REPAGLINIDE ACCORD 0.5mg tablets medication leaflet

Repaglinide Accord 0.5 mg tablets

Each tablet contains 0.5 mg of repaglinide.

For the full list of excipients, see section 6.1.

Tablet.

White to off white, round, biconvex with beveled edge, uncoated tablets, with inscription “R” on oneside and plain on other side.

Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longerbe controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated incombination with metformin in adults with type 2 diabetes mellitus who are not satisfactorilycontrolled on metformin alone.

Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relationto meals.

Repaglinide is given preprandially and is titrated individually to optimise glycaemic control. Inaddition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's bloodglucose must be monitored periodically by the physician to determine the minimum effective dose forthe patient. Glycosylated haemoglobin levels are also of value in monitoring the patient's response totherapy. Periodic monitoring is necessary to detect inadequate lowering of blood glucose at therecommended maximum dose level (i.e. primary failure) and to detect loss of adequate bloodglucose-lowering response after an initial period of effectiveness (i.e. secondary failure).

Short-term administration of repaglinide may be sufficient during periods of transient loss of controlin type 2 diabetic patients usually controlled well on diet.

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 (asdetermined by blood glucose response).

If patients are transferred from another oral hypoglycaemic medicinal product, the recommendedstarting 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.

No clinical studies have been conducted in patients >75 years of age.

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 ofthe product is decreased in patients with renal impairment. As insulin sensitivity is increased indiabetic patients with renal impairment, caution is advised when titrating these patients.

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 andcareful 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 hypoglycaemicmedicinal products. The recommended maximum starting dose of patients transferred to repaglinide is1 mg given before main meals.

Repaglinide can be given in combination with metformin, when the blood glucose is insufficientlycontrolled with metformin alone. In this case, the dosage of metformin should be maintained andrepaglinide administered concomitantly. The starting dose of repaglinide is 0.5 mg, taken before mainmeals; titration is according to blood glucose response as for monotherapy.

The safety and efficacy of repaglinide in children below 18 years have not been established. No dataare available.

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 precedingthe meal to as long as 30 minutes before the meal (i.e. preprandially 2, 3, or 4 meals a day). Patientswho 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 thedosage.

* Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1.

* Diabetes mellitus type 1, C-peptide negative.

* Diabetic ketoacidosis, with or without coma.

* Severe hepatic function disorder.

* Concomitant use of gemfibrozil (see section 4.5).

Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persistdespite adequate attempts at dieting, exercise and weight reduction.

When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such asfever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may benecessary to discontinue repaglinide and treat with insulin on a temporary basis.

Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia.

Combination with insulin secretagogues

The blood glucose-lowering effect of oral hypoglycaemic medicinal products decreases in manypatients over time. This may be due to progression of the severity of the diabetes or to diminishedresponsiveness to the medicinal product. This phenomenon is known as secondary failure, todistinguish it from primary failure, where the medicinal product is ineffective in an individual patientwhen first given. Adjustment of dose and adherence to diet and exercise should be assessed beforeclassifying a patient as a secondary failure.

Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinidein case of secondary failure to insulin secretagogues has not been investigated in clinical trials.

Trials investigating the combination with other insulin secretagogues have not been performed.

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 whichinfluence repaglinide metabolism (see section 4.5). If concomitant use is necessary, carefulmonitoring of blood glucose and close clinical monitoring should be performed.

A number of medicinal products are known to influence repaglinide metabolism. Possible interactionsshould 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 enzymeinvolved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contributionof CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearanceof repaglinide, may be altered by substances which influence these cytochrome P-450 enzymes viainhibition or induction. Special care should be taken when inhibitors of both CYP2C8 and 3A4 areco-administered simultaneously with repaglinide.

Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic aniontransporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential toincrease 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 betablocking substances, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs,octreotide, alcohol, and anabolic steroids.

Co-administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and repaglinide (asingle dose of 0.25 mg) increased the repaglinide AUC 8.1-fold and Cmax 2.4-fold in healthyvolunteers. Half-life was prolonged from 1.3 hr to 3.7 hr, resulting in possibly enhanced andprolonged blood glucose-lowering effect of repaglinide, and plasma repaglinide concentration at 7 hrwas increased 28.6-fold by gemfibrozil. The concomitant use of gemfibrozil and repaglinide iscontraindicated (see section 4.3).

Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, andrepaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, Cmax and t½ (1.6-fold, 1.4-foldand 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. Thislack of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since thesafety profile of this combination has not been established with dosages higher than 0.25 mg forrepaglinide and 320 mg for trimethoprim, the concomitant use of trimethoprim with repaglinideshould be avoided. If concomitant use is necessary, careful monitoring of blood glucose and closeclinical monitoring should be performed (see section 4.4).

Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor ofthe metabolism of repaglinide. Seven days pre-treatment with rifampicin (600 mg), followed byco-administration of repaglinide (a single dose of 4 mg) at day seven resulted in a 50% lower AUC(effect of a combined induction and inhibition). When repaglinide was given 24 hours after the lastrifampicin dose, an 80% reduction of the repaglinide AUC was observed (effect of induction alone).

Concomitant use of rifampicin and repaglinide might therefore induce a need for repaglinide doseadjustment which should be based on carefully monitored blood glucose concentrations at bothinitiation of rifampicin treatment (acute inhibition), following dosing (mixed inhibition andinduction), withdrawal (induction alone) and up to approximately two weeks after withdrawal ofrifampicin where the inductive effect of rifampicin is no longer present. It cannot be excluded thatother inducers, e.g. phenytoin, carbamazepine, phenobarbital, St John’s wort, may have a similareffect.

The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on thepharmacokinetics of repaglinide has been studied in healthy subjects. Co-administration of 200 mgketoconazole increased the repaglinide (AUC and Cmax) by 1.2-fold with profiles of blood glucoseconcentrations altered by less than 8% when administered concomitantly (a single dose of 4 mgrepaglinide). Co-administration of 100 mg itraconazole, an inhibitor of CYP3A4, has also beenstudied in healthy volunteers, and increased the AUC by 1.4-fold. No significant effect on the glucoselevel in healthy volunteers was observed. In an interaction study in healthy volunteers,co-administration of 250 mg clarithromycin, a potent mechanism-based inhibitor of CYP3A4, slightlyincreased the repaglinide (AUC) by 1.4-fold and Cmax by 1.7-fold and increased the mean incremental

AUC of serum insulin by 1.5-fold and the maximum concentration by 1.6-fold. The exact mechanismof this interaction is not clear.

In a study conducted in healthy volunteers, the concomitant administration of repaglinide (a singledose of 0.25 mg) and ciclosporin (repeated dose at 100 mg) increased repaglinide AUC and Cmaxabout 2.5-fold and 1.8-fold respectively. Since the interaction has not been established with dosageshigher than 0.25 mg for repaglinide, the concomitant use of ciclosporin with repaglinide should beavoided. If the combination appears necessary, careful clinical and blood glucose monitoring shouldbe performed (see section 4.4).

In an interaction study with healthy volunteers, co-administration of deferasirox (30 mg/kg/day,4 days), a moderate inhibitor of CYP2C8 and CYP3A4, and repaglinide (single dose, 0.5 mg) resultedin an increase in repaglinide systemic exposure (AUC) to 2.3-fold (90% CI [2.03-2.63]) of control, a1.6-fold (90% CI [1.42-1.84]) increase in Cmax, and a small, significant decrease in blood glucosevalues. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide,the concomitant use of deferasirox with repaglinide should be avoided. If the combination appearsnecessary, careful clinical and blood glucose monitoring should be performed (see section 4.4).

In an interaction study with healthy volunteers, co-administration of clopidogrel (300 mg loadingdose), a CYP2C8 inhibitor, increased repaglinide exposure (AUC0-∞) 5.1-fold and continuedadministration (75 mg daily dose) increased repaglinide exposure (AUC0-∞) 3.9-fold. A small,significant decrease in blood glucose values was observed. Since the safety profile of the co-treatmenthas not been established in these patients, the concomitant use of clopidogrel and repaglinide shouldbe avoided. If concomitant use is necessary, careful monitoring of blood glucose and close clinicalmonitoring should be performed (see section 4.4).

β-blocking medicinal products may mask the symptoms of hypoglycaemia.

Co-administration of cimetidine, nifedipine, oestrogen, or simvastatin with repaglinide, all CYP3A4substrates, did not significantly alter the pharmacokinetic parameters of repaglinide.

Repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin,theophylline or warfarin at steady state, when administered to healthy volunteers. Dosage adjustmentof these compounds when co-administered with repaglinide is therefore not necessary.

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, thepatient 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.

No interaction studies have been performed in children and adolescents.

There are no studies of repaglinide in pregnant women. Repaglinide should be avoided duringpregnancy.

There are no studies in breast-feeding women. Repaglinide should not be used in breast-feedingwomen.

Data from animal studies investigating effects on embryofetal and offspring development as well asexcretion in milk is described in section 5.3.

Repaglinide Accord has no direct influence on the ability to drive and use machines but may causehypoglycaemia.

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

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 dietaryhabits, dosage, exercise and stress.

Based on the experience with repaglinide and with other hypoglycaemic medicinal products thefollowing 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 Commondisorders Hypoglycaemic coma and Not knownhypoglycaemicunconsciousness

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 rareincreased liver enzymes*

Skin and subcutaneous tissue Hypersensitivity* Not knowndisorders

* see section Description of selected adverse reactions below

Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions suchas vasculitis.

Refraction disorders

Changes in blood glucose levels have been known to result in transient visual disturbances, especiallyat the commencement of treatment. Such disturbances have only been reported in very few cases afterinitiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatmentin clinical trials.

Abnormal hepatic function, increased liver enzymes

Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Mostcases were mild and transient, and very few patients discontinued treatment due to increased liverenzymes. In very rare cases, severe hepatic dysfunction has been reported.

Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is noreason to suspect cross-allergenicity with sulphonylurea due to the difference in chemical structure.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Repaglinide has been given with weekly escalating doses from 4 - 20 mg four times daily in a 6 weekperiod. No safety concerns were raised. As hypoglycaemia in this study was avoided throughincreased calorie intake, a relative overdose may result in an exaggerated glucose-lowering effect withdevelopment of hypoglycaemic symptoms (dizziness, sweating, tremor, headache etc.). Should thesesymptoms occur, adequate action should be taken to correct the low blood glucose (oralcarbohydrates). More severe hypoglycaemia with seizure, loss of consciousness or coma should betreated with intravenous glucose.

Pharmaco-therapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl.insulins, ATC code: A10B X02

Repaglinide is a short-acting oral secretagogue. Repaglinide lowers the blood glucose levels acutelyby stimulating the release of insulin from the pancreas, an effect dependent upon functioning β-cellsin the pancreatic islets.

Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target proteindifferent from other secretagogues. This depolarises the β-cell and leads to an opening of the calciumchannels. The resulting increased calcium influx induces insulin secretion from the β-cell.

In type 2 diabetic patients, the insulinotropic response to a meal occurred within 30 minutes after anoral dose of repaglinide. This resulted in a blood glucose-lowering effect throughout the meal period.

The elevated insulin levels did not persist beyond the time of the meal challenge. Plasma repaglinidelevels decreased rapidly, and low concentrations were seen in the plasma of type 2 diabetic patients 4hours post-administration.

A dose-dependent decrease in blood glucose was demonstrated in type 2 diabetic patients whenadministered in doses from 0.5 to 4 mg repaglinide.

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 immediatelypreceding the meal to as long as 30 minutes before the meal.

One epidemiological study suggested an increased risk of acute coronary syndrome in repaglinidetreated patients as compared to sulfonylurea treated patients (see sections 4.4 and 4.8).

Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in theplasma concentration of the active substance. The peak plasma level occurs within one hour postadministration. 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 repaglinidewas 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 theclinical trials. Intraindividual variability is low to moderate (35%) and as repaglinide should betitrated against the clinical response, efficacy is not affected by interindividual variability.

Repaglinide pharmacokinetics are characterised by low volume of distribution, 30 L (consistent withdistribution into intracellular fluid) and is highly bound to plasma proteins in humans (greater than98%).

Repaglinide is eliminated rapidly within 4 - 6 hours from the blood. The plasma elimination half-lifeis approximately one hour.

Repaglinide is almost completely metabolised, and no metabolites with clinically relevanthypoglycaemic effect have been identified.

Repaglinide metabolites are excreted primarily via the bile. A small fraction (less than 8%) of theadministered dose appears in the urine, primarily as metabolites. Less than 1% of repaglinide isrecovered in faeces.

Special patient groups

Repaglinide exposure is increased in patients with hepatic insufficiency and in the elderly type 2diabetic patients. The AUC (SD) after 2 mg single dose exposure (4 mg in patients with hepaticinsufficiency) was 31.4 ng/ml x hr (28.3) in healthy volunteers, 304.9 ng/ml x hr (228.0) in patientswith 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: 20-39 ml/min.), the results showed a significant 2-fold increase of the exposure(AUC) and half-life (t1/2) as compared to patients with normal renal function.

No data are available.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Repaglinide was shown not to be teratogenic in animal studies. Embryotoxicity, abnormal limbdevelopment in rat foetuses and new born pups, was observed in female rats exposed to high doses inthe last stage of pregnancy and during the lactation period. Repaglinide was detected in the milk ofanimals.

Cellulose, microcrystalline (E460)

Calcium hydrogen phosphate, anhydrous

Maize starch

Povidone

Glycerin

Magnesium stearate

Meglumine

Poloxamer 188

Not applicable

2 years

This medicinal product does not require any special storage conditions.

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.

No special requirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/11/743/001-004, EU/1/11/743/005, EU/1/11/743/016

Date of first authorisation: 22 December 2011

Date of latest renewal: 19th September 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu