Glyxambi

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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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

Glyxambi 10 mg/5 mg film-coated tablets
Glyxambi 25 mg/5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Glyxambi 10 mg/5 mg film-coated tablets
Each film-coated tablet contains 10 mg empagliflozin and 5 mg linagliptin.

Glyxambi 25 mg/5 mg film-coated tablets
Each film-coated tablet contains 25 mg empagliflozin and 5 mg linagliptin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Glyxambi 10 mg/5 mg film-coated tablets
Pale yellow, arc triangular, flat faced, bevel-edged, film-coated tablets. One side is debossed with the 
Boehringer Ingelheim company symbol, the other side is debossed with “10/5” (tablet dimensions: 
8 mm each side).

Glyxambi 25 mg/5 mg film-coated tablets
Pale pink, arc triangular, flat faced, bevel-edged, film-coated tablets. One side is debossed with the 
Boehringer Ingelheim company symbol, the other side is debossed with “25/5” (tablet dimensions: 
8 mm each side).

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Glyxambi, fixed dose combination of empagliflozin and linagliptin, is indicated in adults aged 
18 years and older with type 2 diabetes mellitus:
 to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the 

monocomponents of Glyxambi do not provide adequate glycaemic control
 when already being treated with the free combination of empagliflozin and linagliptin

(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied)

4.2 Posology and method of administration

Posology

The recommended starting dose is 1 film-coated tablet of Glyxambi 10 mg/5 mg (10 mg empagliflozin 
plus 5 mg linagliptin) once daily.

In patients who tolerate this starting dose and require additional glycaemic control, the dose can be 



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increased to 1 film-coated tablet of Glyxambi 25 mg/5 mg (25 mg empagliflozin plus 5 mg linagliptin) 
once daily.

When Glyxambi is used in combination with a sulphonylurea or with insulin, a lower dose of the 
sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.4, 4.5 
and 4.8).

Patients switching from empagliflozin (either 10 mg or 25 mg daily dose) and linagliptin (5 mg daily 
dose) to Glyxambi should receive the same daily dose of empagliflozin and linagliptin in the fixed 
dose combination as in separate tablets. The metformin dose should be continued.

Special populations

Renal impairment

Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy of 
empagliflozin (see sections 4.4 and 5.1). 
 In patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or 

creatinine clearance (CrCl) ≥60 mL/min, no dose adjustment is required.
 In patients with an eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min, Glyxambi should not be 

initiated.
 In patients tolerating Glyxambi whose eGFR falls persistently below 60 mL/min/1.73 m2 or 

CrCl below 60 mL/min, the dose of Glyxambi should be adjusted to or maintained at 10 mg 
empagliflozin plus 5 mg linagliptin once daily.

 When eGFR is persistently below 45 mL/min/1.73 m2 or CrCl persistently below 45 mL/min, 
treatment should be discontinued (see sections 4.4, 4.8, 5.1, and 5.2).

 In patients with end-stage renal disease or in patients on dialysis, Glyxambi should not be used 
as empagliflozin is not expected to be effective in these patients (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild to moderate hepatic impairment.

Empagliflozin exposure is increased in patients with severe hepatic impairment and therapeutic 
experience in such patients is limited (see section 5.2). Therefore, Glyxambi is not recommended for 
use in this population.

Elderly

No dosage adjustment based on age is required. However, renal function and risk of volume depletion 
should be taken into account in elderly patients (see sections 4.4 and 4.8). Based on very limited 
experience in patients 75 years and older, initiation of Glyxambi therapy is not recommended in this 
population (see sections 4.4 and 5.2).

Paediatric population

Safety and efficacy of Glyxambi in paediatric patients below 18 years of age have not been 
established. No data are available. 

Method of administration

Glyxambi tablets are for oral use and can be taken with or without a meal at any time of the day at 
regular intervals. The tablets should be swallowed whole with water. If a dose is missed, and it is 12 
hours or more until the next dose, the dose should be taken as soon as the patient remembers. The next 
dose should be taken at the usual time. If a dose is missed, and it is less than 12 hours until the next 
dose, the dose should be skipped and the next dose should be taken at the usual time. A double dose 
should not be taken to compensate for a forgotten dose.



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4.3 Contraindications

Hypersensitivity to the active substances, to any other Sodium-Glucose-Co-Transporter-2 (SGLT2) 
inhibitor, to any other Dipeptidyl-Peptidase-4 (DPP-4) inhibitor, or to any of the excipients listed in 
section 6.1.

4.4 Special warnings and precautions for use

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been 
reported in patients treated with SGLT2 inhibitors, including empagliflozin. In a number of cases, the 
presentation of the condition was atypical with only moderately increased blood glucose values, below 
14 mmol/L (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of 
empagliflozin.

The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, 
anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or 
sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, 
regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with empagliflozin should be 
discontinued immediately. 

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute 
serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of
blood ketone levels is preferred to urine. Treatment with empagliflozin may be restarted when the 
ketone values are normal and the patient’s condition has stabilised.

Before initiating empagliflozin, 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 beta-cell function reserve (e.g. 
type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or 
patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or 
severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin 
requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used 
with caution in these patients. 

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 empagliflozin in patients with type 1 diabetes have not been established and 
empagliflozin 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.

Use with medicinal products known to cause hypoglycaemia

Empagliflozin and linagliptin as single agents showed an incidence of hypoglycaemia comparable to 
placebo when used alone or in combination with other antidiabetics not known to cause 
hypoglycaemia (e.g. metformin, thiazolidinediones). When used in combination with antidiabetics 
known to cause hypoglycaemia (e.g. sulphonylureas and/or insulin), the incidence of hypoglycaemia 
of both agents was increased (see section 4.8).

There are no data about the hypoglycaemic risk of Glyxambi when used with insulin and/or 



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sulphonylurea. However, caution is advised when Glyxambi is used in combination with antidiabetics. 
A dose reduction of the sulphonylurea or insulin may be considered (see section 4.2 and 4.5).

Acute pancreatitis

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acute 
pancreatitis. Acute pancreatitis has been observed in patients taking linagliptin. In a cardiovascular 
and renal safety study (CARMELINA) with median observation period of 2.2 years, adjudicated acute 
pancreatitis was reported in 0.3% of patients treated with linagliptin and in 0.1% of patients treated 
with placebo. Patients should be informed of the characteristic symptoms of acute pancreatitis.

If pancreatitis is suspected, Glyxambi should be discontinued; if acute pancreatitis is confirmed, 
Glyxambi should not be restarted. Caution should be exercised in patients with a history of 
pancreatitis.

Monitoring of renal function

Due to the mechanism of action, the glycaemic efficacy of empagliflozin is dependent on renal 
function (see sections 4.2, 5.1 and 5.2). Therefore, assessment of renal function is recommended:
 prior to Glyxambi initiation and periodically during treatment, i.e. at least yearly,
 prior to initiation of any concomitant medicinal product that may have a negative impact on 

renal function.

Use in patients with renal impairment

In patients with an eGFR below 60 mL/min/1.73 m2 or CrCl <60 mL/min, avoidance, dose adjustment 
or discontinuation of Glyxambi may be necessary (for details see section 4.2). Glyxambi should be 
discontinued when eGFR is persistently below 45 mL/min/1.73 m2 or CrCl is persistenly below 
45 mL/min. In patients with end-stage renal disease or in patients on dialysis, Glyxambi should not be 
used, as empagliflozin is not expected to be effective in these patients (see section 5.2).

Use in patients at risk for volume depletion

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeutic 
glucosuria may lead to a modest decrease in blood pressure (see section 5.1). Therefore, caution 
should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose 
a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy (e.g. 
thiazide and loop diuretics, see also section 4.5) with a history of hypotension or patients aged 
75 years and older.

In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of 
volume status (e.g. physical examination, blood pressure measurements, laboratory tests including 
haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary 
interruption of treatment with Glyxambi should be considered until the fluid loss is corrected.

Urinary tract infections

In Glyxambi clinical trials, the incidence of urinary tract infections was overall similar between the 
patients treated with Glyxambi and the patients treated with empagliflozin or linagliptin. The 
frequencies were comparable to the incidence of urinary tract infections in empagliflozin clinical trials 
(see section 4.8).
In a pool of placebo-controlled double-blind trials of 18 to 24 weeks duration, the overall frequency of 
urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 
25 mg and placebo and higher in patients treated with empagliflozin 10 mg (see section 4.8). Post-
marketing cases of complicated urinary tract infections including pyelonephritis and urosepsis have 
been reported in patients treated with empagliflozin. Pyelonephritis and urosepsis were not reported 
from the clinical trials in patients treated with Glyxambi. However, temporary interruption of 



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Glyxambi should be considered in patients with complicated urinary tract infections.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), 
have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and 
potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms of 
pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware 
that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier´s 
gangrene is suspected, Glyxambi should be discontinued and prompt treatment (including antibiotics 
and surgical debridement) should be instituted.

Lower limb amputations

An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing 
long-term clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class 
effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot-
care.

Hepatic injury

Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship 
between empagliflozin and hepatic injury has not been established.

Cardiac failure

Experience with empagliflozin in New York Heart Association (NYHA) class I-II is limited, and there 
is no experience in clinical studies with empagliflozin in NYHA class III-IV. In the EMPA-REG 
OUTCOME study, 10.1 % of the patients were reported with cardiac failure at baseline. The reduction 
of cardiovascular death in these patients was consistent with the overall study population.

Urine laboratory assessments

Due to the mechanism of action of empagliflozin, patients taking Glyxambi will test positive for 
glucose in their urine.

Elevated haematocrit

Haematocrit increase was observed with empagliflozin treatment (see section 4.8).

Elderly

A higher risk of volume depletion adverse reactions were reported in patients aged 75 years and older, 
treated with empagliflozin, especially at 25 mg/day (see section 4.8). Therefore, special attention 
should be given to their volume intake in case of co-administered medicinal products which may lead 
to volume depletion (e.g. diuretics, ACE inhibitors). Therapeutic experience is limited with Glyxambi 
in patients > 75 years of age, and, no experience is available in patients aged 85 years and older. 
Initiation of therapy with Glyxambi in this population is not recommended (see section 4.2).

Bullous pemphigoid

Bullous pemphigoid has been observed in patients taking linagliptin. In the CARMELINA study, 
bullous pemphigoid was reported in 0.2% of patients on treatment with linagliptin and in no patient on 
placebo. If bullous pemphigoid is suspected, Glyxambi should be discontinued.



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4.5 Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed with Glyxambi and other medicinal products; 
however, such studies have been conducted with the individual active substances. Based on results of 
pharmacokinetic studies, no dose adjustment of Glyxambi is recommended when co-administered with 
commonly prescribed medicinal products, except those mentioned below.

Pharmacodynamic interactions

Insulin and sulphonylureas

Insulin and sulphonylureas may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin 
or sulphonylureas may be required to reduce the risk of hypoglycaemia when used in combination 
with Glyxambi (see sections 4.2, 4.4 and 4.8).

Diuretics

Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of 
dehydration and hypotension (see section 4.4).

Pharmacokinetic interactions

Effects of other medicinal products on empagliflozin

Empagliflozin is mainly excreted unchanged. A minor fraction is metabolised via uridine 5'-
diphosphoglucuronosyltransferases (UGT); therefore, a clinically relevant effect of UGT inhibitors on 
empagliflozin is not expected (see section 5.2). The effect of UGT induction on empagliflozin has not 
been studied. Co-administration with known inducers of UGT enzymes should be avoided because of 
a risk of decreased efficacy of empagliflozin.

Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, 
resulted in a 26 % increase in peak empagliflozin plasma concentrations (Cmax) and a 53 % increase in 
area under the concentration-time curve (AUC). These changes were not considered to be clinically 
meaningful.

An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, 
showed that empagliflozin Cmax increased by 15 % and AUC increased by 59 % following co-
administration. These changes were not considered to be clinically meaningful.

Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75 %
increase in Cmax and a 35 % increase in AUC of empagliflozin. These changes were not considered to 
be clinically meaningful.

Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced by co-
administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, 
ramipril, simvastatin, torasemide and hydrochlorothiazide.

Effects of empagliflozin on other medicinal products

Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically 
relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, 
simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives.

Effects of other medicinal products on linagliptin

Co-administration of rifampicin decreased linagliptin exposure by 40 %, suggesting that the efficacy 
of linagliptin may be reduced when administered in combination with a strong P-glycoprotein (P-gp) 



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or cytochrome P450 (CYP) isozyme CYP3A4 inducer, particularly if these are administed long-term
(see section 5.2). Co-administration with other potent inducers of P-gp and CYP3A4, such as 
carbamazepine, phenobarbital and phenytoin, has not been studied.

Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, 
a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptin 
approximately twofold and threefold, respectively. The unbound concentrations, which are usually less 
than 1 % at the therapeutic dose of linagliptin, were increased 4 to 5-fold after co-administration with 
ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir 
indicated that the increase in exposure will be not associated with an increased accumulation. These 
changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, 
clinically relevant interactions would not be expected with other P-glycoprotein / CYP3A4 inhibitors.

Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of linagliptin 
were not influenced by co-administration with metformin and glibenclamide.

Effects of linagliptin on other medicinal products

Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme 
CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin 
is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low 
potency.

Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, 
simvastatin, pioglitazone, warfarin, digoxin, empagliflozin or oral contraceptives providing in vivo
evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, 
CYP2C8, P-gp and organic cationic transporter (OCT).

4.6 Fertility, pregnancy and lactation

The effects of Glyxambi on pregnancy, breast-feeding and fertility are not known. Effects related to 
the individual active substances are described below.

Pregnancy

There are no data from the use of empagliflozin and linagliptin in pregnant women.
Animal studies show that empagliflozin and linagliptin cross the placenta during late gestation, but do 
not indicate direct or indirect harmful effects with respect to early embryonic development with either 
empagliflozin or linagliptin (see section 5.3). Animal studies with empagliflozin have shown adverse 
effects on postnatal development (see section 5.3). As a precautionary measure it is preferable to avoid 
the use of Glyxambi during pregnancy. 

Breast-feeding

No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available 
non-clinical data in animals have shown excretion of empagliflozin and linagliptin in milk. A risk to 
newborns or infants cannot be excluded. Glyxambi should not be used during breast-feeding.

Fertility

No studies on the effect on human fertility have been conducted with Glyxambi or with the individual 
active substances. Non-clinical studies with empagliflozin and linagliptin as single agents do not 
indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Glyxambi has minor influence on the ability to drive and use machines. Patients should be advised to



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take precautions to avoid hypoglycaemia while driving and using machines, in particular when
Glyxambi is used in combination with other antidiabetic medicinal products known to cause 
hypoglycaemia (e.g. insulin and analogues, sulphonylureas).

4.8 Undesirable effects

Summary of the safety profile

The most frequent adverse reaction was urinary tract infection (7.5 % with Glyxambi 10 mg 
empagliflozin / 5 mg linagliptin and 8.5 % with Glyxambi 25 mg empagliflozin / 5 mg linagliptin) (see 
Description of selected adverse reactions). The most serious adverse reactions were ketoacidosis
(< 0.1%), pancreatitis (0.2%), hypersensitivity (0.6%), and hypoglycaemia (2.4%) (see section 4.4).

Overall, the safety profile of Glyxambi was in line with the safety profiles of the individual active 
substances (empagliflozin and linagliptin). No additional adverse reactions were identified with 
Glyxambi.

The adverse reactions shown in the table below (see Table 1) are listed by system organ class and are 
based on the safety profiles of empagliflozin and linagliptin monotherapy. The information about 
adverse reactions not reported in Glyxambi clinical trials is based on the experience from 
empagliflozin and linagliptin. Adverse reactions marked with an asterisk (*) are further discussed in 
section “Description of selected adverse reactions” below.

Tabulated list of adverse reactions

Frequency categories are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon 
(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot 
be estimated from the available data).



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Table 1 Adverse reactions

System organ class Frequency Adverse reaction

Infections and infestations Common Urinary tract infection1,* (including 
pyelonephritis and urosepsis)4

Common

Common
Not known

Vaginal moniliasis, vulvovaginitis, 
balanitis and other genital infections1,*

Nasopharyngitis2

Necrotising fasciitis of the perineum 
(Fournier´s gangrene)#

Immune system disorders Uncommon Hypersensitivity2

Uncommon Angioedema3,4, urticaria3,4

Metabolism and nutrition 
disorders

Common

Common
Rare

Hypoglycaemia (when used with 
sulphonylurea or insulin)*

Thirst
Diabetic ketoacidosis4,#

Respiratory, thoracic and 
mediastinal disorders

Common Cough2

Gastrointestinal disorders Uncommon
Rare

Pancreatitis2

Mouth ulceration3

Skin and subcutaneous tissue 
disorders

Common
Common
Not known

Pruritus1

Rash3,4

Bullous pemphigoid2,a

Vascular disorders Uncommon Volume depletion1,*

Renal and urinary disorders Common
Uncommon

Increased urination1,*

Dysuria1

Investigations Common
Common
Uncommon
Uncommon
Uncommon

Amylase increased2

Lipase increased2

Haematocrit increased1,5

Serum lipids increased1,6

Blood creatinine increased/Glomerular 
filtration rate decreased1,*

1 derived from empagliflozin experiences
2 derived from linagliptin experiences
3 derived from linagliptin postmarketing experience
4 derived from empagliflozin postmarketing experience
5 Mean changes from baseline in haematocrit were 3.3% and 4.2% for Glyxambi 10 mg/5 mg and 25 mg/5 mg, respectively, 
compared to 0.2% for placebo. In a clinical trial with empagliflozin, haematocrit values returned towards baseline values 
after a follow-up period of 30 days after treatment stop.
6 Mean percent increases from baseline for Glyxambi 10 mg/5 mg and 25 mg/5 mg versus placebo, respectively, were total 
cholesterol 3.2% and 4.6% versus 0.5%; HDL-cholesterol 8.5% and 6.2% versus 0.4%; LDL-cholesterol 5.8% and 11.0% 
versus 3.3%; triglycerides -0.5% and 3.3% versus 6.4 %.
a In the CARMELINA study (see section 5.1), bullous pemphigoid was reported in 0.2% patients treated with linagliptin and 
in no patients treated with placebo.
# see section 4.4
* see subsection below for additional information

Description of selected adverse reactions

Hypoglycaemia

In pooled clinical trials of Glyxambi in patients with type 2 diabetes and inadequate glycaemic control 
on background metformin, the frequency of the reported hypoglycaemic events was 2.4 %. The 
incidence of confirmed hypoglycaemic events was low (< 1,5 %). There was no notable difference of 
the incidence in patients treated with different dose strengths of Glyxambi compared to the treatment 
with empagliflozin or linagliptin.



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One patient administered Glyxambi experienced a confirmed (investigator-defined), major 
hypoglycaemic event (defined as an event requiring assistance) in the active- or placebo-controlled 
trials (overall frequency 0,1 %).

Based on the experience with empagliflozin and linagliptin, an increase of the risk of hypoglycaemia 
is expected with the concomitant treatment of insulin and /or sulphonylurea (see section 4.4 and 
information below)

Hypoglycaemia with empagliflozin

The frequency of hypoglycaemia depended on the background therapy in the respective studies and 
was similar for empagliflozin and placebo as monotherapy, as add-on to metformin, and as add-on to 
pioglitazone +/- metformin. The frequency of patients with hypoglycaemia was increased in patients 
treated with empagliflozin compared to placebo when given as add-on to metformin plus 
sulphonylurea (empagliflozin 10 mg: 16.1 %, empagliflozin 25 mg: 11.5 %, placebo: 8.4 %), add-on 
to basal insulin +/- metformin and +/-sulphonylurea (empagliflozin 10 mg: 19.5 %, empagliflozin 
25 mg: 28.4 %, placebo: 20.6 % during initial 18 weeks treatment when insulin could not be adjusted; 
empagliflozin 10 mg and 25 mg: 36.1 %, placebo 35.3 % over the 78 week trial), and add-on to MDI 
insulin with or without metformin (empagliflozin 10 mg: 39.8 %, empagliflozin 25 mg: 41.3 %, 
placebo: 37.2 % during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 
10 mg: 51.1 %, empagliflozin 25 mg: 57.7 %, placebo: 58 % over the 52-week trial).

Major hypoglycaemia with empagliflozin (events requiring assistance)

The frequency of patients with major hypoglycaemic events was low (< 1 %) and similar for 
empagliflozin and placebo as monotherapy, as add-on to metformin +/- sulfonylurea, and as add-on to 
pioglitazone +/- metformin.

The frequency of patients with major hypoglycaemic events was increased in patients treated with 
empagliflozin compared to placebo when given as add-on to basal insulin +/- metformin and +/-
sulphonylurea (empagliflozin 10 mg: 0 %, empagliflozin 25 mg: 1.3 %, placebo: 0 % during initial 18 
weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0 %, empagliflozin 25 mg: 
1.3 %, placebo 0 % over the 78-week trial), and add-on to MDI insulin with or without metformin 
(empagliflozin 10 mg: 1.6 %, empagliflozin 25 mg: 0.5 %, placebo: 1.6 % during initial 18 weeks 
treatment when insulin could not be adjusted and over the 52-week trial).

Hypoglycaemia with linagliptin

The most frequently reported adverse event in clinical trials with linagliptin was hypoglycaemia 
observed under the triple combination, linagliptin plus metformin plus sulphonylurea (22.9 % vs 
14.8 % in placebo).

Hypoglycaemias in the placebo-controlled studies (10.9 %; N=471) were mild (80 %; N=384), 
moderate (16.6 %; N=78) or severe (1.9 %; N=9) in intensity.

Urinary tract infection

In clinical trials with Glyxambi, there was no notable difference of the frequency of urinary tract 
infections in patients treated with Glyxambi (Glyxambi 25 mg/5 mg: 8.5 %; Glyxambi 10 mg/5 mg: 
7.5 %) compared to the patients treated with empagliflozin and linagliptin. The frequencies have been 
comparable to those reported from the empagliflozin clinical trials (see also section 4.4).

In empagliflozin trials, the overall frequency of urinary tract infection was similar in patients treated 
with empagliflozin 25 mg and placebo (7.0 % and 7.2 %), and higher in patients treated with 
empagliflozin 10 mg (8.8 %). 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 was similar to placebo for mild, moderate and severe intensity 



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reports. Urinary tract infection was reported more frequently in female patients treated with 
empagliflozin compared to placebo, but not in male patients.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

In clinical trials with Glyxambi, genital infections in patients treated with Glyxambi (Glyxambi 
25 mg/5 mg: 3.0 %; Glyxambi 10 mg/5 mg: 2.5 %) were reported more frequently than for linagliptin 
but less freqeuntly than for empagliflozin. Overall, the frequencies for Glyxambi have been 
comparable to those reported from the empagliflozin clinical trials.

In empagliflozin trials, vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were 
reported more frequently for empagliflozin 10 mg (4.0 %) and empagliflozin 25 mg (3.9 %) compared 
to placebo (1.0 %). These infections were reported more frequently for empagliflozin compared to 
placebo in female patients, and the difference in frequency was less pronounced in male patients. The 
genital tract infections were mild and moderate in intensity, none was severe in intensity. 

Increased urination

In clinical trials with Glyxambi, increased urination in patients treated with Glyxambi (Glyxambi 
25 mg/5 mg: 2.6 %; Glyxambi 10 mg/5 mg: 1.4 %) was reported more frequently than for linagliptin 
and with similar frequency than for empagliflozin. Overall, the frequencies for Glyxambi have been 
comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, increased urination (including the predefined terms pollakiuria, 
polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin
(empagliflozin 10 mg: 3.5 %, empagliflozin 25 mg: 3.3 %) compared to placebo (1.4 %). Increased 
urination was mostly mild or moderate in intensity. The frequency of reported nocturia was 
comparable between placebo and empagliflozin (< 1 %).

Volume depletion

In clinical trials with Glyxambi, there was no notable difference in the frequency of volume depletion 
in patients treated with Glyxambi (Glyxambi 25 mg/5 mg: 0.4 %; Glyxambi 10 mg/5 mg: 0.8 %)
compared to the patients treated with empagliflozin and linagliptin. The frequencies have been 
comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, 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) was similar in patients 
treated with empagliflozin (empagliflozin 10 mg: 0.6 %, empagliflozin 25 mg: 0.4 %) and placebo 
(0.3 %). The frequency of volume depletion events was increased in patients 75 years and older treated 
with empagliflozin 10 mg (2.3 %) or empagliflozin 25 mg (4.3 %) compared to placebo (2.1 %).

Blood creatinine increased/Glomerular filtration rate decreased 

In clinical trials with Glyxambi, the frequency of patients with increased blood creatinine (Glyxambi 
25 mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0%) and decreased glomerular filtration rate (Glyxambi 25 
mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0.6%) has been comparable to those reported from the 
empagliflozin clinical trials.

In clinical trials with empagliflozin, the overall frequency of patients with increased blood creatinine 
and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood 
creatinine increased: empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular 
filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).



13

Elderly
In clinical trials, nineteen patients 75 years or older were treated with Glyxambi. No patient was older 
than 85 years. The safety profile of Glyxambi did not differ in the elderly. Based on empagliflozin 
experiences, elderly patients may be at increased risk of volume depletion (see sections 4.2, 4.4 and 
5.2)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Symptoms

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. There is no 
experience with doses above 800 mg in humans.

During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin 
(equivalent to 120 times the recommended dose) were generally well tolerated. There is no experience 
with doses above 600 mg in humans.

Treatment

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove 
unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinical 
measures as required.

The removal of empagliflozin by haemodialysis has not been studied. Linagliptin is not expected to be 
eliminated to a therapeutically significant degree by haemodialysis or peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering 
drugs, ATC code: A10BD19

Mechanism of action

Glyxambi combines two antihyperglycaemic medicinal products with complementary mechanisms of 
action to improve glycaemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose 
co-transporter (SGLT2) inhibitor, and linagliptin, DPP-4 inhibitor.

Empagliflozin

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 5,000 times more selective for SGLT2 versus SGLT1, the major transporter 
responsible for glucose absorption in the gut.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


14

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 mellitus by reducing renal 
glucose re-absorption. The amount of glucose removed by the kidney through this glucuretic
mechanism is dependent upon the blood glucose concentration and GFR. Inhibition of SGLT2 in 
patients with type 2 diabetes mellitus and hyperglycaemia leads to excess glucose excretion in the 
urine. In addition, initiation of empagliflozin increases excretion of sodium resulting in osmotic 
diuresis and reduced intravascular volume.

In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first 
dose of empagliflozin and was 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. 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 diuresis which may contribute to sustained and moderate 
reduction of blood pressure. The glucosuria, natriuresis and osmotic diuresis observed with 
empagliflozin may contribute to the improvement in cardiovascular outcomes.

Linagliptin

Linagliptin is an inhibitor of the enzyme DPP-4 an enzyme which is involved in the inactivation of the 
incretin hormones GLP-1 and GIP (glucagon-like peptide¬1, glucose-dependent insulinotropic 
polypeptide). These hormones are rapidly degraded by the enzyme DPP-4. Both incretin hormones are 
involved in the physiological regulation of glucose homeostasis. Incretins are secreted at a low basal 
level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin 
biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood 
glucose levels. Furthermore GLP-1 also reduces glucagon secretion from pancreatic alpha cells, 
resulting in a reduction in hepatic glucose output. Linagliptin binds very effectively to DPP-4 in a 
reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. 
Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus 
resulting in an overall improvement in the glucose homeostasis. Linagliptin binds selectively to DPP-4 
and exhibits a > 10,000-fold selectivity versus DPP-8 or DPP-9 activity in vitro.

Clinical efficacy and safety

A total of 2,173 patients with type 2 diabetes mellitus and inadequate glycaemic control were treated 
in clinical studies to evaluate the safety and efficacy of Glyxambi; 1,005 patients were treated with 
Glyxambi 10 mg empagliflozin/5 mg linagliptin or 25 mg empagliflozin/5 mg linagliptin. In clinical 
trials, patients were treated for up to 24 or 52 weeks.

Glyxambi added to metformin

In a factorial design study patients inadequately controlled on metformin were treated for 24-weeks 
with Glyxambi 10 mg/5 mg, Glyxambi 25 mg/5 mg, empagliflozin 10 mg, empagliflozin 25 mg or 
linagliptin 5 mg. The treatment with Glyxambi resulted in statistically significant improvements in 
HbA1c and fasting plasma glucose (FPG) compared to linagliptin 5 mg and also compared to 
empagliflozin 10 mg or 25 mg. Glyxambi also provided statistically significant improvements in body 



15

weight compared to linagliptin 5 mg. 

Table 2 Efficacy parameters in clinical study comparing Glyxambi to individual active substances 
as add-on therapy in patients inadequately controlled on metformin

Glyxambi
25 mg / 5 mg

Glyxambi
10 mg / 5 mg

Empagliflozin 
25 mg

Empagliflozin 
10 mg

Linagliptin 
5 mg

Primary endpoint: HbA1c ( %) – 24 weeks

Number of patients analysed 134 135 140 137 128

Baseline mean (SE) 7.90 (0.07) 7.95 (0.07) 8.02 (0.07) 8.00 (0.08) 8.02 (0.08)

Change from baseline at 
week 241:
- adjusted mean2 (SE)

-1.19 (0.06) -1.08 (0.06) -0.62 (0.06) -0.66 (0.06) -0.70 (0.06)

Comparison vs. empagliflozin1:
- adjusted mean2 (SE)
- 95.0 % CI
- p-value

vs. 25 mg
-0.58 (0.09)
-0.75, -0.41

<0.0001

vs. 10 mg
-0.42 (0.09)
-0.59, -0.25

<0.0001

-- -- --

Comparison vs. linagliptin 5 mg1:
- adjusted mean2 (SE)
- 95.0 % CI
- p-value

-0.50 (0.09)
-0.67, -0.32

<0.0001

-0.39 (0.09)
-0.56, -0.21

<0.0001

-- -- --

1 Last observation (prior to glycaemic rescue ) carried forward (LOCF)
2 Mean adjusted for baseline value and stratification 

In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5 %, the reduction 
from baseline in HbA1c at 24 weeks with Glyxambi 25 mg/5 mg was -1.8 % (p<0.0001 versus 
linagliptin 5 mg, p<0.001 versus empagliflozin 25 mg) and with Glyxambi 10 mg/ 5 mg -1.6 %
(p<0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg).

Overall, the effects on HbA1c reduction observed at 24 weeks were sustained at week 52.

Empagliflozin in patients inadequately controlled on metformin and linagliptin 

In patients inadequately controlled on maximally tolerated doses of metformin, open label linagliptin 
5 mg was added for 16 weeks. In patients inadequately controlled after this 16 week period, patients 
received double-blind treatment with either empagliglozin 10 mg, empagliflozin 25 mg or placebo for 
24-weeks. After this double-blind period, treatment with both empagliflozin 10 mg and empagliflozin 
25 mg provided statistically significant improvements in HbA1c, FPG and body weight compared to 
placebo; all patients continued treatment with metformin and linagliptin 5 mg during the study. A 
statistically significant greater number of patients with a baseline HbA1c ≥7.0 % treated with both 
doses of empagliflozin achieved a target HbA1c of <7 % compared to placebo (see Table 3). After 
24-weeks treatment with empagliflozin, both systolic and diastolic blood pressures were 
reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg 
and -1.3/-0.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 10 mg. 

After 24 weeks, rescue therapy was used in 4 (3.6 %) patients treated with empagliflozin 25 mg and in 
2 (1.8 %) patients treated with empagliflozin 10 mg, compared to 13 (12.0 %) patients treated with 
placebo (all patients on background metformin + linagliptin 5 mg).



16

Table 3 Efficacy parameters in the clinical study comparing empagliflozin to placebo as add-on 
therapy in patients inadequately controlled on metformin and linagliptin 5 mg

Metformin + linagliptin 5 mg
Empagliflozin 10 mg1 Empagliflozin 25 mg1 Placebo2

HbA1c ( %) - 24 weeks
3

N 109 110 106
Baseline (mean) 7.97 7.97 7.96
Change from baseline 
(adjusted mean)

-0.65 -0.56 0.14

Comparison vs. placebo
(adjusted mean) 
(95 % CI)2

-0.79
(-1.02, -0.55)

p<0.0001

-0.70
(-0.93, -0.46)

p<0.0001
Body Weight-24 weeks3

N 109 110 106
Baseline (mean) in kg 88.4 84.4 82.3
Change from baseline (adjusted 
mean)

-3.1 -2.5 -0.3

Comparison vs. placebo 
(adjusted mean) (95 % CI)1

-2.8
(-3.5, -2.1)
p<0.0001

-2.2
(-2.9, -1.5)
p<0.0001

Patients ( %) achieving HbA1c
<7 % with baseline HbA1c
≥7 % - 24 weeks4

N 100 107 100
Patients ( %) achieving A1C 
<7 %

37.0 32.7 17.0

Comparison vs.  placebo (odds 
ratio) (95 % CI)5

4.0
(1.9, 8.7)

2.9
(1.4, 6.1)

1 Patients randomized to the empagliflozin 10 mg or 25 mg groups were receiving Glyxambi 10 mg/5 mg or 25 mg/5 mg 
with background metformin

2 Patients randomized to the placebo group were receiving the placebo plus linagliptin 5 mg with background metformin
3 Mixed-effects models for repeated measurements (MMRM) on FAS (OC) includes baseline HbA1c, baseline eGFR 

(MDRD), geographical region, visit treatment,and treatment by visit interaction. For FPG, baseline FPG is also included.
For weight, baseline weight is also included.

4 Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints
5 Logistic regression on FAS (NCF) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, and treatment; 

based on patients with HbA1c of 7 % and above at baseline

In a pre-specified subgroup of patients with baseline HbA1c greater or equal than 8.5 % the reduction 
from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg was -1.3 % at 24 weeks (p<0.0001 
versus placebo and linagliptin 5 mg) and with empagliflozin 10 mg/ linagliptin 5 mg -1.3 % at 24 
weeks (p<0.0001 versus placebo and linagliptin 5 mg).

Linagliptin 5 mg in patients inadequately controlled on metformin and empagliflozin 10 mg or 
empagliflozin 25 mg

In patients inadequately controlled on maximally tolerated doses of metformin, open label 
empagliflozin 10 mg or empagliflozin 25 mg was added for 16 weeks. In patients inadequately 
controlled after this 16 week period, patients received double-blind treatment with either linagliptin 
5 mg or placebo for 24-weeks. After this double-blind period, treatment in both populations 
(metformin + empagliflozin 10 mg and metformin + empagliflozin 25 mg) linagliptin 5 mg provided 
statistically significant improvements in HbA1c compared to placebo; all patients continued treatment 
with metformin and empagliflozin during the study. A statistically significant greater number of 
patients with a baseline HbA1c ≥7.0 % and treated with linagliptin achieved a target HbA1c of <7 %
compared to placebo (see Table 4). 



17

Table 4 Efficacy parameters in clinical studies comparing Glyxambi 10 mg/5 mg to empagliflozin 
10 mg as well as Glyxambi 25 mg/5 mg to empagliflozin 25 mg as add-on therapy in 
patients inadequately controlled on empagliflozin 10 mg/25 mg and metformin

Metformin + 
empagliflozin 10 mg

Metformin + 
empagliflozin 25 mg

Linagliptin 5 mg Placebo Linagliptin 5 mg Placebo
HbA1c ( %) – 24 weeks

1

N 122 125 109 108
Baseline (mean) 8.04 8.03 7.82 7.88
Change from baseline 
(adjusted mean)

-0.53 -0.21 -0.58 -0.10

Comparison vs. placebo (adjusted 
mean) (95 % CI)

-0.32 (-0.52, -0.13)
p=0.0013

-0.47 (-0.66, -0.28)
p<0.0001

Patients ( %) achieving HbA1c
<7 % with baseline HbA1c ≥7 % –
24 weeks2

N 116 119 100 107
Patients ( %) achieving HbA1c <7 % 25.9 10.9 36.0 15.0
Comparison vs. placebo (odds ratio) 
(95 % CI)3

3.965 (1.771, 
8.876)

p=0.0008

4.429 (2.097, 9.353)
p<0.0001

Patients randomized to the linagliptin 5 mg group were receiving either fixed dose combination tablets Glyxambi 10 mg/5 mg 
plus metformin or fixed dose combination tablets Glyxambi 25 mg/5 mg plus metformin; patients randomized to the placebo 
group were receiving placebo plus empagliflozin 10 mg plus metformin or placebo plus empagliflozin 25 mg plus metformin
1 MMRM model on FAS (OC) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, visit, treatment, 

and treatment by visit interaction. For FPG, baseline FPG is also included.
2 Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints
3 Logistic regression on FAS (NCF) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, and treatment; 

based on patients with HbA1c of 7 % and above at baseline

Cardiovascular safety

Empagliflozin cardiovascular outcome (EMPA-REG OUTCOME) study

The double-blind, placebo-controlled EMPA-REG OUTCOME study compared pooled doses of 
empagliflozin 10 mg and 25 mg with placebo as adjunct to standard care therapy in patients with 
type 2 diabetes and established cardiovascular disease. A total of 7020 patients were treated 
(empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 
3.1 years. The mean age was 63 years, the mean HbA1c was 8.1 %, and 71.5 % were male. At 
baseline, 74 % of patients were being treated with metformin, 48 % with insulin, and 43 % with a 
sulfonylurea. About half of the patients (52.2 %) had an eGFR of 60-90 ml/min/1.73 m2, 17.8 % of 
45-60 ml/min/1.73 m2 and 7.7 % of 30-45 ml/min/1.73 m2.

At week 12, an adjusted mean (SE) improvement in HbA1c when compared to baseline of 0.11 % 
(0.02) in the placebo group, 0.65 % (0.02) and 0.71 % (0.02) in the empagliflozin 10 and 25 mg 
groups was observed. After the first 12 weeks glycaemic control was optimized independent of 
investigative treatment. Therefore the effect was attenuated at week 94, with an adjusted mean (SE) 
improvement in HbA1c of 0.08 % (0.02) in the placebo group, 0.50 % (0.02) and 0.55 % (0.02) in the 
empagliflozin 10 and 25 mg groups.

Empagliflozin was superior in preventing the primary combined endpoint of cardiovascular death, 
nonfatal myocardial infarction, or non-fatal stroke, as compared with placebo. The treatment effect 
was driven by a significant reduction in cardiovascular death with no significant change in non-fatal 
myocardial infarction, or non-fatal stroke. The reduction of cardiovascular death was comparable for 
empagliflozin 10 mg and 25 mg and confirmed by an improved overall survival (see Table 5).



18

Table 5 Treatment effect for the primary composite endpoint, its components and mortalitya

Placebo Empagliflozinb

N 2333 4687
Time to first event of CV death, non-fatal MI, 
or non-fatal stroke N (%)

282 (12.1) 490 (10.5)

Hazard ratio vs. placebo (95.02% CI)* 0.86 (0.74, 0.99)
p−value for superiority 0.0382

CV Death N (%) 137 (5.9) 172 (3.7)
Hazard ratio vs. placebo (95% CI) 0.62 (0.49, 0.77)
p-value <0.0001

Non-fatal MI N (%) 121 (5.2) 213 (4.5)
Hazard ratio vs. placebo (95% CI) 0.87 (0.70, 1.09)
p−value 0.2189

Non-fatal stroke N (%) 60 (2.6) 150 (3.2)
Hazard ratio vs. placebo (95% CI) 1.24 (0.92, 1.67)
p−value 0.1638

All-cause mortality N (%) 194 (8.3) 269 (5.7)
Hazard ratio vs. placebo (95% CI) 0.68 (0.57, 0.82)
p-value <0.0001

Non-CV mortality N (%) 57 (2.4) 97 (2.1)
Hazard ratio vs. placebo (95% CI) 0.84 (0.60, 1.16)

CV = cardiovascular, MI = myocardial infarction
a Treated set (TS), i.e. patients who had received at least one dose of study drug
b Pooled doses of empagliflozin 10 mg and 25 mg
* Since data from the trial were included in an interim analysis, a two-sided 95.02% confidence interval applied which 
corresponds to a p-value of less than 0.0498 for significance.

The efficacy for preventing cardiovascular mortality has not been conclusively established in patients 
using empagliflozin concomitantly with DPP-4 inhibitors or in Black patients because the 
representation of these groups in the EMPA-REG OUTCOME study was limited.

Heart failure requiring hospitalization 

In the EMPA-REG OUTCOME study, empagliflozin reduced the risk of heart failure requiring 
hospitalization compared with placebo (empagliflozin 2.7 %; placebo 4.1 %; HR 0.65, 95 % CI 0.50, 
0.85).

Nephropathy

In the EMPA-REG OUTCOME study, for time to first nephropathy event, the HR was 0.61 (95 % CI 
0.53, 0.70) for empagliflozin (12.7 %) vs placebo (18.8 %).

In addition, empagliflozin showed a higher (HR 1.82, 95 % CI 1.40, 2.37) occurrence of sustained 
normo- or micro-albuminuria (49.7 %) in patients with baseline macro-albuminuria compared with 
placebo (28.8 %).

Linagliptin cardiovascular and renal safety (CARMELINA) study

The double-blind, placebo-controlled CARMELINA study evaluated the cardiovascular and renal 
safety of linagliptin versus placebo as adjunct to standard care therapy in patients with type 2 diabetes 
and with increased CV risk evidenced by a history of established macrovascular or renal disease. A 
total of 6979 patients were treated (linagliptin 5 mg: 3494, placebo: 3485) and followed for a median 
of 2.2 years. The study population included 1211 (17.4 %) patients ≥ 75 years of age, the mean HbA1c
was 8.0 %, 63 % were male. Approximately 19 % of the population had an eGFR of 
45-60 mL/min/1.73 m2, 28 % of 30-45 mL/min/1.73 m2 and 15 % of <30 mL/min/1.73 m².

Linagliptin did not increase the risk of the combined endpoint of CV death, non-fatal myocardial 
infarction or non-fatal stroke (MACE-3) [HR=1.02; (95 % CI 0.89, 1.17); p=0.0002 for non-



19

inferiority], or the risk of combined endpoint of renal death, ESRD, 40% or more sustained decrease in 
eGFR [HR=1.04; (95 % CI 0.89, 1.22)]. In analyses for albuminuria progression (change from 
normoalbuminuria to micro-or macroalbuminuria, or from microalbuminuria to macroalbuminuria) the 
estimated hazard ratio was 0.86 (95 % CI 0.78, 0.95) for linagliptin versus placebo. In addition, 
linagliptin did not increase the risk of hospitalization for heart failure [HR=0.90; (95 % CI 0.74, 
1.08)]. No increased risk of CV death or all-cause mortality was observed. 

Safety data from this study was in line with previous known safety profile of linagliptin.

Linagliptin cardiovascular safety (CAROLINA) study

The double-blind parallel group CAROLINA study evaluated the cardiovascular safety of linagliptin 
versus glimepiride as adjunct to standard care therapy in patients with type 2 diabetes and with 
increased CV risk. A total of 6033 patients were treated (linagliptin 5 mg: 3023, glimepiride 1 mg to 
4 mg: 3010) and followed for a median of 6.25 years. The mean age was 64 years, the mean HbA1c 
was 7.15 %, and 60 % were male. Approximately 19 % of the population had an eGFR
<60 mL/min/1.73 m2.

The study was designed to demonstrate non-inferiority for the primary cardiovascular endpoint which 
was a composite of the first occurrence of cardiovascular death or a non-fatal myocardial infarction 
(MI) or a non-fatal stroke (3P-MACE). Linagliptin did not increase the risk of the combined endpoint 
of CV death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) [Hazard Ratio (HR)=0.98; 
(95 % CI 0.84, 1.14); p<0.0001 for non-inferiority], when added to standard of care in adult patients 
with type 2 diabetes with increased CV risk compared to glimepiride (see Table 6). 

Table 6 Major adverse cardiovascular events (MACE) and mortality by treatment group in the 
CAROLINA study

Linagliptin 5mg Glimepiride (1-4mg) Hazard Ratio
Number of 
Subjects 

(%)

Incidence 
Rate per 

1000 PY*

Number of 
Subjects (%)

Incidence 
Rate per 

1000 PY*

(95% CI)

Number of patients 3023 3010
Primary CV 
composite 
(Cardiovascular 
death, non-fatal MI, 
non-fatal stroke)

356 (11.8) 20.7 362 (12.0) 21.2 0.98 (0.84, 
1.14)**

All-cause mortality 308 (10.2) 16.8 336 (11.2) 18.4 0.91 (0.78,1.06)
CV death 169 (5.6) 9.2 168 (5.6) 9.2 1.00 (0.81, 1.24)
Hospitalization for 
heart failure (HHF)

112 (3.7) 6.4 92 (3.1) 5.3 1.21 (0.92, 1.59)

* PY=patient years
** Test on non-inferiority to demonstrate that the upper bound of the 95% CI for the hazard ratio is less than 1.3

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with
Glyxambi in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for 
information on paediatric use).



20

5.2 Pharmacokinetic properties

The rate and extent of absorption of empagliflozin and linagliptin in Glyxambi are equivalent to the 
bioavailability of empagliflozin and linagliptin when administered as individual tablets.The 
pharmacokinetics of empagliflozin and linagliptin as single agents have been extensively characterized 
in healthy subjects and patients with type 2 diabetes. Pharmacokinetics were generally similar in 
healthy subjects and in patients with type 2 diabetes.
Glyxambi showed a similar food effect as the individual active substances. Glyxambi can therefore be 
taken with or without food.

Empagliflozin

Absorption

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 area under the concentration-time curve (AUC) and Cmax were 1,870 nmol.h and 
259 nmol/L with empagliflozin 10 mg and 4,740 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.
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.

Distribution

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 %.

Biotransformation

No major metabolites of empagliflozin were detected in human plasma and the most abundant 
metabolites were three glucuronide conjugates (2-, 3-, and 6-O-glucuronide). Systemic exposure of 
each metabolite was less than 10 % of total drug-related material. In vitro studies suggest that the 
primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-
diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9.

Elimination

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.



21

Linagliptin

Absorption

After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly 
absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post-dose.

After once daily dosing of 5 mg linagliptin, steady-state plasma concentrations are reached by the third 
dose. Plasma AUC of linagliptin increased approximately 33 % following 5 mg doses at steady-state 
compared to the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin 
AUC were small (12.6 % and 28.5 %, respectively). Due to the concentration dependent binding of 
linagliptin to DPP-4, the pharmacokinetics of linagliptin based on total exposure is not linear; indeed 
total plasma AUC of linagliptin increased in a less than dose-proportional manner while unbound 
AUC increases in a roughly dose-proportional manner.

The absolute bioavailability of linagliptin is approximately 30 %. Co-administration of a high-fat meal 
with linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15 % but no 
influence on AUC0-72h was observed. No clinically relevant effect of Cmax and Tmax changes is 
expected; therefore linagliptin may be administered with or without food.

The steady state plasma AUCτ,ss and Cmax,ss concentrations of linagliptin were 153 nmol*hr/L and 12.9 
nmol/L for linagliptin 5 mg once daily for 7 days.

Distribution

As a result of tissue binding, the mean apparent volume of distribution at steady-state following a 
single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1,110 litres, indicating 
that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is 
concentration-dependent, decreasing from about 99 % at 1 nmol/L to 75-89 % at ≥30 nmol/L, 
reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high 
concentrations, where DPP-4 is fully saturated, 70-80 % of linagliptin was bound to other plasma 
proteins than DPP-4, hence 30-20 % were unbound in plasma.

Biotransformation

Following a [14C] linagliptin oral 10 mg dose, approximately 5 % of the radioactivity was excreted in 
urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with 
a relative exposure of 13.3 % of linagliptin at steady-state was detected which was found to be 
pharmacologically inactive and thus to not contribute to the plasma DPP-4 inhibitory activity of 
linagliptin.

Elimination

Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life 
(terminal half-life for linagliptin more than 100 hours) that is mostly related to the saturable, tight 
binding of linagliptin to DPP-4 and does not contribute to the accumulation of the medicinal product. 
The effective half-life for accumulation of linagliptin, as determined from oral administration of 
multiple doses of 5 mg linagliptin, is approximately 12 hours.
Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85 % of
the administered radioactivity was eliminated in faeces (80 %) or urine (5 %) within 4 days of dosing. 
Renal clearance at steady-state was approximately 70 mL/min.

Renal impairment

Empagliflozin

In patients with mild, moderate or severe renal impairment (eGFR <30 to <90 mL/min/1.73 m2) and 



22

patients with kidney failure or 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 eGFR leading to an 
increase in drug exposure (see section 4.2).

Linagliptin

A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg 
dose) in patients with varying degrees of chronic renal insufficiency compared to subjects with normal 
renal function. The study included patients with renal insufficiency classified on the basis of creatinine 
clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min), as 
well as patients with ESRD on haemodialysis. In addition patients with T2DM and severe renal 
impairment (<30 mL/min) were compared to T2DM patients with normal renal function.
Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was 
comparable to healthy subjects. In moderate renal impairment, a moderate increase in exposure of 
about 1.7-fold was observed compared with control. Exposure in T2DM patients with severe RI was 
increased by about 1.4-fold compared to T2DM patients with normal renal function. Steady-state 
predictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that of 
patients with moderate or severe renal impairment. In addition, linagliptin is not expected to be 
eliminated to a therapeutically significant degree by haemodialysis or peritoneal dialysis (see 
section 4.2).

Hepatic impairment

Empagliflozin
In patients with mild, moderate and severe hepatic insufficiency (Child-Pugh classification), mean 
AUC and Cmax of empagliflozin increased (AUC by 23 %, 47 %, 75 % and Cmax by 4 %, 23 %,48 %) 
compared to subjects with normal hepatic function (see section 4.2). 

Linagliptin
In non-diabetic patients with mild, moderate and severe hepatic insufficiency (according to the Child-
Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy subjects following 
administration of multiple 5 mg doses of linagliptin.

Body mass index

No dosage adjustment is necessary for Glyxambi based on body mass index. Body mass index had no 
clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population 
pharmacokinetic analysis.

Gender

Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based 
on population pharmacokinetic analysis.

Race

No clinically relevant difference in pharmacokinetics of empagliflozin and linagliptin were seen in 
population pharmacokinetic analysis and dedicated phase I studies.

Elderly

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin or 



23

linagliptin based on population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had 
comparable plasma concentrations of linagliptin compared to younger subjects.

Paediatric patients

Empagliflozin
A paediatric Phase 1 study examined the pharmacokinetics and pharmacodynamics of empagliflozin
(5 mg, 10 mg and 25 mg) in children and adolescents ≥10 to <18 years of age with type 2 diabetes 
mellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with those 
found in adult subjects.

Linagliptin
A paediatric Phase 2 study examined the pharmacokinetics and pharmacodynamics of 1 mg and 5 mg 
linagliptin in children and adolescents ≥10 to <18 years of age with type 2 diabetes mellitus. The 
observed pharmacokinetic and pharmacodynamic responses were consistent with those found in adult 
subjects. Linagliptin 5 mg showed superiority over 1 mg with regard to trough DPP-4 inhibition (72% 
vs 32%, p=0.0050) and a numerically larger reduction with regard to adjusted mean change from 
baseline in HbA1c (-0.63% vs -0.48%, n.s.). Due to the limited nature of the data set the results should 
be interpreted cautiously.

Drug interactions

No drug interaction studies have been performed with Glyxambi and other medicinal products; 
however, such studies have been conducted with the individual active substances.

In vitro assessment of empagliflozin

Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. 
Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-drug 
interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly 
administered substrates of these enzymes are therefore considered unlikely.

In vitro data suggest that the primary route of metabolism of empagliflozin in humans is 
glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and 
UGT2B7.

Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but 
not Organic Anion Transporter 1 (OAT1) and Organic Cation Transporter 2 (OCT2). Empagliflozin is 
a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is
considered unlikely to cause interactions with medicinal products that are P-gp substrates. Co-
administration of digoxin, a P-gp substrate, with empagliflozin resulted in a 6 % increase in AUC and 
14 % increase in Cmax of digoxin. These changes were not considered to be clinically meaningful.

Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3
in vitro at clinically relevant plasma concentrations and, as such, drug-drug interactions with
substrates of these uptake transporters are considered unlikely.

In vitro assessment of linagliptin

Linagliptin was a substrate for OATP8-, OCT2-, OAT4-, OCTN1- and OCTN2, suggesting a possible 
OATP8-mediated hepatic uptake, OCT2-mediated renal uptake and OAT4-, OCTN1- and OCTN2-
mediated renal secretion and reabsorption of linagliptin in vivo. OATP2, OATP8, OCTN1, OCT1 and 
OATP2 activities were slightly to weakly inhibited by linagliptin.



24

5.3 Preclinical safety data

General toxicity studies in rats up to 13 weeks were performed with the combination of empagliflozin 
and linagliptin. 
Focal areas of hepatocellular necrosis were found in the combination groups at ≥15: 30 mg/kg 
linagliptin: empagliflozin (3.8 times the clinical exposure for linagliptin and 7.8 times the clinical 
exposure for empagliflozin) as well as in the group treated with empagliflozin alone but not in the 
control group. The clinical relevance of this finding remains uncertain.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, the combination of 
empagliflozin and linagliptin was not teratogenic and did not show maternal toxicity. Adverse effects 
on renal development were not observed after administration of empagliflozin alone, linagliptin alone 
or after administration of the combined products.

Empagliflozin

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.

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 with empagliflozin in rats, reduced weight gain in 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.



25

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.

Linagliptin

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 Cynomolgus monkeys, signs of toxicity were observed at 
exposures greater than 300-times the clinical dose of linagliptin. 

Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats. At 
exposures greater than 1,500-times the clinical exposure, side effects on reproductive organs, thyroid 
and the lymphoid organs were seen in rats. Strong pseudo-allergic reactions were observed in dogs at 
medium doses, secondarily causing cardiovascular changes, which were considered dog-specific. 
Liver, kidneys, stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs of 
toxicity in Cynomolgus monkeys at more than 450-times the clinical exposure. At more than 
100-times clinical exposure, irritation of the stomach was the major finding in monkeys.

Oral 2-year carcinogenicity studies in rats and mice revealed no evidence of carcinogenicity in rats or 
male mice. A significantly higher incidence of malignant lymphomas only in female mice at the 
highest dose (>200-times human exposure) is not considered relevant for humans. Based on these 
studies there is no concern for carcinogenicity in humans.

Linagliptin had no adverse effects on fertility or early embryonic development at exposures greater 
than 900-times the clinical exposure. Linagliptin administered during the period of organogenesis was 
not teratogenic. Only at maternally toxic doses, linagliptin caused a slight retardation of skeletal 
ossification in the rat and increased embryofoetal loss in the rabbit.

In the pre- and postnatal toxicity study with linagliptin in rats, reduced weight gain in offspring was 
observed at maternal exposures approximately 1,500-times the maximal clinical exposure to 
linagliptin. No such effect was seen at systemic exposure 49-times the maximal clinical exposure to 
linagliptin.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glyxambi 10 mg/5 mg film-coated tablets
Tablet core
Mannitol (E421)
Pre-gelatinised starch (maize)
Maize starch
Copovidone (K-value nominally 28)
Crospovidone (Type B)
Talc
Magnesium stearate

Film coating
Hypromellose 2910
Mannitol (E421)
Talc
Titanium dioxide (E171)
Macrogol 6000



26

Iron oxide yellow (E172)

Glyxambi 25 mg/5 mg film-coated tablets
Tablet core
Mannitol (E421)
Pre-gelatinised starch (maize)
Maize starch
Copovidone (K-value nominally 28)
Crospovidone (Type B)
Talc
Magnesium stearate

Film coating
Hypromellose 2910
Mannitol (E421)
Talc
Titanium dioxide (E171)
Macrogol 6000
Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

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 7 x 1, 10 x 1, 14 x 1, 28 x 1, 30 x 1, 60 x 1, 70 x 1, 90 x 1 and 100 x 1 film-coated 
tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany



27

8. MARKETING AUTHORISATION NUMBERS

Glyxambi 10 mg/5 mg film-coated tablets
EU/1/16/1146/001 (7 x 1 film-coated tablets)
EU/1/16/1146/002 (10 x 1 film-coated tablets)
EU/1/16/1146/003 (14 x 1 film-coated tablets)
EU/1/16/1146/004 (28 x 1 film-coated tablets)
EU/1/16/1146/005 (30 x 1 film-coated tablets)
EU/1/16/1146/006 (60 x 1 film-coated tablets)
EU/1/16/1146/007 (70 x 1 film-coated tablets)
EU/1/16/1146/008 (90 x 1 film-coated tablets)
EU/1/16/1146/009 (100 x 1 film-coated tablets)

Glyxambi 25 mg/5 mg film-coated tablets
EU/1/16/1146/010 (7 x 1 film-coated tablets)
EU/1/16/1146/011 (10 x 1 film-coated tablets)
EU/1/16/1146/012 (14 x 1 film-coated tablets)
EU/1/16/1146/013 (28 x 1 film-coated tablets)
EU/1/16/1146/014 (30 x 1 film-coated tablets)
EU/1/16/1146/015 (60 x 1 film-coated tablets)
EU/1/16/1146/016 (70 x 1 film-coated tablets)
EU/1/16/1146/017 (90 x 1 film-coated tablets)
EU/1/16/1146/018 (100 x 1 film-coated tablets)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 November 2016

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu


28

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



29

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
GERMANY

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:

 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



30

ANNEX III

LABELLING AND PACKAGE LEAFLET



31

A. LABELLING



32

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Glyxambi 10 mg/5 mg film-coated tablets
empagliflozin/linagliptin

2. STATEMENT OF ACTIVE SUBSTANCES

Each tablet contains 10 mg empagliflozin and 5 mg linagliptin.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
10 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets
30 x 1 film-coated tablets
60 x 1 film-coated tablets
70 x 1 film-coated tablets
90 x 1 film-coated tablets
100 x 1 film-coated 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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



33

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBERS

EU/1/16/1146/001 7 x 1 film-coated tablets
EU/1/16/1146/002 10 x 1 film-coated tablets
EU/1/16/1146/003 14 x 1 film-coated tablets
EU/1/16/1146/004 28 x 1 film-coated tablets
EU/1/16/1146/005 30 x 1 film-coated tablets
EU/1/16/1146/006 60 x 1 film-coated tablets
EU/1/16/1146/007 70 x 1 film-coated tablets
EU/1/16/1146/008 90 x 1 film-coated tablets
EU/1/16/1146/009 100 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Glyxambi 10 mg/5 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN:
NN:



34

MINIMUM PARTICULARS TO APPEAR ON BLISTERS

BLISTER (perforated)

1. NAME OF THE MEDICINAL PRODUCT

Glyxambi 10 mg/5 mg tablets
empagliflozin/linagliptin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



35

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Glyxambi 25 mg/5 mg film-coated tablets
empagliflozin/linagliptin

2. STATEMENT OF ACTIVE SUBSTANCES

Each tablet contains 25 mg empagliflozin and 5 mg linagliptin.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

7 x 1 film-coated tablets
10 x 1 film-coated tablets
14 x 1 film-coated tablets
28 x 1 film-coated tablets
30 x 1 film-coated tablets
60 x 1 film-coated tablets
70 x 1 film-coated tablets
90 x 1 film-coated tablets
100 x 1 film-coated 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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



36

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBERS

EU/1/16/1146/010 7 x 1 film-coated tablets
EU/1/16/1146/011 10 x 1 film-coated tablets
EU/1/16/1146/012 14 x 1 film-coated tablets
EU/1/16/1146/013 28 x 1 film-coated tablets
EU/1/16/1146/014 30 x 1 film-coated tablets
EU/1/16/1146/015 60 x 1 film-coated tablets
EU/1/16/1146/016 70 x 1 film-coated tablets
EU/1/16/1146/017 90 x 1 film-coated tablets
EU/1/16/1146/018 100 x 1 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Glyxambi 25 mg/5 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN:
NN:



37

MINIMUM PARTICULARS TO APPEAR ON BLISTERS

BLISTER (perforated)

1. NAME OF THE MEDICINAL PRODUCT

Glyxambi 25 mg/5 mg tablets
empagliflozin/linagliptin

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



38

B. PACKAGE LEAFLET



39

Package leaflet: Information for the patient

Glyxambi 10 mg/5 mg film-coated tablets
Glyxambi 25 mg/5 mg film-coated tablets

empagliflozin/linagliptin

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Glyxambi is and what it is used for
2. What you need to know before you take Glyxambi
3. How to take Glyxambi
4. Possible side effects
5. How to store Glyxambi
6. Contents of the pack and other information

1. What Glyxambi is and what it is used for

Glyxambi is an anti-diabetic medicine that contains two active substances called empagliflozin and 
linagliptin:
 Empagliflozin works by blocking a protein in the kidneys called sodium glucose co-transporter 

2 (SGLT2). SGLT2 prevents glucose from being excreted in urine by absorbing glucose back 
into the bloodstream as blood is being filtered in the kidneys. By blocking this protein, the 
medicine causes glucose (blood sugar), sodium (salt) and water to be removed via the urine. 
This helps to lower blood glucose levels, which are too high because of your type 2 diabetes.

 Linagliptin works in a different way, namely by enabling the pancreas to produce more insulin
to lower blood glucose levels. It does this by blocking a protein called DPP-4.

Glyxambi is added to metformin and/or sulphonylurea (SU) to treat type 2 diabetes in adult patients 
whose diabetes cannot be controlled when treated with metformin and/or sulphonylurea in 
combination with empagliflozin, or when treated with metformin and/or sulphonylurea in combination 
with linagliptin.
Glyxambi can also be used as an alternative to taking both empagliflozin and linagliptin as single 
tablets. In this case, do not continue taking any one of those tablets separately, if your are taking this 
medicine.

It is important that you continue with your diet and exercise plan as recommended by your doctor, 
pharmacist or nurse.



40

What is type 2 diabetes?
Type 2 diabetes is a condition that comes from both your genes and your lifestyle. If you have type 2 
diabetes, your pancreas may not make enough insulin to control the level of glucose in your blood, and 
your body is unable to use its own insulin effectively. This results in high levels of sugar in your 
blood, which can lead to medical problems like heart disease, kidney disease, blindness, and poor 
circulation in your limbs.

2. What you need to know before you take Glyxambi

Do not take Glyxambi:
- if you are allergic to empagliflozin, linagliptin, any other SGLT2 inhibitor (e.g. dapagliflozin, 

canagliflozin), any other DPP-4 inhibitor (e.g. sitagliptin, vildagliptin), or any of the other 
ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor, before taking this medicine, and during treatment:
 about what you can do to prevent dehydration
 if you have type 1 diabetes (your body does not produce any insulin). Glyxambi should not be 

used to treat type 1 diabetes.
 if you experience rapid weight loss, feeling sick or being sick, stomach pain, excessive thirst, 

fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to your breath, 
a sweet or metallic taste in your mouth, or a different odour to your urine or sweat. Contact a 
doctor or the nearest hospital straight away as these symptoms could be a sign of “diabetic 
ketoacidosis” – a rare, but serious, sometimes life-threatening problem you can get with 
diabetes because of increased levels of “ketone bodies” in your urine or blood, seen in tests. The 
risk of developing diabetic ketoacidosis may be increased with prolonged fasting, excessive
alcohol consumption, dehydration or sudden reductions in insulin dose, or a higher need of 
insulin due to major surgery or serious illness.

 if you are taking other anti-diabetic medicines known as “sulphonylurea” (e.g. glimepiride, 
glipizide) and/or insulin. Your doctor may want to reduce your dose of these medicines when 
you take them together with Glyxambi, in order to avoid too low blood sugar (hypoglycaemia).

 if you have or have had a disease of the pancreas.
 if you have serious kidney problems. Your doctor may ask you to take a different medicine.
 if you are 75 years old or older, as increased passing of urine due to the medicine may affect 

fluid balance in your body and increase your risk of dehydration.For possible signs of 
dehydration, see section 4.

 if you are 75 years old or older as starting this medicine above 75 years is not recommended .

Contact your doctor if you experience any of the following during treatment with Glyxambi:
 if you develop symptoms of acute pancreatitis, like persistent, severe abdominal pain. Possible 

signs are listed in section 4, ‘Possible side effects’. Your doctor may need to change your 
treatment.

 if you are being sick, have diarrhoea or fever, or if you are not able to eat or drink. These 
conditions can cause dehydration. Your doctor may ask you to stop taking Glyxambi until you 
recover, to prevent loss of too much body fluid.

 if you have a serious infection of the kidney or the urinary tract with fever. Your doctor may ask 
you to stop taking Glyxambi until you have recovered.

 if you encounter blistering of the skin it may be a sign for a condition called bullous 
pemphigoid. Your doctor may ask you to stop Glyxambi.

Talk to your doctor immediately if you develop a combination of symptoms of pain, tenderness, 
redness, or swelling of the genitals or the area between the genitals and the anus with fever or feeling 
generally unwell. These symptoms could be a sign of a rare but serious or even life-threatening 
infection, called necrotising fasciitis of the perineum or Fournier´s gangrene which destroys the tissue 
under the skin. Fournier’s gangrene has to be treated immediately.



41

Foot care
Like for all diabetic patients it is important to check your feet regularly and adhere to any other advice 
regarding foot care given by your health care professional.

Kidney function
Before you start treatment with Glyxambi and regularly during treatment, your doctor will check how 
well your kidneys are working.

Urine glucose
Because of how this medicine works, your urine will test positive for sugar while you are taking this 
medicine.

Children and adolescents
This medicine is not recommended for children and adolescents under 18 years, because it has not 
been studied in these patients.

Other medicines and Glyxambi
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
In particular, you should tell your doctor if you are using the following medicines:
 other anti-diabetic medicines, such as insulin or a sulphonylurea. Your doctor may want to 

lower the dose of these other medicines, to prevent your blood sugar levels from getting too 
low.

 medicines used to remove water from your body (diuretics). Your doctor may ask you to stop 
taking Glyxambi.

 medicines that might have an effect on the break down of empagliflozin or linagliptin in your 
body such as rifampicin (an antibiotic used to treat tuberculosis) or certain medicines used to 
treat seizures (such as carbamazepine, phenobarbital or phenytoin). The effect of Glyxambi may 
be reduced.

Pregnancy, breast-feeding and fertility
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for 
advice before taking this medicine.
It is not known whether Glyxambi is harmful to the unborn child. As a precautionary measure it is 
preferrable to avoid the use of this medicine during pregnancy.
It is not known whether the active substances of Glyxambi pass into human breast milk. Do not use 
this medicine if you are breast-feeding.

It is not known wheather Glyxambi has an effect on the fertility in humans.

Driving and using machines
Glyxambi has minor influence on the ability to drive and use machines.

Taking this medicine in combination with sulphonylureas or insulin, can cause your blood sugar levels 
to drop too low (hypoglycaemia), which may cause symptoms such as shaking, sweating and changes
in vision, and may affect your ability to drive and use machines. Do not drive or use any tools or 
machines, if you experience any of these symptoms while taking Glyxambi.

3. How to take Glyxambi

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.

How much to take
The usual starting dose is 10 mg empagliflozin plus 5 mg linagliptin once a day. For this dose 
Glyxambi is available as 10 mg/5 mg film coated tablets.



42

Your doctor will decide whether you need to increase your dose to one film-coated tablet of Glyxambi 
25 mg/5 mg (25 mg empagliflozin plus 5 mg linagliptin) once a day. If you already take 25 mg 
empagliflozin and 5 mg linagliptin as separate tablets and you switch to Glyxambi, you can start 
directly with Glyxambi 25 mg/5 mg.

Renal impairment:
Talk to your doctor if you have kidney problems. Your doctor may limit your dose or decide to use an 
alternative medicine.

Hepatic impairment:
Talk to your doctor in case you suffer from severe hepatic impairment. Glyxambi is not recommended 
and your doctor may decide to use an alternative medicine.

Elderly:
There is very little experience in patients aged 75 years or older. Treatment with Glyxambi should not 
be started in patients above the age of 75.

Taking this medicine
 Swallow the tablet whole with water.
 You can take Glyxambi with or without food.
 You can take the tablet at any time of the day. However, try to take it at the same time each day.

This will help you to remember to take it.

Your doctor may prescribe Glyxambi together with another anti-diabetic medicine. Remember to take 
all medicines as directed by your doctor to achieve the best results for your health.

Diet and exercise can help your body to use its blood sugar better. It is important to stay on the diet 
and exercise program recommended by your doctor during treatment with this medicine.

If you take more Glyxambi than you should
If you take more of this medicine than you should, immediately talk to a doctor or go to a hospital. 
Take the medicine pack with you.

If you forget to take Glyxambi
What to do if you forget to take a tablet depends on how long it is until your next dose:
 If it is 12 hours or more until your next dose, take Glyxambi as soon as you remember. Then 

take your next dose at the usual time.
 If it is less than 12 hours until your next dose, skip the missed dose. Then take your next dose at 

the usual time.
 Do not take a double dose of this medicine to make up for a forgotten dose.

If you stop taking Glyxambi
Do not stop taking this medicine without first consulting your doctor. Your blood sugar levels may 
increase when you stop taking Glyxambi.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.



43

Contact a doctor or the nearest hospital straight away if you have any of the following side 
effects:

Diabetic ketoacidosis, seen rarely (may affect up to 1 in 1,000 people)
These are the signs of diabetic ketoacidosis (see also section 2, ‘Warnings and precautions’):
– increased levels of “ketone bodies” in your urine or blood
– rapid weight loss
– feeling sick or being sick
– stomach pain
– excessive thirst
– fast and deep breathing
– confusion
– unusual sleepiness or tiredness
– a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your 

urine or sweat.

This may occur regardless of blood glucose level. Your doctor may decide to temporarily or 
permanently stop your treatment with this medicine.

Contact your doctor immediately if you notice any of the following side effects:

Allergic reactions, seen uncommonly (may affect up to 1 in 100 people)
This medicine may cause allergic reactions, which may be serious, including hives (urticaria) and 
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing 
(angioedema).

Inflammation of the pancreas (pancreatitis), seen uncommonly 
This medicine may cause pancreatitis, which usually shows as persistent, severe abdominal (stomach) 
pain that might reach through to your back, often accompanied by feeling sick or being sick. Your
doctor will need to change your treatment.

Low blood sugar (hypoglycaemia), seen commonly (may affect up to 1 in 10 people)
If you take Glyxambi with another medicine that can cause low blood sugar, such as a sulphonylurea 
or insulin, you are at risk of getting too low blood sugar (hypoglycaemia). The signs of too low blood 
sugar may include:
 shaking, sweating, feeling very anxious or confused, fast heart beat
 excessive hunger, headache

Your doctor will tell you how to treat low blood sugar levels and what to do if you get any of the signs 
above. If you have symptoms of low blood sugar, eat glucose tablets, a high sugar snack or drink fruit 
juice. Measure your blood sugar if possible and rest.

Urinary tract infection, seen commonly
The signs of urinary tract infection are:
 burning sensation when passing urine
 urine that appears cloudy
 pain in the pelvis, or mid-back pain (when kidneys are infected)

An urge to pass urine or more frequent urination may be due to the way this medicine works, but as 
they can also be signs of urinary tract infection, if you note an increase in such symptoms, you should 
also contact your doctor.

Loss of body fluid (dehydration), seen uncommonly
The signs of dehydration are not specific, but may include:
 unusual thirst
 lightheadedness or dizziness upon standing
 fainting or loss of consciousness



44

Other side effects while taking Glyxambi:

Seen commonly
 genital yeast infection like thrush
 inflamed nose or throat (nasopharyngitis)
 cough
 passing more urine than usual or needing to pass urine more often
 itching
 skin rash
 increased blood enzyme amylase
 increased pancreas enzyme lipase
 thirst

Seen uncommonly
 straining or pain when emptying the bladder
 laboratory blood tests may show changes in blood fat levels, an increase in the amount of red 

blood cells (increase in haematocrit), and changes related to kidney function (decrease in 
filtration rate and increase in blood creatinine)

Seen rarely
 sore in the mouth

Frequency not known (cannot be estimated from the available data)
 blistering of skin (bullous pemphigoid)
 necrotising fasciitis of the perineum or Fournier´s gangrene, a serious soft tissue infection of the 

genitals or the area between the genitals and the anus

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Glyxambi

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP.
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not use this medicine if you notice that the packaging is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Glyxambi contains
- The active substances are empagliflozin and linagliptin. Each film-coated tablet contains 10 mg 

empagliflozin and 5 mg linagliptin.
- The other ingredients are:

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45

Tablet core: mannitol (E421), pre-gelatinised starch (maize), maize starch, copovidone, 
crospovidone, talc and magnesium stearate.
Film coating: hypromellose, mannitol (E421), talc, titanium dioxide (E171), macrogol 6000 and 
iron oxide yellow (E172).

- The active substances are empagliflozin and linagliptin. Each film-coated tablet contains 25 mg 
empagliflozin and 5 mg linagliptin.

- The other ingredients are:
Tablet core: mannitol (E421), pre-gelatinised starch (maize), maize starch, copovidone, 
crospovidone, talc and magnesium stearate.
Film coating: hypromellose, mannitol (E421), talc, titanium dioxide (E171), macrogol 6000 and 
iron oxide red (E172).

What Glyxambi looks like and contents of the pack

Glyxambi 10 mg/5 mg film-coated tablets (tablets) are pale yellow, arc triangular, flat faced and 
bevel-edged. They have “10/5” on one side and the Boehringer Ingelheim logo on the other side.Each 
side of the tablet is 8 mm long.

Glyxambi 25 mg/5 mg film-coated tablets (tablets) are pale pink, arc triangular, flat faced and bevel-
edged. They have “25/5” on one side and the Boehringer Ingelheim logo on the other side. Each side 
of the tablet is 8 mm long.

Glyxambi is available in PVC/PVDC/aluminium perforated unit dose blisters.

The pack sizes are 7 x 1, 10 x 1, 14 x 1, 28 x 1, 30 x 1, 60 x 1, 70 x 1, 90 x 1 and 100 x 1 film-coated 
tablets.

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



46

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Belgique/Belgien
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Lilly Deutschland GmbH
Tel. +49 (0) 6172 273 2222

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Lilly S.A.
Tel: +34 91 663 50 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Lilly France SAS
Tél: +33 1 55 49 34 34

Portugal
Boehringer Ingelheim, Unipessoal, Lda., 
Tel: +351 21 313 53 00

Lilly Portugal Produtos Farmacêuticos, Lda
Tel: +351 21 412 66 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucureşti
Tel: +40 21 302 28 00



47

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Eli Lilly and Company (Ireland) Limited
Tel: +353 1 661 4377

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG 
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Eli Lilly Italia S.p.A.
Tel: +39 05 5425 71

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

Eli Lilly and Company Limited
Tel: +44 1256 315 000

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET