, 90, 120, 180 or 270 tablets.
HDPE bottle containing 100 tablets in packs of 1 bottle.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited,
Sage house, 319 Pinner road, Harrow, HA1 4HF
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 22 December 2011
Date of latest renewal:
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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