ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Enyglid 0.5 mg tablets
2.
Each tablet contains 0.5 mg repaglinide.
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are white, round and biconvex with bevelled edges.
4.
Repaglinide is indicated in patients with Type 2 diabetes (Non Insulin-Dependent Diabetes Mellitus
(NIDDM)) whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction
and exercise. Repaglinide is also indicated in combination with metformin in Type 2 diabetes patients
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.
Repaglinide is given preprandially and is titrated individually to optimise the glycaemic control. In
addition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's blood
glucose must be monitored periodically by the physician to determine the minimum effective dose for
the patient. Glycosylated haemoglobin levels are also of value in monitoring the patient's response to
therapy. Periodic monitoring is necessary to detect inadequate lowering of blood glucose at the
recommended maximum dose level (i.e. primary failure) and to detect loss of adequate blood-glucose-
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 control in
Type 2 diabetic patients usually controlled well on diet.
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.
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
2
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 agent the recommended starting dose is
1 mg.
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Specific patient groups
Repaglinide is primarily excreted via the bile and excretion is therefore not affected by renal disorders.
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.
No clinical studies have been conducted in patients >75 years of age or in patients with hepatic
insufficiency (see section 4.4).
Repaglinide is not recommended for use in children below age 18 due to a lack of data on safety
and/or efficacy.
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 agents (OHAs)
Patients can be transferred directly from other oral hypoglycaemic agents to repaglinide. However, no
exact dosage relationship exists between repaglinide and the other oral hypoglycaemic agents. 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.
-
Type 1 diabetes (Insulin-Dependent Diabetes Mellitus: IDDM), 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 persist
despite adequate attempts at dieting, exercise and weight reduction.
Repaglinide like other insulin secretagogues is capable of producing hypoglycaemia.
The blood glucose lowering effect of oral hypoglycaemic agents decreases in many patients over time.
This may be due to progression of the severity of the diabetes or to diminished responsiveness to the
medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary
failure, where the substance is ineffective in an individual patient when first given. Adjustment of dose
and adherence to diet and exercise should be assessed before classifying a patient as a secondary
failure.
3
Maintenance
-
Hypersensitivity to repaglinide or to any of the excipients in Enyglid.
General
Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in
case of secondary failure to insulin secretagogues has not been investigated in clinical trials.
Trials investigating the combination with other insulin secretagogues and acarbose have not been
performed.
Trials of combination therapy with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
have been performed. However, the benefit risk profile remains to be established when comparing to
other combination therapies.
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
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.
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.
No clinical studies have been conducted in patients with impaired hepatic function. No clinical studies
have been performed in children and adolescents <18 years of age or in patients >75 years of age.
Therefore, treatment is not recommended in these patient groups.
Careful dose titration is recommended in debilitated or malnourished patients. The initial and
maintenance dosages should be conservative (see section 4.2).
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 medicinal products which influence these cytochrome P-450 enzymes
via inhibition or induction. Special care should be taken when both inhibitors of CYP2C8 and 3A4 are
co-administered simultaneously with repaglinide.
Based on
in vitro
data, repaglinide appears to be a substrate for active hepatic uptake (organic anion
transporting protein OATP1B1). Medicinal products 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, other antidiabetic
agents, monoamine oxidase inhibitors (MAOI), non selective beta blocking agents, 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 (a
single dose of 0.25 mg) increased the repaglinide area under curve (AUC) 8.1-fold and maximum
plasma concentration (C
max
) 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7
4
Specific patient groups
hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and
plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use
of gemfibrozil and repaglinide is contraindicated (see section 4.3).
Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and
repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, C
max
and t
½
(1.6-fold, 1.4-fold
and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack
of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety
profile of this combination has not been established with dosages higher than 0.25 mg for repaglinide
and 320 mg for trimethoprim, the concomitant use of trimethoprim with repaglinide should be
avoided. If concomitant use is necessary, careful monitoring of blood glucose and close clinical
monitoring should be performed (see section 4.4).
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of
the metabolism of repaglinide. Seven days pre-treatment with rifampicin (600 mg) followed by co-
administration of repaglinide (a single dose of 4 mg) at day seven resulted in a 50% lower AUC (effect
of combined induction and inhibition). When repaglinide was given 24 hours after the last rifampicin
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 dose adjustment which
should be based on carefully monitored glucose concentrations at both initiation of rifampicin
treatment (acute inhibition), following dosing (mixed inhibition and induction), withdrawal (induction
alone) and up to approximately two weeks after withdrawal of rifampicin where the inductive effect of
rifampicin is no longer present. It cannot be excluded that other inducers, e.g. phenytoin,
carbamazepine, phenobarbital, St John's wort, may have a similar effect.
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the
pharmacokinetics of repaglinide has been studied in healthy subjects. Co-administration of 200 mg
ketoconazole increased the repaglinide (AUC and C
max
) by 1.2-fold with profiles of blood glucose
concentrations altered by les than 8% when administered concomitantly (a single dose of 4 mg
repaglinide). Co-administration of 100 mg itraconazole, an inhibitor of CYP3A4, has also been studied
in healthy volunteers, and increased the AUC by 1.4-fold. No significant effect on the glucose level 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, slightly increased the
repaglinide (AUC) by 1.4-fold and C
max
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 mechanism of this
interaction is not clear.
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 C
max
about
2.5-fold and 1.8-fold respectively. Since the interaction has not been established with dosages higher
than 0.25 mg for repaglinide, the concomitant use of ciclosporin with repaglinide should be avoided. If
the combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4).
β-blocking agents may mask the symptoms of hypoglycaemia.
Co-administration of cimetidine, nifedipine, oestrogen, or simvastatin with repaglinide, all CYP3A4
substrates, 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 adjustment
of 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.
5
When these medicinal products 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.
There are no studies of repaglinide in pregnant or breast-feeding women. Therefore the safety of
repaglinide in pregnant women cannot be assessed. Up to now repaglinide showed not to be
teratogenic in animal studies. Embryotoxicity, abnormal limb development in foetuses and new born
pups, was observed in rats exposed to high doses in the last stage of pregnancy and during the
lactation period. Repaglinide is detected in the milk of experimental animals. For that reason
repaglinide should be avoided during pregnancy and should not be used in breast-feeding women.
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.
Based on the experience with repaglinide and with other hypoglycaemic agents the following adverse
events 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), not known (cannot be estimated from the available data)
Immune system disorders
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as
vasculitis.
Metabolism and nutrition disorders
Common: Hypoglycaemia
Not known: Hypoglycaemic coma and hypoglycaemic unconsciousness
As with other hypoglycaemic agents, hypoglycaemic reactions have been observed after
administration of repaglinide. These reactions are mostly mild and easily handled through intake of
carbohydrates. If severe, requiring third party assistance, infusion of glucose may be necessary. The
occurrence of such reactions depends, as for every diabetes therapy, on individual factors, such as
dietary habits, dosage, exercise and stress (see section 4.4). Interactions with other medicinal products
may increase the risk of hypoglycaemia (see section 4.5). During post marketing experience, cases of
hypoglycaemia have been reported in patients treated in combination with metformin or
thiazolidinedione.
Gastro-intestinal disorders
Very rare: Vomiting and constipation
Not known: Nausea
Gastro-intestinal complaints such as abdominal pain, diarrhoea, nausea, vomiting and constipation
have been reported in clinical trials. The rate and severity of these symptoms did not differ from that
seen with other oral insulin secretagogues.
6
Very rare: Allergy
Common: Abdominal pain and diarrhoea
Skin and subcutaneous tissue disorders
Not known: Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no
reason to suspect cross-allergenicity with sulphonylurea medicinal products due to the difference of
the chemical structure.
Eye disorders
Very rare: Visual disturbances
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.
Cardiac disorders
Type 2 diabetes is associated with an increased risk for cardiovascular disease. In one epidemiological
study, a higher incidence of acute coronary syndrome was reported in the repaglinide group. However,
the causality of the relationship remains uncertain (see sections 4.4 and 5.1).
Hepatobiliary disorders
In very rare cases, severe hepatic dysfunction has been reported. However, a causal relationship with
repaglinide has not been established.
Very rare: Increased liver enzymes
Isolated cases of increase in liver enzymes have been reported during treatment with repaglinide. Most
cases were mild and transient, and very few patients discontinued treatment due to increase in liver
enzymes.
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 glucose lowering effect with
development of hypoglycaemic symptoms (dizziness, sweating, tremor, headache etc.). Should these
symptoms occur, adequate action should be taken to correct the low blood glucose (oral
carbohydrates). More severe hypoglycaemia with seizure, loss of consciousness or coma should be
treated with i.v. glucose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Carbamoylmethyl benzoic acid derivative, ATC code: A10B X02.
Repaglinide is a novel short-acting oral secretagogue. Repaglinide lowers the blood glucose levels
acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning
β-cells in the pancreatic islets.
Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target protein
different from other secretagogues. This depolarises the β-cell and leads to an opening of the calcium
channels. 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 an
oral 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 repaglinide
levels decreased rapidly, and low substance concentrations were seen in the plasma of Type 2 diabetic
patients 4 hours post-administration.
7
Rare: Cardiovascular disease
Very rare: Hepatic function abnormal
A dose-dependent decrease in blood glucose was demonstrated in Type 2 diabetic patients when
administered 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 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
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the
plasma concentration of the substance. The peak plasma level occurs within one hour post
administration. After reaching a maximum, the plasma level decreases rapidly, and repaglinide is
eliminated within 4 - 6 hours. The plasma elimination half-life is approximately one hour.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (coefficient
of variation (CV) 11%), low volume of distribution, 30 L (consistent with distribution into
intracellular fluid), and rapid elimination from the blood.
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.
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: 20 – 39 ml/min), the results showed a significant 2-fold increase of the exposure
(AUC) and half-life (t½) as compared to subjects with normal renal function.
Repaglinide is highly bound to plasma proteins in humans (greater than 98%).
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.
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant
hypoglycaemic effect have been identified. Repaglinide and its 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 the parent substance is recovered in faeces.
5.3
Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
6.
6.1 List of excipients
Microcrystalline cellulose (E460)
Calcium hydrogen phosphate, anhydrous
Croscarmellose sodium
Povidone K25
Glycerol
Magnesium stearate
8
Meglumine
Poloxamer
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5
Nature and contents of container
Blister pack (OPA/Al/PVC-Al): 30, 60, 90, 120, 180, 270 and 360 tablets in the box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
30 tablets: EU/1/09/580/001
60 tablets: EU/1/09/580/002
90 tablets: EU/1/09/580/003
120 tablets: EU/1/09/580/004
180 tablets: EU/1/09/580/019
270 tablets: EU/1/09/580/005
360 tablets: EU/1/09/580/006
9.
14/10/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
9
1.
Enyglid 1 mg tablets
2.
Each tablet contains 1 mg repaglinide.
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are pale brown-yellow, round, biconvex with bevelled edges and possible darker spots.
4.
Repaglinide is indicated in patients with Type 2 diabetes (Non Insulin-Dependent Diabetes Mellitus
(NIDDM)) whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction
and exercise. Repaglinide is also indicated in combination with metformin in Type 2 diabetes patients
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.
Repaglinide is given preprandially and is titrated individually to optimise the glycaemic control. In
addition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's blood
glucose must be monitored periodically by the physician to determine the minimum effective dose for
the patient. Glycosylated haemoglobin levels are also of value in monitoring the patient's response to
therapy. Periodic monitoring is necessary to detect inadequate lowering of blood glucose at the
recommended maximum dose level (i.e. primary failure) and to detect loss of adequate blood-glucose-
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 control in
Type 2 diabetic patients usually controlled well on diet.
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.
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
10
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 agent the recommended starting dose is
1 mg.
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Specific patient groups
Repaglinide is primarily excreted via the bile and excretion is therefore not affected by renal disorders.
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.
No clinical studies have been conducted in patients >75 years of age or in patients with hepatic
insufficiency (see section 4.4).
Repaglinide is not recommended for use in children below age 18 due to a lack of data on safety
and/or efficacy.
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 agents (OHAs)
Patients can be transferred directly from other oral hypoglycaemic agents to repaglinide. However, no
exact dosage relationship exists between repaglinide and the other oral hypoglycaemic agents. 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.
-
Type 1 diabetes (Insulin-Dependent Diabetes Mellitus: IDDM), 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 persist
despite adequate attempts at dieting, exercise and weight reduction.
Repaglinide like other insulin secretagogues is capable of producing hypoglycaemia.
The blood glucose lowering effect of oral hypoglycaemic agents decreases in many patients over time.
This may be due to progression of the severity of the diabetes or to diminished responsiveness to the
medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary
failure, where the substance is ineffective in an individual patient when first given. Adjustment of dose
and adherence to diet and exercise should be assessed before classifying a patient as a secondary
failure.
11
Maintenance
-
Hypersensitivity to repaglinide or to any of the excipients in Enyglid.
General
Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in
case of secondary failure to insulin secretagogues has not been investigated in clinical trials.
Trials investigating the combination with other insulin secretagogues and acarbose have not been
performed.
Trials of combination therapy with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
have been performed. However, the benefit risk profile remains to be established when comparing to
other combination therapies.
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
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.
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.
No clinical studies have been conducted in patients with impaired hepatic function. No clinical studies
have been performed in children and adolescents <18 years of age or in patients >75 years of age.
Therefore, treatment is not recommended in these patient groups.
Careful dose titration is recommended in debilitated or malnourished patients. The initial and
maintenance dosages should be conservative (see section 4.2).
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 medicinal products which influence these cytochrome P-450 enzymes
via inhibition or induction. Special care should be taken when both inhibitors of CYP2C8 and 3A4 are
co-administered simultaneously with repaglinide.
Based on
in vitro
data, repaglinide appears to be a substrate for active hepatic uptake (organic anion
transporting protein OATP1B1). Medicinal products 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, other antidiabetic
agents, monoamine oxidase inhibitors (MAOI), non selective beta blocking agents, 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 (a
single dose of 0.25 mg) increased the repaglinide area under curve (AUC) 8.1-fold and maximum
plasma concentration (C
max
) 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7
12
Specific patient groups
hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and
plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use
of gemfibrozil and repaglinide is contraindicated (see section 4.3).
Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and
repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, C
max
and t
½
(1.6-fold, 1.4-fold
and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack
of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety
profile of this combination has not been established with dosages higher than 0.25 mg for repaglinide
and 320 mg for trimethoprim, the concomitant use of trimethoprim with repaglinide should be
avoided. If concomitant use is necessary, careful monitoring of blood glucose and close clinical
monitoring should be performed (see section 4.4).
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of
the metabolism of repaglinide. Seven days pre-treatment with rifampicin (600 mg) followed by co-
administration of repaglinide (a single dose of 4 mg) at day seven resulted in a 50% lower AUC (effect
of combined induction and inhibition). When repaglinide was given 24 hours after the last rifampicin
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 dose adjustment which
should be based on carefully monitored glucose concentrations at both initiation of rifampicin
treatment (acute inhibition), following dosing (mixed inhibition and induction), withdrawal (induction
alone) and up to approximately two weeks after withdrawal of rifampicin where the inductive effect of
rifampicin is no longer present. It cannot be excluded that other inducers, e.g. phenytoin,
carbamazepine, phenobarbital, St John's wort, may have a similar effect.
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the
pharmacokinetics of repaglinide has been studied in healthy subjects. Co-administration of 200 mg
ketoconazole increased the repaglinide (AUC and C
max
) by 1.2-fold with profiles of blood glucose
concentrations altered by les than 8% when administered concomitantly (a single dose of 4 mg
repaglinide). Co-administration of 100 mg itraconazole, an inhibitor of CYP3A4, has also been studied
in healthy volunteers, and increased the AUC by 1.4-fold. No significant effect on the glucose level 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, slightly increased the
repaglinide (AUC) by 1.4-fold and C
max
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 mechanism of this
interaction is not clear.
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 C
max
about
2.5-fold and 1.8-fold respectively. Since the interaction has not been established with dosages higher
than 0.25 mg for repaglinide, the concomitant use of ciclosporin with repaglinide should be avoided. If
the combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4).
β-blocking agents may mask the symptoms of hypoglycaemia.
Co-administration of cimetidine, nifedipine, oestrogen, or simvastatin with repaglinide, all CYP3A4
substrates, 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 adjustment
of 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.
13
When these medicinal products 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.
There are no studies of repaglinide in pregnant or breast-feeding women. Therefore the safety of
repaglinide in pregnant women cannot be assessed. Up to now repaglinide showed not to be
teratogenic in animal studies. Embryotoxicity, abnormal limb development in foetuses and new born
pups, was observed in rats exposed to high doses in the last stage of pregnancy and during the
lactation period. Repaglinide is detected in the milk of experimental animals. For that reason
repaglinide should be avoided during pregnancy and should not be used in breast-feeding women.
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.
Based on the experience with repaglinide and with other hypoglycaemic agents the following adverse
events 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), not known (cannot be estimated from the available data)
Immune system disorders
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as
vasculitis.
Metabolism and nutrition disorders
Common: Hypoglycaemia
Not known: Hypoglycaemic coma and hypoglycaemic unconsciousness
As with other hypoglycaemic agents, hypoglycaemic reactions have been observed after
administration of repaglinide. These reactions are mostly mild and easily handled through intake of
carbohydrates. If severe, requiring third party assistance, infusion of glucose may be necessary. The
occurrence of such reactions depends, as for every diabetes therapy, on individual factors, such as
dietary habits, dosage, exercise and stress (see section 4.4). Interactions with other medicinal products
may increase the risk of hypoglycaemia (see section 4.5). During post marketing experience, cases of
hypoglycaemia have been reported in patients treated in combination with metformin or
thiazolidinedione.
Gastro-intestinal disorders
Very rare: Vomiting and constipation
Not known: Nausea
Gastro-intestinal complaints such as abdominal pain, diarrhoea, nausea, vomiting and constipation
have been reported in clinical trials. The rate and severity of these symptoms did not differ from that
seen with other oral insulin secretagogues.
14
Very rare: Allergy
Common: Abdominal pain and diarrhoea
Skin and subcutaneous tissue disorders
Not known: Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no
reason to suspect cross-allergenicity with sulphonylurea medicinal products due to the difference of
the chemical structure.
Eye disorders
Very rare: Visual disturbances
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.
Cardiac disorders
Type 2 diabetes is associated with an increased risk for cardiovascular disease. In one epidemiological
study, a higher incidence of acute coronary syndrome was reported in the repaglinide group. However,
the causality of the relationship remains uncertain (see sections 4.4 and 5.1).
Hepatobiliary disorders
In very rare cases, severe hepatic dysfunction has been reported. However, a causal relationship with
repaglinide has not been established.
Very rare: Increased liver enzymes
Isolated cases of increase in liver enzymes have been reported during treatment with repaglinide. Most
cases were mild and transient, and very few patients discontinued treatment due to increase in liver
enzymes.
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 glucose lowering effect with
development of hypoglycaemic symptoms (dizziness, sweating, tremor, headache etc.). Should these
symptoms occur, adequate action should be taken to correct the low blood glucose (oral
carbohydrates). More severe hypoglycaemia with seizure, loss of consciousness or coma should be
treated with i.v. glucose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Carbamoylmethyl benzoic acid derivative, ATC code: A10B X02.
Repaglinide is a novel short-acting oral secretagogue. Repaglinide lowers the blood glucose levels
acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning
β-cells in the pancreatic islets.
Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target protein
different from other secretagogues. This depolarises the β-cell and leads to an opening of the calcium
channels. 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 an
oral 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 repaglinide
levels decreased rapidly, and low substance concentrations were seen in the plasma of Type 2 diabetic
patients 4 hours post-administration.
15
Rare: Cardiovascular disease
Very rare: Hepatic function abnormal
A dose-dependent decrease in blood glucose was demonstrated in Type 2 diabetic patients when
administered 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 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
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the
plasma concentration of the substance. The peak plasma level occurs within one hour post
administration. After reaching a maximum, the plasma level decreases rapidly, and repaglinide is
eliminated within 4 - 6 hours. The plasma elimination half-life is approximately one hour.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (coefficient
of variation (CV) 11%), low volume of distribution, 30 L (consistent with distribution into
intracellular fluid), and rapid elimination from the blood.
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.
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: 20 – 39 ml/min), the results showed a significant 2-fold increase of the exposure
(AUC) and half-life (t½) as compared to subjects with normal renal function.
Repaglinide is highly bound to plasma proteins in humans (greater than 98%).
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.
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant
hypoglycaemic effect have been identified. Repaglinide and its 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 the parent substance is recovered in faeces.
5.3
Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
6.
6.1 List of excipients
Microcrystalline cellulose (E460)
Calcium hydrogen phosphate, anhydrous
Croscarmellose sodium
Povidone K25
Glycerol
Magnesium stearate
16
Meglumine
Poloxamer
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5
Nature and contents of container
Blister pack (OPA/Al/PVC-Al): 30, 60, 90, 120, 180, 270 and 360 tablets in the box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
30 tablets: EU/1/09/580/007
60 tablets: EU/1/09/580/008
90 tablets: EU/1/09/580/009
120 tablets: EU/1/09/580/010
180 tablets: EU/1/09/580/020
270 tablets: EU/1/09/580/011
360 tablets: EU/1/09/580/012
9.
14/10/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
17
1.
Enyglid 2 mg tablets
2.
Each tablet contains 2 mg repaglinide.
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are pink, marbled, round, biconvex with bevelled edges and possible darker spots.
4.
Repaglinide is indicated in patients with Type 2 diabetes (Non Insulin-Dependent Diabetes Mellitus
(NIDDM)) whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction
and exercise. Repaglinide is also indicated in combination with metformin in Type 2 diabetes patients
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.
Repaglinide is given preprandially and is titrated individually to optimise the glycaemic control. In
addition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's blood
glucose must be monitored periodically by the physician to determine the minimum effective dose for
the patient. Glycosylated haemoglobin levels are also of value in monitoring the patient's response to
therapy. Periodic monitoring is necessary to detect inadequate lowering of blood glucose at the
recommended maximum dose level (i.e. primary failure) and to detect loss of adequate blood-glucose-
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 control in
Type 2 diabetic patients usually controlled well on diet.
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.
Initial dose
The dosage should be determined by the physician, according to the patient's requirements.
18
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 agent the recommended starting dose is
1 mg.
The recommended maximum single dose is 4 mg taken with main meals.
The total maximum daily dose should not exceed 16 mg.
Specific patient groups
Repaglinide is primarily excreted via the bile and excretion is therefore not affected by renal disorders.
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.
No clinical studies have been conducted in patients >75 years of age or in patients with hepatic
insufficiency (see section 4.4).
Repaglinide is not recommended for use in children below age 18 due to a lack of data on safety
and/or efficacy.
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 agents (OHAs)
Patients can be transferred directly from other oral hypoglycaemic agents to repaglinide. However, no
exact dosage relationship exists between repaglinide and the other oral hypoglycaemic agents. 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.
-
Type 1 diabetes (Insulin-Dependent Diabetes Mellitus: IDDM), 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 persist
despite adequate attempts at dieting, exercise and weight reduction.
Repaglinide like other insulin secretagogues is capable of producing hypoglycaemia.
The blood glucose lowering effect of oral hypoglycaemic agents decreases in many patients over time.
This may be due to progression of the severity of the diabetes or to diminished responsiveness to the
medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary
failure, where the substance is ineffective in an individual patient when first given. Adjustment of dose
and adherence to diet and exercise should be assessed before classifying a patient as a secondary
failure.
19
Maintenance
-
Hypersensitivity to repaglinide or to any of the excipients in Enyglid.
General
Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in
case of secondary failure to insulin secretagogues has not been investigated in clinical trials.
Trials investigating the combination with other insulin secretagogues and acarbose have not been
performed.
Trials of combination therapy with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones
have been performed. However, the benefit risk profile remains to be established when comparing to
other combination therapies.
Combination treatment with metformin is associated with an increased risk of hypoglycaemia.
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.
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.
No clinical studies have been conducted in patients with impaired hepatic function. No clinical studies
have been performed in children and adolescents <18 years of age or in patients >75 years of age.
Therefore, treatment is not recommended in these patient groups.
Careful dose titration is recommended in debilitated or malnourished patients. The initial and
maintenance dosages should be conservative (see section 4.2).
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 medicinal products which influence these cytochrome P-450 enzymes
via inhibition or induction. Special care should be taken when both inhibitors of CYP2C8 and 3A4 are
co-administered simultaneously with repaglinide.
Based on
in vitro
data, repaglinide appears to be a substrate for active hepatic uptake (organic anion
transporting protein OATP1B1). Medicinal products 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, other antidiabetic
agents, monoamine oxidase inhibitors (MAOI), non selective beta blocking agents, 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 (a
single dose of 0.25 mg) increased the repaglinide area under curve (AUC) 8.1-fold and maximum
plasma concentration (C
max
) 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7
20
Specific patient groups
hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and
plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use
of gemfibrozil and repaglinide is contraindicated (see section 4.3).
Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and
repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, C
max
and t
½
(1.6-fold, 1.4-fold
and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack
of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety
profile of this combination has not been established with dosages higher than 0.25 mg for repaglinide
and 320 mg for trimethoprim, the concomitant use of trimethoprim with repaglinide should be
avoided. If concomitant use is necessary, careful monitoring of blood glucose and close clinical
monitoring should be performed (see section 4.4).
Rifampicin, a potent inducer of CYP3A4, but also CYP2C8, acts both as an inducer and inhibitor of
the metabolism of repaglinide. Seven days pre-treatment with rifampicin (600 mg) followed by co-
administration of repaglinide (a single dose of 4 mg) at day seven resulted in a 50% lower AUC (effect
of combined induction and inhibition). When repaglinide was given 24 hours after the last rifampicin
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 dose adjustment which
should be based on carefully monitored glucose concentrations at both initiation of rifampicin
treatment (acute inhibition), following dosing (mixed inhibition and induction), withdrawal (induction
alone) and up to approximately two weeks after withdrawal of rifampicin where the inductive effect of
rifampicin is no longer present. It cannot be excluded that other inducers, e.g. phenytoin,
carbamazepine, phenobarbital, St John's wort, may have a similar effect.
The effect of ketoconazole, a prototype of potent and competitive inhibitors of CYP3A4, on the
pharmacokinetics of repaglinide has been studied in healthy subjects. Co-administration of 200 mg
ketoconazole increased the repaglinide (AUC and C
max
) by 1.2-fold with profiles of blood glucose
concentrations altered by les than 8% when administered concomitantly (a single dose of 4 mg
repaglinide). Co-administration of 100 mg itraconazole, an inhibitor of CYP3A4, has also been studied
in healthy volunteers, and increased the AUC by 1.4-fold. No significant effect on the glucose level 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, slightly increased the
repaglinide (AUC) by 1.4-fold and C
max
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 mechanism of this
interaction is not clear.
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 C
max
about
2.5-fold and 1.8-fold respectively. Since the interaction has not been established with dosages higher
than 0.25 mg for repaglinide, the concomitant use of ciclosporin with repaglinide should be avoided. If
the combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4).
β-blocking agents may mask the symptoms of hypoglycaemia.
Co-administration of cimetidine, nifedipine, oestrogen, or simvastatin with repaglinide, all CYP3A4
substrates, 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 adjustment
of 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.
21
When these medicinal products 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.
There are no studies of repaglinide in pregnant or breast-feeding women. Therefore the safety of
repaglinide in pregnant women cannot be assessed. Up to now repaglinide showed not to be
teratogenic in animal studies. Embryotoxicity, abnormal limb development in foetuses and new born
pups, was observed in rats exposed to high doses in the last stage of pregnancy and during the
lactation period. Repaglinide is detected in the milk of experimental animals. For that reason
repaglinide should be avoided during pregnancy and should not be used in breast-feeding women.
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.
Based on the experience with repaglinide and with other hypoglycaemic agents the following adverse
events 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), not known (cannot be estimated from the available data)
Immune system disorders
Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as
vasculitis
.
Metabolism and nutrition disorders
Common: Hypoglycaemia
Not known: Hypoglycaemic coma and hypoglycaemic unconsciousness
As with other hypoglycaemic agents, hypoglycaemic reactions have been observed after
administration of repaglinide. These reactions are mostly mild and easily handled through intake of
carbohydrates. If severe, requiring third party assistance, infusion of glucose may be necessary. The
occurrence of such reactions depends, as for every diabetes therapy, on individual factors, such as
dietary habits, dosage, exercise and stress (see section 4.4). Interactions with other medicinal products
may increase the risk of hypoglycaemia (see section 4.5). During post marketing experience, cases of
hypoglycaemia have been reported in patients treated in combination with metformin or
thiazolidinedione.
Gastro-intestinal disorders
Very rare: Vomiting and constipation
Not known: Nausea
Gastro-intestinal complaints such as abdominal pain, diarrhoea, nausea, vomiting and constipation
have been reported in clinical trials. The rate and severity of these symptoms did not differ from that
seen with other oral insulin secretagogues.
22
Very rare: Allergy
Common: Abdominal pain and diarrhoea
Skin and subcutaneous tissue disorders
Not known: Hypersensitivity
Hypersensitivity reactions of the skin may occur as erythema, itching, rashes and urticaria. There is no
reason to suspect cross-allergenicity with sulphonylurea medicinal products due to the difference of
the chemical structure.
Eye disorders
Very rare: Visual disturbances
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.
Cardiac disorders
Type 2 diabetes is associated with an increased risk for cardiovascular disease. In one epidemiological
study, a higher incidence of acute coronary syndrome was reported in the repaglinide group. However,
the causality of the relationship remains uncertain (see sections 4.4 and 5.1).
Hepatobiliary disorders
In very rare cases, severe hepatic dysfunction has been reported. However, a causal relationship with
repaglinide has not been established.
Very rare: Increased liver enzymes
Isolated cases of increase in liver enzymes have been reported during treatment with repaglinide. Most
cases were mild and transient, and very few patients discontinued treatment due to increase in liver
enzymes.
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 glucose lowering effect with
development of hypoglycaemic symptoms (dizziness, sweating, tremor, headache etc.). Should these
symptoms occur, adequate action should be taken to correct the low blood glucose (oral
carbohydrates). More severe hypoglycaemia with seizure, loss of consciousness or coma should be
treated with i.v. glucose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Carbamoylmethyl benzoic acid derivative, ATC code: A10B X02.
Repaglinide is a novel short-acting oral secretagogue. Repaglinide lowers the blood glucose levels
acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning
β-cells in the pancreatic islets.
Repaglinide closes ATP-dependent potassium channels in the β-cell membrane via a target protein
different from other secretagogues. This depolarises the β-cell and leads to an opening of the calcium
channels. 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 an
oral 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 repaglinide
levels decreased rapidly, and low substance concentrations were seen in the plasma of Type 2 diabetic
patients 4 hours post-administration.
23
Rare: Cardiovascular disease
Very rare: Hepatic function abnormal
A dose-dependent decrease in blood glucose was demonstrated in Type 2 diabetic patients when
administered 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 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
Repaglinide is rapidly absorbed from the gastrointestinal tract, which leads to a rapid increase in the
plasma concentration of the substance. The peak plasma level occurs within one hour post
administration. After reaching a maximum, the plasma level decreases rapidly, and repaglinide is
eliminated within 4 - 6 hours. The plasma elimination half-life is approximately one hour.
Repaglinide pharmacokinetics are characterised by a mean absolute bioavailability of 63% (coefficient
of variation (CV) 11%), low volume of distribution, 30 L (consistent with distribution into
intracellular fluid), and rapid elimination from the blood.
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.
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: 20 – 39 ml/min), the results showed a significant 2-fold increase of the exposure
(AUC) and half-life (t½) as compared to subjects with normal renal function.
Repaglinide is highly bound to plasma proteins in humans (greater than 98%).
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.
Repaglinide is almost completely metabolised, and no metabolites with clinically relevant
hypoglycaemic effect have been identified. Repaglinide and its 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 the parent substance is recovered in faeces.
5.3
Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
6.
6.1 List of excipients
Microcrystalline cellulose (E460)
Calcium hydrogen phosphate, anhydrous
Croscarmellose sodium
Povidone K25
Glycerol
Magnesium stearate
24
Meglumine
Poloxamer
Red iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5
Nature and contents of container
Blister pack (OPA/Al/PVC-Al): 30, 60, 90, 120, 180, 270 and 360 tablets in the box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
30 tablets: EU/1/09/580/013
60 tablets: EU/1/09/580/014
90 tablets: EU/1/09/580/015
120 tablets: EU/1/09/580/016
180 tablets: EU/1/09/580/021
270 tablets: EU/1/09/580/017
360 tablets: EU/1/09/580/018
9.
14/10/2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
25
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
KRKA, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia
TAD Pharma GmbH
Heinz-Lohmann-Straße 5
27472 Cuxhaven
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version
DescPhSys000001/17 (29 January 2009) presented in Module 1.8.1. of the Marketing Authorisation
Application, is in place and functioning before and whilst the product is on the market.
Risk Management plan
A Risk Management Plan was not submitted. The application is based on a reference medicinal
product for which no safety concerns requiring additional risk minimization activities have been
identified.
PSURs
The PSUR submission schedule for Enyglid tablets should follow the PSURs submission schedule for
the reference medicinal product (NovoNorm tablets).
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box/Carton
1.
Enyglid 0.5 mg tablets
Repaglinide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 0.5 mg repaglinide.
3.
LIST OF EXCIPIENTS
4.
30 tablets
60 tablets
90 tablets
120 tablets
180 tablets
270 tablets
360 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
30
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
12.
30 tablets: EU/1/09/580/001
60 tablets: EU/1/09/580/002
90 tablets: EU/1/09/580/003
120 tablets: EU/1/09/580/004
180 tablets: EU/1/09/580/019
270 tablets: EU/1/09/580/005
360 tablets: EU/1/09/580/006
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Enyglid 0.5 mg
31
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister/OPA/Al/PVC-Al
1.
Enyglid 0.5 mg tablets
Repaglinide
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box/Carton
1.
Enyglid 1 mg tablets
Repaglinide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 1 mg repaglinide.
3.
LIST OF EXCIPIENTS
4.
30 tablets
60 tablets
90 tablets
120 tablets
180 tablets
270 tablets
360 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
33
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
12.
30 tablets: EU/1/09/580/007
60 tablets: EU/1/09/580/008
90 tablets: EU/1/09/580/009
120 tablets: EU/1/09/580/010
180 tablets: EU/1/09/580/020
270 tablets: EU/1/09/580/011
360 tablets: EU/1/09/580/012
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Enyglid 1 mg
34
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister/OPA/Al/PVC-Al
1.
Enyglid 1 mg tablets
Repaglinide
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box/Carton
1.
Enyglid 2 mg tablets
Repaglinide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 2 mg repaglinide.
3.
LIST OF EXCIPIENTS
4.
30 tablets
60 tablets
90 tablets
120 tablets
180 tablets
270 tablets
360 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
36
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
12.
30 tablets: EU/1/09/580/013
60 tablets: EU/1/09/580/014
90 tablets: EU/1/09/580/015
120 tablets: EU/1/09/580/016
180 tablets: EU/1/09/580/021
270 tablets: EU/1/09/580/017
360 tablets: EU/1/09/580/018
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Enyglid 2 mg
37
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister/OPA/Al/PVC-Al
1.
Enyglid 2 mg tablets
Repaglinide
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Enyglid 0.5 mg tablets
Enyglid 1 mg tablets
Enyglid 2 mg tablets
Repaglinide
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Enyglid is and what it is used for
2. Before you take Enyglid
3. How to take Enyglid
4. Possible side effects
5. How to store Enyglid
6. Further information
1.
WHAT ENYGLID IS AND WHAT IT IS USED FOR
Enyglid is an oral antidiabetic treatment medicine containing repaglinide which helps your pancreas
produce more insulin and thereby lower blood sugar levels.
Type 2 diabetes is a disease in which your pancreas does not make enough insulin to control the sugar
in your blood or where your body does not respond normally to the insulin it produces (formerly
known as
non-insulin-dependent diabetes mellitus
or
maturity onset diabetes
).
Enyglid is used to control type 2 diabetes as add-on to diet and exercise: treatment is usually started if
diet, exercise and weight loss alone have not been able to control (or lower) your blood sugar.
Enyglid can also be given in combination with metformin.
2.
BEFORE YOU TAKE ENYGLID
Do not take Enyglid
•
if you are hypersensitive (allergic) to repaglinide or any of the other components of Enyglid,
•
if you have type 1 diabetes (insulin-dependent),
•
if the acid level in your body is raised (diabetic ketoacidosis),
•
if you have a severe liver disease,
•
if you take gemfibrozil (a medicine used to lower fat levels in the blood).
If any of these apply to you,
tell your doctor
and do not take Enyglid.
Take special care with Enyglid
•
if you have liver problems. Enyglid is not recommended in patients with moderate liver disease.
Enyglid should not be taken if you have a severe liver disease (see
Do not take
Enyglid
).
•
if you have kidney problems. Enyglid should be taken with caution.
40
•
if you are about to have major surgery or you have recently suffered a severe illness or infection.
At such times diabetic control may be lost.
•
if you are under 18 or over 75 years of age. Repaglinide has not been studied in these age groups,
therefore it is not recommended.
Talk to your doctor if any of the above applies to you. Enyglid may not be suitable for you to use.
Your doctor will advise you.
If you get a hypo
You may get a hypo (short for a hypoglycaemic reaction and is symptoms of low blood sugar) if your
blood sugar gets too low. This may happen:
•
if you take too much Enyglid,
•
if you exercise more than usual,
•
if you take other medicines or suffer from liver or kidney problems (see other sections of
2. Before
you take Enyglid
).
The warning signs of a hypo
may come on suddenly and can include: cold sweat, cool pale skin,
headache, rapid heart beat, feeling sick, feeling very hungry, temporary changes in vision, drowsiness,
unusual tiredness and weakness, nervousness or tremor, feeling anxious, feeling confused, difficulty in
concentrating.
If your blood sugar is low or you feel a hypo coming on
eat glucose tablets or a high sugar snack or
drink, then rest.
When symptoms of hypoglycaemia have disappeared or when blood sugar levels are stabilised
continue repaglinide treatment.
Tell people you have diabetes and that if you pass out
(become unconscious) due to a hypo, they
must turn you on your side and get medical help straight away. They must not give you any food or
drink. It could choke you.
If severe hypoglycaemia
is not treated, it can cause brain damage (temporary or permanent) and even
death.
If you have a hypo
that makes you pass out, or a lot of hypos, talk to your doctor. The amount of
Enyglid, food or exercise may need to be adjusted.
If your blood sugar gets too high
Your blood sugar may get too high (hyperglycaemia). This may happen:
•
if you take too little Enyglid,
•
if you have an infection or a fever,
•
if you eat more than usual,
•
if you exercise less than usual.
The warning signs
appear gradually. They include: increased urination, feeling thirsty, dry skin and
dry mouth. Talk to your doctor. The amount of Enyglid, food or exercise may need to be adjusted.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
If you take gemfibrozil (used to lower increased fat levels in the blood) you should not take Enyglid.
Your body’s response to Enyglid may change if you take other medicines, especially these:
•
Metformin, another anti-diabetic medicine leading to increased chances of low blood sugars.
•
Monoamine oxidase inhibitors (used to treat depression).
•
Non-selective beta blocking agents (used to treat high blood pressure and certain heart conditions).
•
Angiotensin converting enzyme (ACE)-inhibitors (used to treat certain heart conditions).
•
Salicylates (e.g. aspirin).
•
Octreotide (used to treat cancer).
41
•
Non-steroid anti-inflammatory drugs (NSAID, a painkiller).
•
Steroids (anabolic steroids and corticosteroids – used for anaemia or to treat inflammation).
•
Oral contraceptives (used for birth control).
•
Thiazides (used to stimulate urine output).
•
Danazol (used to treat breast cysts and endometriosis).
•
Thyroid products (used to treat low levels of thyroid hormones).
•
Sympathomimetics (used to treat asthma).
•
Clarithromycin, trimethoprim, rifampicin (antibiotic medicine).
•
Itraconazole, ketokonazole (antifungal medicines).
•
Gemfibrozil (used to treat high blood fats).
•
Ciclosporin (used to suppress the immune system).
•
Phenytoin, carbamazepine, phenobarbital (used to treat epilepsy).
•
St.John’s wort (herbal medicine).
Taking Enyglid with food and drink
Take Enyglid before main meals. Alcohol can change the ability of Enyglid to reduce the blood sugar.
Watch for signs of a hypo.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
You should not take Enyglid if you are pregnant or you are planning to become pregnant. See your
doctor as soon as possible if you become pregnant or are planning to become pregnant during
treatment.
You should not take Enyglid if you are breast-feeding.
Driving and using machines
Your ability to drive or operate a machine may be affected if your blood sugar is low or high. Bear in
mind that you could endanger yourself or others. Please ask your doctor whether you can drive a car if
you:
•
have frequent hypos,
•
have few or no warning signs of hypos.
3.
HOW TO TAKE ENYGLID
Your doctor will work out your dose.
•
The normal starting dose is 0.5 mg before each main meal. Swallow the tablets with a glass of
water immediately before or up to 30 minutes before each main meal.
•
The dose may be adjusted by your doctor by up to 4 mg to be taken immediately before or up to
30 minutes before each main meal. The maximum recommended daily dose is 16 mg.
Do not take more Enyglid than your doctor has recommended. Always take Enyglid exactly as your
doctor has told you. Check with your doctor if you are not sure.
If you take more Enyglid than you should
If you take more tablets than you should, your blood sugar may become too low leading to a
hypoglycaemic event. Please see
If you get a hypo
on what a hypo is and how to treat it.
If you forget to take Enyglid
If you forget to take a dose, take the next dose as usual.
Do not take a double dose to make up for a forgotten tablet.
42
If you stop taking Enyglid
Be aware that the desired effect is not achieved if you stop taking Enyglid. Your diabetes may get
worse. If any change is necessary it is absolutely important to contact your doctor first.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Enyglid can cause side effects, although not everybody gets them.
Possible side effects
Common
(affects 1 to 10 users in 100):
•
Hypoglycaemia (see
If you get a hypo
)
The risk of getting a hypo may increase if you take other medicines
.
•
Stomach pain
•
Diarrhoea
Rare
(affects 1 to 10 users in 10,000):
•
Acute coronary syndrome (sudden heart pain), but it may not be due to the drug
Very rare
(affects less than 1 user in 10,000):
•
Allergy (such as swelling, difficulty in breathing, rapid heart beat, feeling dizzy, sweating which
could be signs of anaphylactic reaction)
Contact a doctor immediately.
•
Vomiting
•
Constipation
•
Visual disturbances
•
Severe liver problems (abnormal liver function, increased liver enzymes in your blood)
Not known
(frequency cannot be estimated from the available data):
•
Hypoglycaemic coma or unconsciousness (very severe hypoglycaemic reactions). A doctor should
be contacted immediately. See the section
Take special care
for symptoms and advice in
If you get
a hypo
or low blood sugar.
•
Hypersensitivity (such as rash, itchy skin, reddening of the skin, swelling of the skin; if this
happens tell your doctor as soon as possible)
•
Feeling sick (nausea)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ENYGLID
Keep out of the reach and sight of children.
Do not use Enyglid after the expiry date which is stated on the blister and outer carton. The expiry date
refers to the last day of that month.
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
43
6.
FURTHER INFORMATION
What Enyglid contains
•
The active substance is repaglinide. Each tablet contains 0.5 mg, 1 mg, 2 mg repaglinide.
•
The other ingredients are: microcrystalline cellulose (E460); calcium hydrogen phosphate,
anhydrous; croscarmellose sodium; povidone K25; glycerol; magnesium stearate; meglumine;
poloxamer; yellow iron oxide (E172) only in the 1 mg tablets and red iron oxide (E172) only in
the 2 mg tablets
What Enyglid looks like and contents of the pack
The 0.5 mg tablets are white, round and biconvex with bevelled edges.
The 1 mg tablets are pale brown-yellow, round, biconvex with bevelled edges and possible darker
spots.
The 2 mg tablets are pink, marbled, round, biconvex with bevelled edges and possible darker spots.
Boxes of 30, 60, 90, 120, 180, 270 or 360 tablets in blisters are available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 671 658
Österreich
KRKA Pharma GmbH, Wien
Tel:
+
43 (0)1 66 24 300
44
Ελλάδα
QUALIA PHARMA S.A.
Τηλ:
+
30 (0) 210 2832941
Polska
KRKA-POLSKA Sp.z o.o.
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA Romania S.R.L., Bucharest
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
Κύπρος
Kipa pharmacal Ltd.
Τηλ:
+
357 24 651 882
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 6 733 86 10
United Kingdom
Consilient Health (UK) Ltd.
Tel:
+
44 (0) 2089562310
Lietuva
UAB KRKA Lietuva
Tel:
+
370 5 236 27 40
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu/
.
45
Source: European Medicines Agency
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