Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
Ebymect 5 mg/850 mg
Ebymect 5 mg/1,000 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Ebymect 5 mg/850 mg
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 850 mg of metformin hydrochloride.
Ebymect 5 mg/1,000 mg
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 1,000 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Ebymect 5 mg/850 mg
Brown, biconvex, 9.5 x 20 mm oval,
Ebymect 5 mg/1,000 mg
Yellow, biconvex, 10.5 x 21.5 mm oval,
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Ebymect is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
•in patients inadequately controlled on their maximally tolerated dose of metformin alone
•in combination with other
•in patients already being treated with the combination of dapagliflozin and metformin as separate tablets.
4.2Posology and method of administration
Posology
Adults with normal renal function (GFR ≥ 90 mL/min)
For patients inadequately controlled on metformin monotherapy or metformin in combination with other
The recommended dose is one tablet twice daily. Each tablet contains a fixed dose of dapagliflozin and metformin (see section 2). Patients not adequately controlled on metformin alone or in combination with other
For patients switching from separate tablets of dapagliflozin and metformin
Patients switching from separate tablets of dapagliflozin (10 mg total daily dose) and metformin to Ebymect should receive the same daily dose of dapagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin.
Special populations Renal impairment
No dose adjustment is recommended for patients with mild renal impairment, GFR 60 - 89 mL/min. The maximum daily dose is 3000 mg metformin and should preferably be divided into 2 - 3 daily doses. However, dose reduction may be considered in relation to declining renal function. If no adequate strength of Ebymect is available, individual
A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every
Ebymect is not recommended for use in patients with GFR < 60 mL/min (see section 4.4). The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment.
Hepatic impairment
This medicinal product must not be used in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).
Elderly (≥ 65 years)
Because metformin is eliminated in part by the kidney, and because elderly patients are more likely to have decreased renal function, this medicinal product should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of
Paediatric population
The safety and efficacy of Ebymect in children and adolescents aged 0 to < 18 years have not yet been established. No data are available.
Method of administration
Ebymect should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.
4.3Contraindications
Ebymect is contraindicated in patients with:
hypersensitivity to the active substances or to any of the excipients listed in section 6.1;
any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
diabetic
severe renal failure (GFR < 30 mL/min) (see sections 4.4 and 5.2);
acute conditions with the potential to alter renal function such as:
-dehydration,
-severe infection,
-shock;
acute or chronic disease which may cause tissue hypoxia such as:
-cardiac or respiratory failure,
-recent myocardial infarction,
-shock;
hepatic impairment (see sections 4.2, 4.4 and 5.2);
acute alcohol intoxication, alcoholism (see section 4.5).
4.4Special warnings and precautions for use
General
Ebymect should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Ebymect should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in
Patients and/or
Renal function
The efficacy of dapagliflozin, a component of this medicinal product, is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with
severe renal impairment. Therefore, this medicinal product is not recommended for use in patients with moderate to severe renal impairment (patients with GFR < 60 mL/min) (see section 4.2).
Metformin is excreted by the kidney, and moderate to severe renal insufficiency increases the risk of lactic acidosis (see section 4.4).
Renal function should be assessed:
•Before initiation of treatment and regularly thereafter (see sections 4.2, 4.8, 5.1 and 5.2).
•For renal function with GFR levels approaching moderate renal impairment and in elderly patients, at least 2 to 4 times per year.
•Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter.
•If renal function falls below GFR < 60 mL/min, treatment should be discontinued.
•Metformin is contraindicated in patients with GFR of < 30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating
Use in patients at risk for volume depletion, hypotension and/or electrolyte imbalances
Due to its mechanism of action, dapagliflozin increases diuresis associated with a modest decrease in blood pressure (see section 5.1), which may be more pronounced in patients with high blood glucose concentrations.
This medicinal product is not recommended for use in patients receiving loop diuretics (see section 4.5) or who are volume depleted, e.g. due to acute illness (such as gastrointestinal illness).
Caution should be exercised in patients for whom a
For patients receiving this medicinal product, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).
Diabetic ketoacidosis
Rare cases of diabetic ketoacidosis (DKA), including
The risk of diabetic ketoacidosis must be considered in the event of
In patients where DKA is suspected or diagnosed, treatment with dapagliflozin should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with dapagliflozin may be restarted once the patient’s condition has stabilised.
Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of dapagliflozin in patients with type 1 diabetes have not been established and dapagliflozin should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.
Urinary tract infections
Urinary tract infections were more frequently reported for dapagliflozin compared to placebo in a pooled analysis up to 24 weeks (see section 4.8). Pyelonephritis was uncommon and occurred at a similar frequency to control. Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of treatment should be considered when treating pyelonephritis or urosepsis.
Elderly (≥ 65 years)
Elderly patients are more likely to have impaired renal function, and/or to be treated with
In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to renal impairment or failure compared with placebo. The most commonly reported adverse reaction related to renal function was serum creatinine increases, the majority of which were transient and reversible (see section 4.8).
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to volume depletion (see section 4.8).
Therapeutic experience in patients 75 years and older is limited. Initiation of therapy in this population is not recommended (see sections 4.2 and 5.2).
Cardiac failure
Experience in NYHA class
Use in patients treated with pioglitazone
While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and 5.3), as a precautionary measure, this medicinal product is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.
Elevated haematocrit
Haematocrit increase was observed with dapagliflozin treatment (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.
Lower limb amputations
An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing
Urine laboratory assessments
Due to its mechanism of action, patients taking this medicinal product will test positive for glucose in their urine.
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Ebymect should be discontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been
Surgery
Ebymect must be discontinued at the time of surgery with general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been
Change in clinical status of patients with previously controlled type 2 diabetes
As this medicinal product contains metformin, a patient with type 2 diabetes previously
4.5Interaction with other medicinal products and other forms of interaction
Coadministration of multiple doses of dapagliflozin and metformin does not meaningfully alter the pharmacokinetics of either dapagliflozin or metformin in healthy subjects.
No interaction studies have been performed for Ebymect. The following statements reflect the information available on the individual active substances.
Dapagliflozin
Pharmacodynamic interactions Diuretics
This medicinal product may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin (see sections 4.2 and 4.8).
Pharmacokinetic interactions
The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by
In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, this medicinal product is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.
Effect of other medicinal products on dapagliflozin
Interaction studies conducted in healthy subjects, using mainly a
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55 % increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on
Effect of dapagliflozin on other medicinal products
In interaction studies conducted in healthy subjects, using mainly a
Other interactions
The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of dapagliflozin have not been studied.
Interference with
Monitoring glycaemic control with
Paediatric population
Interaction studies have only been performed in adults.
Metformin
Concomitant use not recommended
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50 % and Cmax by 81 %. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are coadministered.
Alcohol
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case of fasting, malnutrition or hepatic impairment due to the metformin active substance of this medicinal product (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Ebymect must be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes),
Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with metformin (see sections 4.2 and 4.8)
4.6Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of Ebymect or dapagliflozin in pregnant women. Studies in rats treated with dapagliflozin have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, the use of this medicinal product is not recommended during the second and third trimesters of pregnancy. A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).
When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal
as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.
It is unknown whether this medicinal product or dapagliflozin (and/or its metabolites) are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as
This medicinal product should not be used while
Fertility
The effect of this medicinal product or dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. For metformin, studies in animals have not shown reproductive toxicity (see section 5.3).
4.7Effects on ability to drive and use machines
Dapagliflozin or metformin have no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when this medicinal product is used in combination with other
4.8Undesirable effects
Ebymect has been demonstrated to be bioequivalent with coadministered dapagliflozin and metformin (see section 5.2). There have been no therapeutic clinical trials conducted with Ebymect tablets.
Dapagliflozin plus metformin
Summary of the safety profile
In an analysis of 5
Dapagliflozin
Summary of the safety profile
In a
The most frequently reported adverse reaction was hypoglycaemia, which depended on the type of background therapy used in each study. The frequency of minor episodes of hypoglycaemia was similar between treatment groups, including placebo, with the exceptions of studies with
Tabulated list of adverse reactions
The following adverse reactions have been identified in the
Table 1. Adverse reactions in dapagliflozin and metformin
System organ | Very common | Common | Uncommon | Rare | Very rare |
class |
|
|
|
|
|
Infections and |
| Vulvovaginitis, | Fungal |
|
|
infestations |
| balanitis and | infection** |
|
|
|
| related genital |
|
|
|
|
| infections*,b,c |
|
|
|
|
| Urinary tract |
|
|
|
|
| infection*,b,d |
|
|
|
Metabolism and | Hypoglycaemia |
| Volume | Diabetic | Lactic |
nutrition | (when used with |
| depletionb,e | ketoacidosisk | acidosis |
disorders | SU or insulin)b |
| Thirst** |
| Vitamin B12 |
|
|
|
|
| deficiencyh,§ |
Nervous system |
| Taste |
|
|
|
disorders |
| disturbance§ |
|
|
|
|
| Dizziness |
|
|
|
|
|
|
|
|
|
Gastrointestinal | Gastrointestinal |
| Constipation** |
|
|
disorders | symptomsi,§ |
| Dry mouth** |
|
|
Hepatobiliary |
|
|
|
| Liver |
disorders |
|
|
|
| function |
|
|
|
|
| disorders§ |
|
|
|
|
| Hepatitis§ |
Skin and |
| Rashl |
|
| Urticaria§ |
subcutaneous |
|
|
|
| Erythema§ |
tissue disorders |
|
|
|
| Pruritus§ |
Musculoskeletal |
| Back pain* |
|
|
|
and connective |
|
|
|
|
|
tissue disorders |
|
|
|
|
|
|
|
|
|
|
|
Renal and |
| Dysuria | Nocturia** |
|
|
urinary |
| Polyuria*,f | Renal |
|
|
disorders |
|
| impairment**,b |
|
|
Reproductive |
|
| Vulvovaginal |
|
|
system and |
|
| pruritus** |
|
|
breast disorders |
|
| Pruritus |
|
|
|
|
| genital** |
|
|

System organ | Very common | Common | Uncommon | Rare | Very rare |
class |
|
|
|
|
|
Investigations |
| Haematocrit | Blood |
|
|
|
| increasedg | creatinine |
|
|
|
| Creatinine renal | increased**,b |
|
|
|
| clearance | Blood urea |
|
|
|
| decreasedb | increased** |
|
|
|
| Dyslipidaemiaj | Weight |
|
|
|
|
| decreased** |
|
|
aThe table shows adverse reactions identified from up to
bSee corresponding subsection below for additional information.
cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.
dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.
eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension. fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
gMean changes from baseline in haematocrit were 2.30 % for dapagliflozin 10 mg versus
jMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5 % versus 0.0 %; HDL cholesterol 6.0 % versus 2.7 %; LDL cholesterol 2.9 % versus
triglycerides
lAdverse reaction was identified through postmarketing surveillance with the use of dapagliflozin. Rash includes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rash pruritic, rash macular, rash
*Reported in ≥ 2 % of subjects and ≥ 1 % more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.
**Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥ 0.2 % of subjects and ≥ 0.1 % more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.
Description of selected adverse reactions
Dapagliflozin plus metformin Hypoglycaemia
In studies with dapagliflozin in
In an
Dapagliflozin
Hypoglycaemia
The frequency of hypoglycaemia depended on the type of background therapy used in each study.
For studies of dapagliflozin as
In an
Volume depletion
Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1 % and 0.7 % of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2 % of subjects balanced between dapagliflozin 10 mg and placebo (see section 4.4).
Vulvovaginitis, balanitis and related genital infections
Vulvovaginitis, balanitis and related genital infections were reported in 5.5 % and 0.6 % of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4 % and 1.2 % for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection.
Urinary tract infections
Urinary tract infections were more frequently reported for dapagliflozin compared with placebo (4.7 % versus 3.5 %, respectively; see section 4.4). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection.
Increased creatinine
Adverse drug reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). This grouping of reactions was reported in 3.2 % and 1.8 % of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR
≥ 60 mL/min/1.73 m2) this grouping of reactions were reported in 1.3 % and 0.8 % of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m2 (18.5 % dapagliflozin 10 mg vs. 9.3 % placebo).
Further evaluation of patients who had

Parathyroid hormone (PTH)
Small increases in serum PTH levels were observed with increases being larger in subjects with higher baseline PTH concentrations. Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of two years.
Malignancies
During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50 %) and placebo/comparator (1.50 %), and there was no carcinogenicity or mutagenicity signal in animal data (see section 5.3). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in
Special populations
Elderly (≥ 65 years)
In subjects ≥ 65 years of age, adverse reactions related to renal impairment or failure were reported in 7.7 % of subjects treated with dapagliflozin and 3.8 % of subjects treated with placebo (see section 4.4). The most commonly reported adverse reaction related to renal function was increased serum creatinine. The majority of these reactions were transient and reversible. In subjects ≥ 65 years of age, adverse
reactions of volume depletion, most commonly reported as hypotension, were reported in 1.7 % and 0.8 % of
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9Overdose
Removal of dapagliflozin by haemodialysis has not been studied. The most effective method to remove metformin and lactate is haemodialysis.
Dapagliflozin
Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.
Metformin
High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood
Mechanism of action
Ebymect combines two
Dapagliflozin
Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of
The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, reabsorption of filtered glucose continues. Dapagliflozin improves both fasting and
Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium
Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
Metformin
Metformin is a biguanide with
Metformin may act via three mechanisms:
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;
by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation in muscle;
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters
Pharmacodynamic effects
Dapagliflozin
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for
The pharmacodynamics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were compared in healthy subjects. The
Metformin
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled,
In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.
Clinical efficacy and safety
The coadministration of dapagliflozin and metformin has been studied in subjects with type 2 diabetes inadequately controlled on metformin alone or in combination with a
Glycaemic control
In a

(glipizide) as
Table 2. Results at Week 52 (LOCFa) in an
| Dapagliflozin | Glipizide |
Parameter | + metformin | + metformin |
Nb | ||
HbA1c (%) |
|
|
Baseline (mean) | 7.69 | 7.74 |
Change from baselinec | ||
Difference from glipizide + metforminc | 0.00d |
|
(95 % CI) |
| |
Body weight (kg) |
|
|
Baseline (mean) | 88.44 | 87.60 |
Change from baselinec | 1.44 | |
Difference from glipizide + metforminc |
| |
(95 % CI) |
|
aLOCF: Last observation carried forward
bRandomised and treated subjects with baseline and at least 1
Dapagliflozin as an
(p < 0.0001; Table 3).
The reductions in HbA1c observed at Week 24 were sustained in the
and
In a separate analysis of subjects on insulin plus metformin, similar reductions in HbA1C to those seen in the total study population were seen in subjects treated with dapagliflozin with insulin plus metformin. At Weeks 24, HbA1c change from baseline in subjects treated with dapagliflozin plus insulin with metformin was
Table 3. Results of (LOCFa)
|
|
|
|
|
| ||
| Metformin1 | Metformin1, b | Metformin1 + Sitagliptin2 | ||||
|
|
|
|
|
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| Dapagliflozin | Placebo | Dapagliflozin | Placebo | Dapagliflozin | Placebo | |
Nc | 10 mg QD | QD | 5 mg BID | BID | 10 mg QD | QD | |
| |||||||
HbA1c (%) |
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Baseline | 7.92 | 8.11 | 7.79 | 7.94 | 7.80 | 7.87 |
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(mean) |
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Change from |
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baselined |
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Difference |
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from |
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placebod |
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(95 % CI) |
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Subjects (%) |
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achieving: |
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HbA1c < 7 % |
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Adjusted for | 40.6** |
| 38.2** |
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baseline | 25.9 | 21.4 |
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| ||
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| (N=90) | (N=87) |
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Body weight | 86.28 | 87.74 | 93.62 | 88.82 | 93.95 | 94.17 |
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(kg) |
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Baseline |
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(mean) |
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Change from |
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baselined |
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Difference from |
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placebod |
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(95 % CI) |
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Abbreviations: QD: once daily; BID: twice daily
1Metformin ≥ 1500 mg/day;
2Sitagliptin 100 mg/day
aLOCF: Last observation (prior to rescue for rescued subjects) carried forward
cAll randomised subjects who took at least one dose of
dLeast squares mean adjusted for baseline value
***The percent change in body weight was analysed as a key secondary endpoint (p < 0.0001); absolute body weight change (in kg) was analysed with a nominal
Table 4. Results of a
|
| |
|
| Sulphonylurea |
|
| + Metformin1 |
| Dapagliflozin | Placebo |
| 10 mg |
|
Na | ||
HbA1c (%)b | 8.08 | 8.24 |
Baseline (mean) | ||
Change from Baselinec | ||
Difference from Placeboc | −0.69* |
|
(95 % CI) | (−0.89, −0.49) |
|
Subjects (%) achieving: |
|
|
HbA1c < 7 % | 31.8* | 11.1 |
Adjusted for baseline | ||
Body weight (kg) |
|
|
Baseline (mean) | 88.57 | 90.07 |
Change from Baselinec | ||
Difference from Placeboc | ||
(95 % CI) | −2.07* |
|
| (−2.79, −1.35) |
|
1Metformin (immediate- or
aRandomised and treated patients with baseline and at least 1
cLeast squares mean adjusted for baseline value

Table 5. Results at Week 24 (LOCFa) in a
| Dapagliflozin 10 mg | Placebo |
| + insulin | + insulin |
| ± oral | ± oral |
Parameter | medicinal products2 | medicinal products2 |
Nb | ||
HbA1c (%) |
|
|
Baseline (mean) | 8.58 | 8.46 |
Change from baselinec | ||
Difference from placeboc |
| |
(95 % CI) |
| |
Body weight (kg) |
|
|
Baseline (mean) | 94.63 | 94.21 |
Change from baselinec | 0.02 | |
Difference from placeboc |
| |
(95 % CI) |
| |
Mean daily insulin dose (IU)1 |
|
|
Baseline (mean) | 77.96 | 73.96 |
Change from baselinec | 5.08 | |
Difference from placeboc |
| |
(95 % CI) |
| |
Subjects with mean daily |
|
|
insulin dose reduction of at | 19.7** |
|
least 10 % (%) | 11.0 |
aLOCF: Last observation (prior to or on the date of the first insulin
bAll randomised subjects who took at least one dose of
cLeast squares mean adjusted for baseline value and presence of oral
2Fifty percent of subjects were on insulin monotherapy at baseline; 50 % were on 1 or 2 oral
Combination therapy with
In a

Table 6. Results of one
| Dapagliflozin 10 mg | Dapagliflozin 10 mg | ||
| QD | QD | exenatide 2 mg | |
| + | + | QW | |
| Placebo QW | + | ||
Parameter | exenatide 2 mg QW |
| Placebo QD | |
N | ||||
HbA1c (%) |
|
|
| |
Baseline (mean) | 9.29 | 9.25 | 9.26 | |
Change from baselinea | ||||
Mean difference in change |
| |||
from baseline between |
| |||
combination and single active |
| |||
agent (95% CI) |
|
|
| |
Subjects (%) achieving | 44.7 | 19.1 | 26.9 | |
HbA1c 7% | ||||
|
|
| ||
Body weight (kg) |
|
|
| |
Baseline (mean) | 92.13 | 90.87 | 89.12 | |
Change from baseline a | ||||
Mean difference in change |
|
|
| |
from baseline between |
| |||
combination and single active |
| |||
agent (95% CI) |
|
|
|
QD=once daily, QW=once weekly, N=number of patients, CI=confidence interval.
aAdjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by week interaction as fixed factors, and baseline value as a covariate.
*p < 0.001, **p < 0.01.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study medicinal product.
Fasting plasma glucose
Treatment with dapagliflozin as an
Combination therapy of dapagliflozin 10 mg and
to
- Xigduo - A10BD15
Prescription drugs listed. ATC Code: "A10BD15"
Treatment with dapagliflozin 10 mg as an
Combination therapy of dapagliflozin 10 mg and
Body weight
Dapagliflozin as an
As an
(p < 0.0001, Table 2) that was sustained at 104 and 208 weeks
The combination of dapagliflozin 10 mg and
A
Blood pressure
In a
Combination therapy of dapagliflozin 10 mg and
In two
study and an
Cardiovascular safety
A
0.79 (95 % Confidence interval [CI]: 0.58, 1.07), indicating that in this analysis dapagliflozin is not
associated with an increase in cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovascular death, MI and stroke were observed with a hazard ratio of 0.77 (95 % CI: 0.54, 1.10).
Patients with baseline HbA1c ≥ 9 %
In a
Metformin
The prospective randomised (UKPDS) study has established the
a significant reduction of the absolute risk of any
(40.1 events/1,000
a significant reduction of the absolute risk of any
7.5events/1,000
a significant reduction of the absolute risk of overall mortality: metformin
13.5events/1,000
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Ebymect in all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2 for information on paediatric use).
5.2Pharmacokinetic properties
Ebymect combination tablets are considered to be bioequivalent to coadministration of corresponding doses of dapagliflozin and metformin hydrochloride administered together as individual tablets.
The pharmacokinetics of 5 mg dapagliflozin twice daily and 10 mg dapagliflozin once daily were compared in healthy subjects. Administration of 5 mg dapagliflozin twice daily gave similar overall exposures (AUCss) over a
Interaction with food
The administration of this medicinal product in healthy volunteers after a high fat meal compared to after the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin. The meal resulted in a delay of 1 to 2 hours in the peak concentrations and a decrease in the maximum plasma concentration of 29 % of dapagliflozin and 17 % of metformin. These changes are not considered to be clinically meaningful.
Paediatric population
Pharmacokinetics in the paediatric population have not been studied.
The following statements reflect the pharmacokinetic properties of the individual active substances of this medicinal product.
Dapagliflozin
Absorption
Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean
Distribution
Dapagliflozin is approximately 91 % protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean
Biotransformation
Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin
Elimination
The mean plasma terminal
Linearity
Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.
Special populations Renal impairment
At
Hepatic impairment
In subjects with mild or moderate hepatic impairment
Elderly (≥ 65 years)
There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to
Gender
The mean dapagliflozin AUCss in females was estimated to be about 22 % higher than in males.
Race
There were no clinically relevant differences in systemic exposures between White, Black or Asian races.
Body weight
Dapagliflozin exposure was found to decrease with increased weight. Consequently,
Paediatric population
Pharmacokinetics in the paediatric population have not been studied.
Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is
Distribution
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 Vd ranged between
Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
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
Special populations Renal impairment
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood
5.3Preclinical safety data
Coadministration of dapagliflozin and metformin
The following statements reflect the preclinical safety data of the individual active substances of Ebymect.
Dapagliflozin
Reproductive and developmental toxicity
Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. These findings were associated with
In a separate study of pre- and postnatal development, maternal rats were dosed from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and 137 times, respectively, the human values at the maximum recommended human dose). Additional developmental toxicity was limited to
≥ 15 mg/kg/day (associated with pup exposures that are ≥ 29 times the human values at the maximum recommended human dose). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The no observed adverse effect level (NOAEL) for developmental toxicity, the lowest dose tested, is associated with a maternal systemic exposure multiple that is approximately 19 times the human value at the maximum recommended human dose.
In additional studies of
Metformin
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Tablet core:
Hydroxypropyl cellulose (E463)
Microcrystalline cellulose (E460(i))
Magnesium stearate (E470b)
Sodium starch glycolate type A
Ebymect 5 mg/850 mg
Polyvinyl alcohol (E1203)
Macrogol 3350 (E1520(iii))
Talc (E553b)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Iron oxide red (E172)
Ebymect 5 mg/1000 mg
Polyvinyl alcohol (E1203)
Macrogol 3350 (E1520(iii))
Talc (E553b)
Titanium dioxide (E171)
Iron oxide yellow (E172)
6.2Incompatibilities
Not applicable.
6.3Shelf life
3 years
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
PVC/PCTFE/Alu blister.
Pack sizes:
14, 28, 56 and 60
Multipack containing 196 (2 packs of 98)
Not all pack sizes may be marketed.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
AstraZeneca AB
Sweden
8.MARKETING AUTHORISATION NUMBER(S)
Ebymect 5 mg/850 mg
EU/1/15/1051/001 5 mg/850 mg 14 tablets
EU/1/15/1051/002 5 mg/850 mg 28 tablets
EU/1/15/1051/003 5 mg/850 mg 56 tablets
EU/1/15/1051/004 5 mg/850 mg 60 tablets
EU/1/15/1051/005 5 mg/850 mg 60 x 1 tablet (unit dose)
EU/1/15/1051/006 5 mg/850 mg 196 (2 x 98) tablets (multipack)
Ebymect 5 mg/1,000 mg
EU/1/15/1051/007 5 mg/1000 mg 14 tablets
EU/1/15/1051/008 5 mg/1000 mg 28 tablets
EU/1/15/1051/009 5 mg/1000 mg 56 tablets
EU/1/15/1051/010 5 mg/1000 mg 60 tablets
EU/1/15/1051/011 5 mg/1000 mg 60 x 1 tablet (unit dose)
EU/1/15/1051/012 5 mg/1000 mg 196 (2 x 98) tablets (multipack)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16 November 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.
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