2 Identified adverse reactions of empagliflozin monotherapy
3 Identified adverse reactions of metformin monotherapy
4 Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia)
5 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
Description of selected adverse reactions
The frequency of hypoglycaemia depended on the background therapy in the respective studies.
The frequency of patients with hypoglycaemic events was similar for empagliflozin and placebo as add-on to metformin. An increased frequency was noted when empagliflozin given as add-on to metformin and a sulfonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5% and placebo: 8.4%) or as add-on to metformin and insulin (empagliflozin 10 mg: 31.3%, empagliflozin 25 mg: 36.2% and placebo: 34.7%).
Major hypoglycaemia (hypoglycaemia requiring assistance)
The frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo as add-on to metformin. Major hypoglycaemic events occurred in 0.5%, 0% and 0.5% of patients treated with empagliflozin 10 mg, empagliflozin 25 mg and placebo when added on to metformin and insulin, respectively. No patient had a major hypoglycaemic event in the combination with metformin and a sulphonylurea.
Urinary tract infection
The overall frequency of urinary tract infection adverse events was higher in metformin-treated patients who received empagliflozin 10 mg (8.8%) compared to empagliflozin 25 mg (6.6%) or placebo (7.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections (i.e. mild/moderate/severe) was similar to placebo. Urinary tract infection events were reported more frequently for empagliflozin 10 mg compared with placebo in female patients, but not for empagliflozin 25 mg. The frequencies of urinary tract infections were low for male patients and were balanced across treatment groups.
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in metformin-treated patients who received empagliflozin 10 mg (4.0%) and empagliflozin 25 mg (3.9%) compared to placebo (1.3%), and were reported more frequently for empagliflozin compared to placebo in female patients. The difference in frequency was less pronounced in male patients. Genital tract infections were mild and moderate in intensity, none was severe in intensity.
As expected from the mechanism of action, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in metformin-treated patients who received empagliflozin 10 mg (3.0%) and empagliflozin 25 mg (2.9%) compared to placebo (1.4%) as add-on to metformin therapy. Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin (<1%).
The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) in metformin-treated patients who received empagliflozin was low: 0.6% for empagliflozin 10 mg, 0.3% for empagliflozin 25 mg and 0.1% for placebo. The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older. In patients ≥75 years of age volume depletion events have been reported in a single patient treated with empagliflozin 25 mg as add-on to metformin therapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
Yellow Card Scheme
IRL – Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
The Medicines Authority
203 Level 3, Rue D'Argens
In controlled clinical studies single doses of up to 800 mg empagliflozin (equivalent to 32-times the highest recommended daily dose) in healthy volunteers and multiple daily doses of up to 100 mg empagliflozin (equivalent to 4-times the highest recommended daily dose) in patients with type 2 diabetes did not show any toxicity. Empagliflozin increased urine glucose excretion leading to an increase in urine volume. The observed increase in urine volume was not dose-dependent and is not clinically meaningful. There is no experience with doses above 800 mg in humans.
Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital.
In the event of an overdose, treatment should be initiated as appropriate to the patient's clinical status. The most effective method to remove lactate and metformin is haemodialysis. The removal of empagliflozin by haemodialysis has not been studied.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD20
Mechanism of action
Synjardy combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: empagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), and metformin hydrochloride, a member of the biguanide class.
Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive inhibitor of SGLT2. Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000-times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.
Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine.
In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/day with empagliflozin 25 mg. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.
Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure.
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via 3 mechanisms:
• reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis,
• in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization,
• and delay of intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy and safety
A total of 4704 patients with type 2 diabetes were treated in 7 double-blind, placebo or active-controlled clinical studies of at least 24 weeks duration, of which 1109 patients received empagliflozin 10 mg and 1863 received empagliflozin 25 mg as add-on to metformin therapy. Of these, a total of 530 patients received empagliflozin as add-on to metformin plus insulin, of which 266 patients were treated with empagliflozin 10 mg and 264 with empagliflozin 25 mg.
Treatment with empagliflozin in combination with metformin with or without other antidiabetic medicinal products (pioglitazone, sulfonylurea, DPP-4 inhibitors, and insulin) led to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic blood pressure. Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of less than 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. In patients age 75 years and older, numerically lower reductions in HbA1c were observed with empagliflozin treatment. Higher baseline HbA1c was associated with a greater reduction in HbA1c.
Empagliflozin as add-on to metformin, sulphonylurea, pioglitazone
Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone and metformin resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 2). In addition it resulted in a clinically meaningful reduction in FPG, systolic and diastolic blood pressure compared to placebo.
In the double-blind placebo-controlled extension of these studies, reduction of HbA1c, body weight and blood pressure were sustained up to Week 76.
Table 2: Efficacy results of 24 week placebo-controlled studies
bSubgroup analysis for patients on additional background of metformin (FAS, LOCF)
1 Mean adjusted for baseline value
2 Not evaluated for statistical significance as a part of the sequential confirmatory testing procedure
3 LOCF, values after antihypertensive rescue censored
* p-value <0.0001
** p-value <0.01
Empagliflozin 24 months data, as add-on to metformin in comparison to glimepiride
In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (up to 4 mg per day) in patients with inadequate glycaemic control on metformin alone, treatment with empagliflozin daily resulted in superior reduction in HbA1c (Table 3), and a clinically meaningful reduction in FPG, compared to glimepiride. Empagliflozin daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure and a statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin, 24.2% for glimepiride, p<0.0001).
Table 3: Efficacy results at 104 week in an active controlled study comparing empagliflozin to glimepiride as add on to metformina
b Up to 4 mg glimepiride
1 Mean adjusted for baseline value
2 Not evaluated for statistical significance as a part of the sequential confirmatory testing procedure
3 LOCF, values after antihypertensive rescue censored
* p-value <0.0001 for non-inferiority, and p-value = 0.0153 for superiority
** p-value <0.0001
Add-on to insulin therapy
Empagliflozin as add-on to multiple daily insulin
The efficacy and safety of empagliflozin as add-on to multiple daily insulin with concomitant metformin therapy was evaluated in a double-blind, placebo-controlled trial of 52 weeks duration. During the initial 18 weeks and the last 12 weeks, the insulin dose was kept stable, but was adjusted to achieve pre-prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-prandial glucose levels <140 mg/dl [7.8 mmol/l] between Weeks 19 and 40.
At Week 18, empagliflozin provided statistically significant improvement in HbA1c compared with placebo (Table 4).
At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared with placebo and a reduction in body weight.
Table 4: Efficacy results at 18 and 52 weeks in a placebo-controlled study of empagliflozin as add-on to multiple daily doses of insulin with concomitant metformin therapy
b Subgroup analysis for patients on additional background of metformin (PPS-Completers, LOCF)
1 Mean adjusted for baseline value
2 not evaluated for statistical significance as a part of the sequential confirmatory testing procedure
3 Week 19-40: treat-to-target regimen for insulin dose adjustment to achieve pre-defined glucose target levels (pre-prandial <100 mg/dl (5.5 mmol/l), post-prandial <140 mg/dl (7.8 mmol/l)
* p-value ≤0.0005
** p-value <0.005
Empagliflozin as add on to basal insulin
The efficacy and safety of empagliflozin as add on to basal insulin with concomitant metformin therapy was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. During the initial 18 weeks the insulin dose was kept stable, but was adjusted to achieve a FPG <110 mg/dl in the following 60 weeks.
At week 18, empagliflozin provided statistically significant improvement in HbA1c. A greater proportion of patients treated with empagliflozin and with a baseline HbA1c ≥7.0% achieved a target HbA1c of <7% compared to placebo (Table 5).
At 78 weeks, the decrease in HbA1c and insulin sparing effect of empagliflozin was maintained. Furthermore, empagliflozin resulted in a reduction in FPG, body weight and blood pressure.
Table 5 Efficacy results at 18 and 78 weeks in a placebo-controlled study of empagliflozin as add on to basal insulin with metformina
1 mean adjusted for baseline value
* p-value <0.0001
** p-value ≤0.025
Empagliflozin and linagliptin as add-on therapy to metformin
In a double-blind trial in patients with inadequate glycemic control, 24-weeks treatment with both doses of empagliflozin plus linagliptin as add-on to metformin therapy provided statistically significant (p<0.0001) reductions in HbA1c (change from baseline of -1.08% for empagliflozin 10 mg plus linagliptin 5 mg, -1.19% for empagliflozin 25 mg plus linagliptin 5 mg, -0.70% for linagliptin 5 mg). Compared to linagliptin 5 mg, both doses of empagliflozin plus linagliptin 5 mg provided statistically significant reductions in FPG and blood pressure. Both doses provided similar statistically significant reductions in body weight, expressed as kg and percentage change. A greater proportion of patients with a baseline HbA1c ≥7.0% and treated with empagliflozin plus linagliptin achieved a target HbA1c of <7% compared to linagliptin 5 mg. Clinically meaningful reductions in HbA1c were maintained for 52 weeks.
Empagliflozin twice daily versus once daily as add on to metformin therapy
The efficacy and safety of empagliflozin twice daily versus once daily (daily dose of 10 mg and 25 mg) as add-on therapy in patients with in sufficient glycemic control on metformin monotherapy was evaluated in a double blind placebo-controlled study of 16 weeks duration. All treatments with empagliflozin resulted in significant reductions in HbA1c from baseline (total mean 7.8%) after 16 weeks of treatment compared with placebo. Empagliflozin twice daily dose regimens on a background of metformin led to comparable reductions in HbA1c versus once daily dose regimens with a treatment difference in HbA1c reductions from baseline to week 16 of -0.02% (95% CI -0.16, 0.13) for empagliflozin 5 mg twice daily versus 10 mg once daily, and -0.11% (95% CI -0.26, 0.03) for empagliflozin 12.5 mg twice daily versus 25 mg once daily.
In a prospective, pre-specified meta-analysis of independently adjudicated cardiovascular events from 12 phase 2 and 3 clinical studies involving 10,036 patients with type 2 diabetes, empagliflozin did not increase cardiovascular risk.
2 hour post-prandial glucose
Treatment with empagliflozin as add-on to metformin or metformin plus sulfonylurea resulted in clinically meaningful improvement of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks (add-on to metformin, placebo: +5.9 mg/dl, empagliflozin 10 mg: -46.0 mg/dl, empagliflozin 25 mg: -44.6 mg/dl; add-on to metformin plus sulphonylurea, placebo: -2.3 mg/dl, empagliflozin 10 mg: -35.7 mg/dl, empagliflozin 25 mg: -36.6 mg/dl).
Patients with baseline HbA1c ≥9%
In a pre-specified analysis of subjects with baseline HbA1c ≥9.0%, treatment with empagliflozin 10 mg or 25 mg as add-on to metformin resulted in statistically significant reductions in HbA1c at Week 24 (adjusted mean change from baseline of -1.49% for empagliflozin 25 mg, -1.40% for empagliflozin 10 mg, and -0.44% for placebo).
In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin (68% of all patients were on metformin background) resulted in body weight reduction compared to placebo at week 24 (-2.04 kg for empagliflozin 10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg for placebo) that was maintained up to week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg for empagliflozin 25 mg and -0.16 kg for placebo).
The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo controlled study of 12 weeks duration in patients with type 2 diabetes and high blood pressure on different antidiabetic and up to 2 antihypertensive therapies. Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, and 24 hour mean systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring (Table 6). Treatment with empagliflozin provided reductions in seated SBP and DBP.
Table 6 Efficacy results at 12 week in a placebo-controlled study of empagliflozin in patients with type 2 diabetes and uncontrolled blood pressurea
1 LOCF, values after taking antidiabetic rescue therapy censored
2 Mean adjusted for baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
3 LOCF, values after taking antidiabetic rescue therapy or changing antihypertensive rescue therapy censored
4 Mean adjusted for baseline SBP, baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
5 Mean adjusted for baseline DBP, baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
* p-value <0.0001
** p-value <0.001
In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin (68% of all patients were on metformin background) resulted in a reduction in systolic blood pressure (empagliflozin 10 mg: -3.9 mmHg, empagliflozin 25 mg: -4.3 mmHg) compared with placebo (-0.5 mmHg), and in diastolic blood pressure (empagliflozin 10 mg: -1.8 mmHg, empagliflozin 25 mg: -2.0 mmHg) compared with placebo (-0.5 mmHg), at week 24, that were maintained up to week 52.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
• a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034,
• a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017,
• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021),
• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
The European Medicines Agency has waived the obligation to submit the results of studies with Synjardy in all subsets of the paediatric population in type 2 diabetes (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The results of bioequivalence studies in healthy subjects demonstrated that Synjardy (empagliflozin/metformin hydrochloride) 5 mg/850 mg, 5 mg/1,000 mg, 12.5 mg/850 mg, and 12.5 mg/1,000 mg combination tablets are bioequivalent to co-administration of corresponding doses of empagliflozin and metformin as individual tablets.
Administration of empagliflozin/metformin 12.5 mg/1,000 mg under fed conditions resulted in 9% decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant. However, as metformin is recommended to be given with meals, Synjardy is also proposed to be given with food.
The following statements reflect the pharmacokinetic properties of the individual active substances of Synjardy.
The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers and patients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax of 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol.h and 259 nmol/l with empagliflozin 10 mg and 4740 nmol.h and 687 nmol/l with empagliflozin 25 mg once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar suggesting linear pharmacokinetics with respect to time. There were no clinically relevant differences in empagliflozin pharmacokinetics between healthy volunteers and patients with type 2 diabetes.
The pharmacokinetics of 5 mg empagliflozin twice daily and 10 mg empagliflozin once daily were compared in healthy subjects. Overall exposure (AUCss) of empagliflozin over a 24-hour period with empagliflozin 5 mg administered twice daily was similar to empagliflozin 10 mg administered once daily. As expected, empagliflozin 5 mg administered twice daily compared with 10 mg empagliflozin once daily resulted in lower Cmax and higher trough plasma empagliflozin concentrations (Cmin).
Administration of empagliflozin 25 mg after intake of a high-fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax by approximately 37% compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food. Similar results were obtained when Synjardy (empagliflozin/metformin) combination tablets were administered with high-fat and high calorie meal.
The apparent steady-state volume of distribution was estimated to be 73.8 l based on the population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy volunteers, the red blood cell partitioning was approximately 37% and plasma protein binding was 86%.
No major metabolites of empagliflozin were detected in human plasma, as defined by at least 10% of total drug-related material, and the most abundant metabolites were three glucuronide conjugates (2-, 3-, and 6-O-glucuronide). In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
Based on the population pharmacokinetic analysis, the apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 l/hour. The inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with the half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [14C]-empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
In patients with mild, moderate or severe renal impairment (creatinine clearance <30 - <90 ml/min) and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. The population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in creatinine clearance leading to an increase in drug exposure.
In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and Cmax by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
Body Mass Index
Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis. In this analysis, AUC was estimated to be 5.82%, 10.4%, and 17.3% lower in subjects with BMI of 30, 35, and 45 kg/m2, respectively, compared to subjects with a body mass index of 25 kg/m2.
Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
In the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asians with a body mass index of 25 kg/m2 compared to non-Asians with a body mass index of 25 kg/m2.
Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
After an oral dose of metformin, tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%. After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are non-linear. At the recommended metformin doses and dosing schedules, steady-state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg metformin hydrochloride, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63 - 276 l.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Renal clearance of metformin is >400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Single dose study: after single doses of metformin hydrochloride 500 mg, paediatric patients have shown a similar pharmacokinetic profile to that observed in healthy adults.
Multiple-dose study: After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were approximately 33% and 40% lower, respectively, compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.
5.3 Preclinical safety data
Empagliflozin and metformin
General toxicity studies in rats of up to 13 weeks were performed with the combination of empagliflozin and metformin and did not reveal any additional target organs when compared to empagliflozin or metformin alone. Some responses were increased by the combination treatment, such as effects on renal physiology, electrolyte balance and acid/base state. However, only hypochloremia was considered adverse at exposures of approximately 9- and 3-times the clinical AUC exposure of the maximum recommended dose of empagliflozin and metformin, respectively.
An embryofetal development study in pregnant rats did not indicate a teratogenic effect attributed to the co-administration of empagliflozin and metformin at exposures of approximately 14-times the clinical AUC exposure of empagliflozin associated with the highest dose, and 4-times the clinical AUC exposure of metformin associated with the 2000 mg dose.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, fertility and early embryonic development.
In long term toxicity studies in rodents and dogs, signs of toxicity were observed at exposures greater than or equal to 10-times the clinical dose of empagliflozin. Most toxicity was consistent with secondary pharmacology related to urinary glucose loss and electrolyte imbalances including decreased body weight and body fat, increased food consumption, diarrhoea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein metabolism and gluconeogenesis, urinary changes such as polyuria and glucosuria, and microscopic changes including mineralisation in kidney and some soft and vascular tissues. Microscopic evidence of the effects of exaggerated pharmacology on the kidney observed in some species included tubular dilatation, and tubular and pelvic mineralisation at approximately 4-times the clinical AUC exposure of empagliflozin associated with the 25 mg dose.
Empagliflozin is not genotoxic.
In a 2 year carcinogenicity study, empagliflozin did not increase the incidence of tumours in female rats up to the highest dose of 700 mg/kg/day, which corresponds to approximately 72-times the maximal clinical AUC exposure to empagliflozin. In male rats, treatment-related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node were observed at the highest dose, but not at 300 mg/kg/day, which corresponds to approximately 26-times the maximal clinical exposure to empagliflozin. Interstitial cell tumours in the testes were observed with a higher incidence in rats at 300 mg/kg/day and above, but not at 100 mg/kg/day which corresponds to approximately 18-times the maximal clinical exposure to empagliflozin. Both tumours are common in rats and are unlikely to be relevant to humans.
Empagliflozin did not increase the incidence of tumours in female mice at doses up to 1,000 mg/kg/day, which corresponds to approximately 62-times the maximal clinical exposure to empagliflozin. Empagliflozin induced renal tumours in male mice at 1,000 mg/kg/day, but not at 300 mg/kg/day, which corresponds to approximately 11-times the maximal clinical exposure to empagliflozin. The mode of action for these tumours is dependent on the natural predisposition of the male mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouse renal tumours are considered not relevant to humans.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, empagliflozin had no adverse effects on fertility or early embryonic development. Empagliflozin administered during the period of organogenesis was not teratogenic. Only at maternally toxic doses, empagliflozin also caused bent limb bones in the rat and increased embryofetal loss in the rabbit.
In pre- and postnatal toxicity studies in rats, reduced weight gain of offspring was observed at maternal exposures approximately 4-times the maximal clinical exposure to empagliflozin. No such effect was seen at systemic exposure equal to the maximal clinical exposure to empagliflozin. The relevance of this finding to humans is unclear.
In a juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day 21 until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in juvenile rats was seen only at 100 mg/kg/day, which approximates 11-times the maximum clinical dose of 25 mg. These findings were absent after a 13 weeks drug-free recovery period.
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential or reproductive toxicity. At dose levels of 500 mg/kg/day administered to Wistar Hannover rats, associated with 7-times the maximum recommended human dose (MRHD) of metformin, teratogenicity of metformin was observed, mostly evident as an increase in the number of skeletal malformations.
6. Pharmaceutical particulars
6.1 List of excipients
Synjardy 5 mg/850 mg film-coated tablets and Synjardy 5 mg/1,000 mg film-coated tablets
Copovidone (K-value nominally 28)
Colloidal anhydrous silica
Titanium dioxide (E171)
Iron oxide yellow (E172)
Synjardy 12.5 mg/850 mg film-coated tablets and Synjardy 12.5 mg/1,000 mg film-coated tablets
Copovidone (K-value nominally 28)
Colloidal anhydrous silica
Titanium dioxide (E171)
Iron oxide black (E172)
Iron oxide red (E172)
6.3 Shelf life
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVDC/aluminium perforated unit dose blisters.
Pack sizes of 10 x 1, 14 x 1, 30 x 1, 56 x 1, 60 x 1, 90 x 1 and 100 x 1 film-coated tablets and multipacks containing 120 (2 packs of 60 x 1), 180 (2 packs of 90 x 1) and 200 (2 packs of 100 x 1) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
8. Marketing authorisation number(s)
Synjardy 5 mg/850 mg film-coated tablets
Synjardy 5 mg/1,000 mg film-coated tablets
Synjardy 12.5 mg/850 mg film-coated tablets
Synjardy 12.5 mg/1,000 mg film-coated tablets
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 27 May 2015
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Synjardy filmcoated tablets(复方恩格列净/盐酸二甲双胍片)
简介： 2015年5月28日,勃林格-礼来糖尿病联盟研发的2性糖尿病复方新药Synjardy（empagliflozin/盐酸二甲双胍）获欧盟委员会（EC）批准，用于2型糖尿病（T2D）成人患者的治疗。Synjardy每日口服2次，该药有4种剂 ...