Mandatory in

File information TD Printfile 1.See subsections below for additional information 1 T he dose of insulin as background medication was to be stable
• Hepatic insufficiency, acute alcohol intoxication, alcoholism Diagnosis including haematocrit) and electrolytes is recommended for these human uptake transporters at clinically relevant plasma Improvement of surrogate markers of beta cell function including

­ mpagliflozin
E 2 Identified side effects of e ­ mpagliflozin as add-on Placebo
E ­ mpagliflozin ­Empagliflozin
E
Issue date of TD: 06.03.2015 Yes Yes (see section Interactions) Lactic acidosis is characterised by acidotic dyspnoea, abdominal patients receiving ­empagliflozin. Temporary interruption of concentrations and, as such, drug-drug interactions with sub- ­ mpagliflozin monotherapy for the first 18 weeks Homeostasis Model Assessment-B (HOMA-β) and proinsulin to
3 Identified side effects, based on EU m 2 Eight treatment arms: 4 combination treatments of to ­metformin therapy 10 mg 25 mg
pain and hypothermia followed by coma. Diagnostic laboratory treatment should be considered until the fluid loss is corrected. strates of these uptake transporters are considered unlikely. ­ etformin SmPC insulin ratio were noted. In addition urinary glucose excretion
PPM SKU: P038623 No Yes Special warnings and precautions findings are decreased blood pH, plasma lactate levels above 4 Long-term treatment with m ­ etformin has been associated with ­empagliflozin (5 mg or 12.5 mg BID) and m­ etformin (500 or triggers calorie loss, associated with body fat loss and body

­Metformin HCl
Patients (%) achieving 4.8 21.2 23.0
PPM SKU version:  -001 No Yes General 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. Urinary tract infections In vivo assessment of drug interactions a decrease in vitamin B12 absorption which may result in clini- 1000 mg BID) and treatment with the individual components of weight reduction.
weight loss of >5%2
In case of lactic acidosis, the patient should be hospitalised cally significant vitamin B12 deficiency (e.g. megaloblastic ­empagliflozin (10 mg or 25 mg QD) or m
­ etformin (500 mg or
Issue date of artwork: 06.10.2015 No Yes
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) should not be
E immediately (see section Overdose). The overall frequency of urinary tract infection reported as No clinically meaningful pharmacokinetic interactions were anaemia) 1000 mg BID). The glucosuria observed with e
­ mpagliflozin is accompanied by N 207 217 213
Print colors: PAN BLACK No Yes used in patients with type 1 diabetes. adverse event was higher in patients treated with e ­ mpagliflozin observed when e ­ mpagliflozin was coadministered with other 5 Gastrointestinal symptoms such as nausea, vomiting, diar- 3 T his was a fixed-dose combination of e­ mpagliflozin with lina- mild diuresis which may contribute to sustained and moderate

Mat. No. Pack. Site: 309887-01
Min. font size: 7pt BISansNEXT
Legend case version: V4.0 01/OCT/2012 (please do not change or remove it)
Technical information
a = Batch No.
c = Manufacturing date
Technical colors
BI-Diecut-Legendcase
Additional Requirements of Packaging site
Template name: TD-PI_850x378_85x55
Only for BI-internal use, Template according to Drawing no.: SP-14-0053-001-B_Index_d
Jardiance Duo®
No Yes
Example
Technical information
Control Code Type: Laetus Code
Formulation
All information for ISEE mark
b = Expiry date are given by responsible OPU. 1 film-coated tablet contains 5 or 12.5 mg
d = Price/Sample/Clinic See „Additional PPM require- D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-
furanyl]oxy]phenyl]methyl]phenyl]-, (1S) (= ­empagliflozin) and
ments OPU“ in File Attr.
500 mg, 850 mg, or 1000 mg N,N-dimethylimidodicarbonimidic
Free area Gluepoints diamide hydrochloride (= ­metformin hydrochloride)
Indications
­Empagliflozin + ­Metformin HCl (JARDIANCE DUO) is indicated as
Index: g an adjunct to diet and exercise to improve glycaemic control in
adult patients with type 2 diabetes mellitus
• when treatment with both e ­ mpagliflozin and ­metformin is
appropriate
• inadequately controlled with ­metformin or ­empagliflozin alone
• inadequately controlled with ­empagliflozin or ­metformin in
combination with other glucose-lowering products including
insulin (see section Clinical Trials)
• already treated with e­ mpagliflozin and ­metformin co-adminis-
tered as separate tablets
Dosage and administration
The recommended dose is one tablet twice daily. The dosage
should be individualised on the basis of the patient’s current
regimen, effectiveness, and tolerability while not exceeding the
maximum recommended daily dose of 25 mg of e ­ mpagliflozin
and 2000 mg of ­metformin.
• In patients not adequately controlled on ­metformin alone or in
combination with other products, including insulin, the recom-
mended starting dose of E ­ mpagliflozin + ­Metformin HCl
(­JARDIANCE DUO) should provide ­empagliflozin 5 mg twice
daily (10 mg total daily dose) and the dose of ­metformin similar
to the dose already being taken. In patients tolerating a total
daily dose of e­ mpagliflozin 10 mg, the dose can be increased to
a total daily dose of ­empagliflozin 25 mg.
• Patients already treated with e
­ mpagliflozin should continue to
take the same daily dose of ­empagliflozin.
• Patients switching from separate tablets of ­empagliflozin
abcd (10 mg or 25 mg total daily dose) and ­metformin to
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) should
receive the same daily dose of ­empagliflozin and ­metformin
already being taken or the nearest therapeutically appropriate
dose of m
­ etformin.
When E ­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) is used
Jardiance Duo®
in combination with a sulphonylurea and/or insulin, a lower dose
of sulphonylurea and/or insulin may be required to reduce the
risk of hypoglycaemia (see sections Interactions and Side
­ etformin HCl
M Effects).
For the different doses of ­metformin, ­Empagliflozin +
­Empagliflozin
­Metformin HCl (­JARDIANCE DUO) is available in strengths of
5 mg e
­ mpagliflozin plus 500 mg, 850 mg or 1000 mg ­metformin
hydrochloride or 12.5 mg ­empagliflozin plus 500 mg, 850 mg or
1000 mg ­metformin hydrochloride.
[1]
abcd
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) should be
E The risk of diabetic ketoacidosis must be considered in the event
given with meals to reduce the gastrointestinal undesirable
effects associated with ­metformin.
Patients with renal impairment
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) must not be
E *p-value <0.0001
used in patients with eGFR <45 mL/min/1.73 m2 or CrCl <45 mL/
min (see section Contraindications).
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) may be used in
E asymptomatic. Special caution should be exercised in situations
patients with eGFR of 45 - 59 mL/min/1.73 m2 or CrCl of
45 - 59 mL/min only in the absence of other conditions that may
increase the risk of lactic acidosis. The maximum recommended
dose of m
­ etformin in such patients is 500 mg given twice daily.
The renal function should be closely monitored (see section
Special warnings and precautions).
If CrCl or eGFR fall <45 mL/min or <45 mL/min/1.73 m2 respec-
tively, E
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) must be
discontinued immediately (see section Contraindications).
Elderly patients
Due to the potential for decreased renal function in elderly sub-
jects, the m
­ etformin dosage should be adjusted based on renal
function. Regular assessment of renal function is necessary (see
section Special warnings and precautions).
Missed dose
If a dose is missed, it should be taken as soon as the patient
remembers. However, a double dose should not be taken at the
same time. In that case, the missed dose should be skipped.
Paediatric population
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) is not recom-
E N
mended for use in children below 18 years due to lack of data on
safety and efficacy.
Contraindications
• Hypersensitivity to active ingredients ­empagliflozin and/or
­metformin or to any of the excipients
• Diabetic ketoacidosis
• Diabetic pre-coma
• Moderate (stage 3b) and severe renal failure or renal dysfunc-
tion (CrCl <45 mL/min or eGFR <45 mL/min/1.73m2).
• Acute conditions with the potential to alter renal function such
as: dehydration, severe infection, shock, intravascular adminis-
tration of iodinated contrast agents (see section Special warn-
ings and precautions)
• Disease which may cause tissue hypoxia (especially acute
disease, or worsening of chronic disease) such as: decompen-
sated heart failure, respiratory failure, recent myocardial
infarction, shock
Diabetic ketoacidosis
Rare cases of diabetic ketoacidosis (DKA) have been reported in
patients treated with SGLT2 inhibitors, including ­empagliflozin.
In a number of reported cases, the presentation of the condition
was atypical with only moderately increased blood glucose val-
ues, below 14 mmol/l (250 mg/dl).
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. Discontinua-
tion or temporary interruption of E
­ mpagliflozin + ­Metformin HCl
(­JARDIANCE DUO) should be considered, until the situation is
clarified.
Patients who may be at higher risk of DKA while taking SGLT2
inhibitors include patients on a very low carbohydrate diet (as the
combination may further increase ketone body production),
severely dehydrated patients, and patients with a history of
ketoacidosis or who are known to have a low beta-cell function
reserve. ­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO)
should be used with caution in these patients. When reducing
the insulin dose (see Dosage and Administration) in patients
requiring insulin, caution should be taken.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the
absence of prompt treatment), metabolic complication that can
occur due to ­metformin hydrochloride accumulation. Reported
cases of lactic acidosis in patients on ­metformin hydrochloride
have occurred primarily in diabetic patients with impaired renal
function or acute worsening of renal function. Special caution
should be paid to situations where renal function may become
impaired, for example in case of dehydration (severe diarrhoea or
vomiting), or when initiating antihypertensive therapy or diuretic
therapy and when starting therapy with a non-steroidal anti-
inflammatory drug (NSAID). In the acute conditions listed,
­metformin should be temporarily discontinued.
Other associated risk factors should be considered to avoid lactic
acidosis such as poorly controlled diabetes, ketosis, prolonged
fasting, excessive alcohol intake, hepatic insufficiency and any
condition associated with hypoxia (such as decompensated
cardiac failure, acute myocardial infarction) (see section
Contraindications).
The risk of lactic acidosis must be considered in the event of
non-specific signs such as muscle cramps, digestive disorders as
abdominal pain and severe asthenia. Patients should be
instructed to notify these signs immediately to their physicians if
they occur, notably if patients had a good tolerance to
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) before.
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) should be
discontinued, at least temporarily, until the situation is clarified.
Reintroduction of ­Empagliflozin + ­Metformin HCl (­JARDIANCE
DUO) should then be discussed taking into account the benefit/
risk ratio in an individual basis as well as renal function.
[2]
Physicians should alert the patients on the risk and on the symp-
toms of lactic acidosis.
Renal function
Due to the mechanism of action, decreased renal function will
result in reduced efficacy of ­empagliflozin. Metformin hydro-
chloride is excreted by the kidney. Therefore, serum creatinine
levels should be determined before initiating treatment and
regularly thereafter:
• at least annually in patients with normal renal function
• at least two to four times a year in patients with serum creati-
nine levels at the upper limit of normal and in elderly subjects
In case CrCl is <45 mL/min or eGFR is <45 mL/min/1.73m2,
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) is contraindi-
cated (see section Contraindications).
Decreased renal function in elderly subjects is frequent and
where renal function may become impaired, for example in case
of dehydration, or when initiating antihypertensive therapy or
diuretic therapy and when starting therapy with an NSAID.
In these cases, it is also recommended to check renal function
before initiating treatment with E
­ mpagliflozin + ­Metformin HCl
(­JARDIANCE DUO).
Cardiac function
Patients with heart failure are more at risk of hypoxia and renal
impairment. In patients with stable chronic heart failure,
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) may be used
with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, ­Empagliflozin
+M­ etformin HCl (­JARDIANCE DUO) is contraindicated due to the
­metformin component (see section Contraindications).
Elderly patients
Patients aged 75 years and older may be at an increased risk of
volume depletion, therefore, ­Empagliflozin + ­Metformin HCl
(­JARDIANCE DUO) should be prescribed with caution in these
patients (see section Side effects). Therapeutic experience in
patients aged 85 years and older is limited. Initiation of treat-
ment in this population is not recommended.
As ­metformin is excreted via the kidney, and elderly patients
have a tendency to decreased renal function, elderly patients
taking ­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) should
have their renal function monitored regularly.
Use in patients at risk for volume depletion
Based on the mode of action of SGLT-2 inhibitors, osmotic diure-
sis accompanying therapeutic glucosuria may lead to a modest
decrease in blood pressure. Therefore, caution should be exer-
cised in patients for whom an e
­ mpagliflozin-induced drop in
blood pressure could pose a risk, such as patients with known
cardiovascular disease, patients on anti-hypertensive therapy
with a history of hypotension or patients aged 75 years and older.
In case of conditions that may lead to fluid loss (e.g. gastrointes-
tinal illness), careful monitoring of volume status (e.g. physical
examination, blood pressure measurements, laboratory tests
10 mg plus m­ etformin as compared to patients treated with
placebo plus m­ etformin or ­empagliflozin 25 mg plus m­ etformin
(see section Side Effects). Complicated urinary tract infection
(e.g., pyelonephritis or urosepsis) occurred at a similar frequency
in patients treated with e­ mpagliflozin compared to placebo.
However, temporary interruption of treatment should be consid-
ered in patients with complicated urinary tract infections.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast materials
in radiologic studies can lead to renal failure. This may induce
­metformin accumulation and may increase the risk for lactic
acidosis. In patients with eGFR >60 mL/min/1.73 m2,
­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) must be dis-
continued prior to, or at the time of the test and not be reinsti-
tuted until at least 48 hours afterwards, and only after renal
function has been re-evaluated and has not deteriorated further
(see section Interactions).
In patients with moderate renal impairment (stage 3a, eGFR
45 - 60 mL/min/1.73 m2), ­Empagliflozin + ­Metformin HCl
(­JARDIANCE DUO) must be discontinued 48 hours before admin-
istration of iodinated contrast media and not be reinstituted until
at least 48 hours afterwards and only after renal function has
been re-evaluated and has not deteriorated further (see section
Interactions).
Surgery
Due to the ­metformin component, ­Empagliflozin +
­Metformin HCl (­JARDIANCE DUO) must be discontinued 48 hours
before elective surgery with general, spinal or peridural anaes-
thesia. Therapy may be restarted no earlier than 48 hours follow-
ing surgery or resumption of oral nutrition and only if normal
renal function has been established.
USE IN SPECIFIC POPULATIONS
Fertility, Pregnancy and Lactation
Pregnancy
There are limited data from the use of ­Empagliflozin +
­Metformin HCl (­JARDIANCE DUO) or its individual components
in pregnant women. Nonclinical studies with ­empagliflozin alone
do not indicate direct or indirect harmful effects with respect to
reproductive toxicity. Animal studies with the combination of
­empagliflozin and m­ etformin or with ­metformin alone have
shown reproductive toxicity at higher doses of ­metformin only
(see section Toxicology).
As a precautionary measure, it is recommended to avoid the use
of ­Empagliflozin + ­Metformin HCl (­JARDIANCE DUO) during
pregnancy unless clearly needed.
Lactation
Metformin is excreted into human breast milk. No adverse effects
were observed in breastfed newborns/infants. It is unknown
whether ­empagliflozin is excreted in human milk.
Available nonclinical data in animals have shown excretion of
­empagliflozin in milk. A risk to human newborns/infants cannot
be excluded. It is recommended to discontinue breast feeding
during treatment with ­Empagliflozin + ­Metformin HCl
(­JARDIANCE DUO).
Fertility
commonly used medicinal products. Based on results of pharma-
cokinetic studies no dose adjustment of ­empagliflozin is recom-
mended when co-administered with commonly prescribed
medicinal products.
­ mpagliflozin pharmacokinetics were similar with and without
E The overall frequency of urinary tract infection adverse events
co-administration of glimepiride, pioglitazone, sitagliptin, lina-
gliptin, warfarin, verapamil, ramipril, simvastatin, torasemide
and hydrochlorothiazide in healthy volunteers. Increases in
overall exposure (AUC) of e
­ mpagliflozin were seen following
co-administration with gemfibrozil (59%), rifampicin (35%), or
probenecid (53%). These changes were not considered to be
clinically meaningful.
­ mpagliflozin had no clinically relevant effect on the pharmaco-
E tazone +/- ­metformin, and as add-on with linagliptin +
kinetics of glimepiride, pioglitazone, sitagliptin, linagliptin,
warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide,
torasemide and oral contraceptives when co-administered in
healthy volunteers.
Metformin
There is increased risk of lactic acidosis in acute alcohol intoxi-
cation (particularly in the case of fasting, malnutrition or hepatic
insufficiency) due to the m­ etformin compound of ­Empagliflozin
+M­ etformin HCl (­JARDIANCE DUO) (see section Special warn-
ings and precautions). Consumption of alcohol and medicinal
products containing alcohol should be avoided.
Cationic agents that are eliminated by renal tubular secretion
(e.g., cimetidine) may interact with ­metformin by competing for
common renal tubular transport systems. A study conducted in
seven normal healthy volunteers showed that cimetidine, admin-
istered as 400 mg twice daily, increased m­ etformin systemic
exposure (AUC) by 50% and Cmax by 81%. Therefore, close moni-
toring of glycaemic control, dose adjustment within the recom-
mended posology and changes in diabetic treatment should be
considered when cationic agents that are eliminated by renal
tubular secretion are co-administered.
Intravascular administration of iodinated contrast media may
lead to renal failure, resulting in ­metformin accumulation and
a risk of lactic acidosis. In patients with eGFR >60 mL/min/
1.73 m2, treatment must be discontinued prior to, or at the time
of the test and not be reinstituted until at least 48 hours after-
wards, and only after renal function has been re-evaluated and
has not detoriated further (see section Special warnings and
precautions).
In patients with moderate renal impairment (eGFR between
45 and 60 mL/min/1.73 m2), treatment must be discontinued
48 hours before administration of iodinated contrast media and
not be reinstituted until at least 48 hours afterwards and only
after renal function has been re-evaluated and has not detoriated
further.
Side effects
A total of 7052 patients with type 2 diabetes were treated in
clinical studies to evaluate the safety of ­empagliflozin plus
­metformin, of which 4740 patients were treated with
­empagliflozin plus m­ etformin, either alone, or in addition to
a sulfonylurea, pioglitazone, DPP4 inhibitors, or insulin. In these
trials 1270 patients received treatment with ­empagliflozin 10 mg
plus m­ etformin and 2065 patients treatment with ­empagliflozin
25 mg plus m ­ etformin for at least 24 weeks and 643 or
1286 patients for at least 76 weeks.
Placebo-controlled, double-blind trials of 18 to 24 weeks of
exposure included 3456 patients, of which 1271 were treated
rhoea, abdominal pain and loss of appetite occur most fre- gliptin 5 mg with a background treatment with ­metformin. (see reduction of blood pressure. SBP (mmHg)2
quently during initiation of therapy and resolve spontaneously also Clinical Trials section).
in most cases. Metformin is a biguanide with antihyperglycaemic effects, lower- Baseline (mean) 128.6 129.6 130.0
Urinary tract infection ing both basal and postprandial plasma glucose. It does not
Description of selected side effects stimulate insulin secretion and therefore does not produce Change from baseline1 -0.4 -4.5 -5.2
hypoglycaemia.
The frequencies below are calculated for side effects regardless was higher in patients treated with e ­ mpagliflozin 10 mg plus Metformin hydrochloride may act via 3 mechanisms: Difference from -4.1* -4.8*
of causality. ­metformin (8.8%) as compared to ­empagliflozin 25 mg plus (1) reduction of hepatic glucose production by inhibiting gluco- placebo1 (95% CI) (-6.2, -2.1) (-6.9, -2.7)
­metformin (6.6%) or placebo plus ­metformin (7.8%). Similar to neogenesis and glycogenolysis
Hypoglycaemia placebo, urinary tract infection was reported more frequently for (2) in muscle, by increasing insulin sensitivity, improving periph-
1 mean adjusted for baseline value and stratification
­empagliflozin plus m­ etformin in patients with a history of eral glucose uptake and utilisation 2 not evaluated for statistical significance; not part of sequential
The frequency of hypoglycaemia depended on the background chronic or recurrent urinary tract infections. The intensity of (3) and delay of intestinal glucose absorption.
testing procedure for the secondary endpoints
therapy in the respective studies and was similar to placebo for urinary tract infections was similar to placebo. Urinary tract 3 L ast observation (prior to glycemic rescue) carried forward
­empagliflozin as add-on to ­metformin and as add-on to piogli- infection events were reported more frequently for e ­ mpagliflozin Metformin hydrochloride stimulates intracellular glycogen syn-
(LOCF)
10 mg plus m­ etformin compared with placebo in female patients, thesis by acting on glycogen synthase.
­metformin. The frequency of patients with hypoglycaemia was but not for e
­ mpagliflozin 25 mg plus m­ etformin. The frequencies
increased in patients treated with e
­ mpagliflozin compared to of urinary tract infections were low for male patients and were Metformin hydrochloride increases the transport capacity of all
placebo when given as add-on to ­metformin plus sulfonylurea, balanced across treatment groups. types of membrane GLUTs known to date.
­ mpagliflozin and m
E ­ etformin combination therapy in drug-naïve
patients
and as add-on to insulin +/- m
­ etformin and +/-sulfonylurea. (see
section Dosage and Administration; see Table 2 below). Vaginal moniliasis, vulvovaginitis, balanitis and other genital In humans, independently of its action on glycaemia, ­metformin
A factorial design study of 24 weeks duration was conducted to
infection hydrochloride has favourable effects on lipid metabolism. This
evaluate the efficacy and safety of e ­ mpagliflozin in drug-naïve
Major hypoglycaemia (events requiring assistance) has been shown at therapeutic doses in controlled, medium- or
patients. Treatment with e ­ mpagliflozin in combination with
Vaginal moniliasis, vulvovaginitis, balanitis and other genital long-term clinical studies: ­metformin hydrochloride reduces total
­metformin (5 mg and 500 mg; 5 mg and 1000 mg; 12.5 mg and
The overall frequency of patients with major hypoglycaemic infections were reported more frequently for e ­ mpagliflozin 10 mg cholesterol, LDL cholesterol and triglyceride levels.
500 mg, and 12.5 mg and 1000 mg given twice daily) provided
events was low (<1%) and similar for e
­ mpagliflozin and placebo plus ­metformin (4.0%) and ­empagliflozin 25 mg plus m ­ etformin
statistically significant improvements in HbA1c and led to signifi-
on a background of ­metformin. (3.9%) compared to placebo plus ­metformin (1.3%), and were Clinical Trials
cantly greater reductions in FPG and body weight compared to
reported more frequently for ­empagliflozin plus m­ etformin com-
the individual components. A greater proportion of patients with
Table 2 Frequency of patients with confirmed hypoglycaemic pared to placebo in female patients. The difference in frequency A total of 5037 patients with type 2 diabetes were treated in
a baseline HbA1c ≥7.0% and treated with e ­ mpagliflozin in combi-
events per trial and indication (1245.19, 1245.23(met), was less pronounced in male patients. Genital tract infections 8 double-blind, placebo- or active-controlled clinical studies of
nation with m ­ etformin achieved a target HbA1c <7% compared to
1245.23(met+SU), 1245.33, 1245.49, 1276.1 and were mild and moderate in intensity, none was severe in at least 24 weeks duration, of which 1221 patients received
the individual components (Tables 4 and 5).
1276.10 – TS) intensity. ­empagliflozin 10 mg and 1973 received e ­ mpagliflozin 25 mg as
add-on to ­metformin therapy.
[1]
Treatment Placebo ­ mpagliflozin
E ­ mpagliflozin
E Increased urination
Treatment with e ­ mpagliflozin in combination with ­metformin
group 10 mg 25 mg [2]
As expected via its mechanism of action, increased urination (as with or without other background (pioglitazone, sulfonylurea,
In combination with m
­ etformin (1245.23 (met)) (24 weeks) assessed by PT search including pollakiuria, polyuria, nocturia) DPP-4 inhibitors, and insulin) led to clinically relevant improve-
­Empagliflozin as add on to a combination of m
­ etformin and sul-
was observed at higher frequencies in patients treated with ments in HbA1c, fasting plasma glucose, body weight, systolic
phonylurea therapy
N 206 217 214 ­empagliflozin 10 mg plus m ­ etformin (3.0%) and ­empagliflozin and diastolic blood pressure. Administration of e ­ mpagliflozin
25 mg plus ­metformin (2.9%) compared to placebo plus 25 mg resulted in a higher proportion of patients achieving
A double-blind, placebo-controlled study of 24 weeks duration
Overall 0.5% 1.8% 1.4% ­metformin (1.4%). Increased urination was mostly mild or mod- HbA1c goal of < 7% and fewer patients needing glycaemic rescue
was conducted to evaluate the efficacy and safety of
confirmed (%) erate in intensity. The frequency of reported nocturia was com- compared to e ­ mpagliflozin 10 mg and placebo. There was
­empagliflozin in patients not sufficiently treated with a combina-
parable between placebo and ­empagliflozin, both on a back- a clinically meaningful improvement in HbA1c in all subgroups of
tion of m
­ etformin and a sulphonylurea. Treatment with
Major (%) 0% 0% 0% ground of m­ etformin (<1%). gender, race, geographic region, time since diagnosis of T2DM
­empagliflozin resulted in statistically significant improvements
and body mass index (BMI). In patients aged 75 years and older,
In Combination with Metformin + Sulfonylurea (1245.23 in HbA1c and body weight and clinically meaningful reductions in
Volume depletion numerically lower reductions in HbA1c were observed with
(met + SU)) (24 weeks) FPG and blood pressure compared to placebo (Table 6).
­empagliflozin treatment. Higher baseline HbA1c was associated
The overall frequency of volume depletion (including the pre- with a greater reduction in HbA1c. ­Empagliflozin in combination
225 224 217 In the double-blind placebo-controlled extension of this study,
defined terms blood pressure (ambulatory) decreased, blood with ­metformin in drug-naïve patients led to clinically meaning-
reductions of HbA1c (change from baseline of -0.74% for
pressure systolic decreased, dehydration, hypotension, hypovo- ful reductions in HbA1c, FPG, body weight and BP.
Overall 8.4% 16.1% 11.5% ­empagliflozin 10 mg, -0.72% for e ­ mpagliflozin 25 mg and -0.03%
laemia, orthostatic hypotension, and syncope) was low and
confirmed (%) for placebo), body weight (change from baseline of -2.44 kg for
comparable to placebo (­empagliflozin 10 mg plus m ­ etformin ­Empagliflozin as add on to m
­ etformin therapy
­empagliflozin 10 mg, -2.28 kg for e ­ mpagliflozin 25 mg and
(0.6%), e
­ mpagliflozin 25 mg plus m­ etformin (0.3%) and placebo
Major (%) 0% 0% 0% -0.63 kg for placebo) and blood pressure (SBP: change from
plus ­metformin (0.1%). The effect of ­empagliflozin on urinary A double-blind, placebo-controlled study of 24 weeks duration
baseline of -3.8 mmHg for e ­ mpagliflozin 10 mg, -3.7 mmHg for
glucose excretion is associated with osmotic diuresis, which was conducted to evaluate the efficacy and safety of
In Combination with Pioglitazone +/- Metformin (1245.19) ­empagliflozin 25 mg and -1.6 mmHg for placebo, DBP: change
could affect the hydration status of patients aged 75 years and ­empagliflozin in patients not sufficiently treated with m ­ etformin.
(24 weeks) from baseline of -2.6 mmHg for empagliflozin10 mg, -2.3 mmHg
older. In patients ≥75 years of age, volume depletion events have Treatment with e­ mpagliflozin resulted in statistically significant
for e
­ mpagliflozin 25 mg and -1.4 mmHg for placebo) were sus-
been reported in a single patient treated with e­ mpagliflozin improvements in HbA1c and body weight, and clinically mean-
N 165 165 168 tained up to Week 76.
25 mg plus ­metformin. ingful reductions in FPG and blood pressure compared to pla-
cebo (Table 3).
Overall 1.8% 1.2% 2.4% Table 6 Results of a 24 week (LOCF)3 placebo-controlled study
Overdose
confirmed (%) of e
­ mpagliflozin as add-on to ­metformin and a sulpho-
During controlled clinical trials in healthy subjects, single doses In the double-blind placebo-controlled extension of this study,
nylurea (Full Analysis Set)
Major (%) 0% 0% 0% of up to 800 mg ­empagliflozin, equivalent to 32 times the maxi- reductions of HbA1c (change from baseline of -0.62% for
mum recommended daily dose, were well tolerated. There is no ­empagliflozin 10 mg, -0.74% for e ­ mpagliflozin 25 mg and -0.01%
experience with doses above 800 mg in humans. for placebo), body weight (change from baseline of -2.39 kg for ­ mpagliflozin as
E Placebo ­ mpagliflozin
E ­ mpagliflozin
E
In Combination with Basal Insulin +/- Metformin (1245.33)
­empagliflozin 10 mg, -2.65 kg for ­empagliflozin 25 mg and add-on to ­metformin 10 mg 25 mg
(18 weeks1 / 78 weeks)
Hypoglycaemia has not been seen with m ­ etformin hydrochloride -0.46 kg for placebo) and blood pressure (SBP: change from and a sulphonylurea
N 170 169 155 doses of up to 85 g, although lactic acidosis has occurred in such baseline of -5.2 mmHg for e ­ mpagliflozin 10 mg, -4.5 mmHg for therapy
circumstances. High overdose of ­metformin hydrochloride or ­empagliflozin 25 mg and -0.8 mmHg for placebo, DBP: change
Overall 20.6% / 35.3% 19.5 / 36.1% 28.4% / 36.1% concomitant risks may lead to lactic acidosis. Lactic acidosis is from baseline of -2.5 mmHg for ­empagliflozin 10 mg, -1.9 mmHg N 225 225 216

­ mpagliflozin
E
Table 4 Results of a 24-week (OC)2 study comparing ­empagliflozin 10 mg in combination with ­metformin to the individual Table 5 Results of a 24-week (OC)2 study comparing ­empagliflozin 25 mg in combination with ­metformin to the individual mono- No studies on the effect on human fertility have been conducted with ­empagliflozin 10 mg plus m
­ etformin and 1259 with confirmed (%) a medical emergency and must be treated in hospital. for e
­ mpagliflozin 25 mg and -0.5 mmHg for placebo) were sus-
components therapy components with E
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) or its ­empagliflozin 25 mg plus m
­ etformin. tained up to Week 76. HbA1c (%)
individual components. Major (%) 0% / 0% 0% / 0% 1.3% / 1.3% Therapy

­Metformin HCl The most frequently reported adverse event in clinical trials was Table 3 Results of a 24-week (LOCF)3 placebo-controlled Baseline (mean) 8.15 8.07 8.10
­ mpagliflozin 10 mg
E ­ mpagliflozin 10 mg
E ­ mpagliflozin
E Metformin Metformin ­ mpagliflozin 25 mg
E ­ mpagliflozin 25 mg
E ­ mpagliflozin
E Metformin Metformin
+­metformin 1000 mga +­metformin 2000 mg a 10 mg (qd) 1000 mga 2000 mga +­metformin 1000 mga +­metformin 2000 mga 25 mg qd 1000 mga 2000 mga Non-clinical studies in animals with the individual components hypoglycaemia, which depended on the type of background In Combination with MDI Insulin +/-Metformin (1245.49) In the event of an overdose, supportive treatment should be study of e
­ mpagliflozin as add-on to ­metformin
Change from -0.17 -0.82 -0.77
do not indicate direct or indirect harmful effects with respect to therapy used in the respective studies (see description of (18 weeks1 / 52 weeks) initiated as appropriate to the patient’s clinical status. The most (Full Analysis Set)
baseline1
309887-01

Jardiance Duo® N

HbA1c (%)
161 167 169 167 162 N

HbA1c (%)
165 169 163 167 162 fertility.

Driving and Using Machines

selected side effects).

No additional side effects were identified in clinical trials with

N 188 186 189
effective method to remove lactate and m ­ etformin hydrochloride
is haemodialysis whereas removal of ­empagliflozin by haemodi-
alysis has not been studied.
­ mpagliflozin as add-on Placebo
E
to ­metformin therapy
­ mpagliflozin ­Empagliflozin
E
10 mg 25 mg
Difference from
placebo1 (97.5% CI)
-0.64*
(-0.79, -0.49)
-0.59*
(-0.74, -0.44)
­empagliflozin plus m
­ etformin compared to the side effects of the Overall 37.2% / 58.0% 39.8% / 51.1% 41.3% / 57.7%
Baseline (mean) 8.7 8.7 8.6 8.7 8.6 Baseline (mean) 8.8 8.7 8.9 8.7 8.6 No studies on the effects on the ability to drive and use machines single components. confirmed (%) Pharmacological properties N 207 217 213 N 216 209 202
have been performed. Pharmacotherapeutic group: Combinations of oral blood glucose

abcd
Change from baseline1 -2.0 -2.1 -1.4 -1.2 -1.8 Change from baseline 1 -1.9 -2.1 -1.4 -1.2 -1.8 Table 1 Side effects (regardless of investigator reported causal- Major (%) 1.6% / 1.6% 1.6% / 1.6% 0.5% / 0.5% lowering drugs, ATC code: A10BD20 HbA1c (%) Patients (%) achiev- 9.3 26.3 32.2
Interactions ity assessment) reported in patients who received ing HbA1c <7% with
Comparison vs. ­empagliflozin (95% CI) 1 -0.6* (-0.9, -0.4)b -0.7* (-1.0, -0.5)b Comparison vs. ­empagliflozin (95% CI) 1 -0.6* (-0.8, -0.3)b -0.7* (-1.0, -0.5)b ­Empagliflozin a combination of e­ mpagliflozin and m­ etformin in ­ mpagliflozin BID versus QD as add on to ­metformin (1276.10) (16
E Mode of Action Baseline (mean) 7.90 7.94 7.86
weeks) baseline HbA1c ≥7%2
Pharmacodynamic Interactions placebo controlled double- blind studies of up to
Comparison vs. ­metformin (95% CI) 1 -0.8* (-1.0, -0.6)b -0.3* (-0.6, -0.1)b Comparison vs. ­metformin (95% CI) 1 -0.8* (-1.0, -0.5)b -0.3* (-0.6, -0.1)b 24 weeks, classified by MedDRA System organ class ­ mpagliflozin is a reversible, highly potent and selective com-
E Change from baseline1 -0.13 -0.70 -0.77 N 224 225 215
Diuretics and MedDRA Preferred terms Placebo Empa 10 mg Empa 25 mg petitive inhibitor of SGLT2 with an IC50 of 1.3 nM. It has
N 153 161 159 166 159 N 159 163 158 166 159 ­Empagliflozin may add to the diuretic effect of thiazide and loop a 5000-fold selectivity over human SGLT1 (IC50 of 6278 nM), Difference from -0.57* -0.64* FPG (mg/dl) [mmol/l]2
N 107 439 437 placebo1 (97.5% CI) (-0.72, -0.42) (-0.79, -0.48)
diuretics and may increase the risk of dehydration and ­Empagliflozin and ­metformin responsible for glucose absorption in the gut. Furthermore high
Patients (%) achieving HbA1c <7% with 96 (63%) 112 (70%) 69 (43%) 63 (38%) 92 (58%) Patients (%) achieving HbA1c <7% with 91 (57%) 111 (68%) 51 (32%) 63 (38%) 92 (58%) hypotension. selectivity could be shown toward other glucose transporters Baseline (mean) 151.7 [8.42] 151.0 [8.38] 156.5 [8.68]
baseline HbA1c ≥7% baseline HbA1c ≥7% Overall 0.9% 0.5% 0.2% N 184 199 191
System Organ class Side effect (GLUTs) responsible for glucose homeostasis in the different
confirmed (%)
Insulin and insulin secretagogues tissues. Change from 5.5 [0.31] -23.3 [-1.29] -23.3 [-1.29]
N 161 166 168 165 164 N 163 167 163 165 164 Insulin and insulin secretagogues, such as sulphonylureas, may Patients (%) achieving 12.5 37.7 38.7 baseline1
Infections and Vaginal moniliasis, vulvovaginitis, bala- Major (%) 0% 0% 0%
increase the risk of hypoglycaemia. Therefore, a lower dose of infestations nitis and other genital infections1, 2 SGLT-2 is highly expressed in the kidney, whereas expression in HbA1c <7% with baseline
FPG (mg/dL) [mmol/L] FPG (mg/dL) [mmol/L] HbA1c ≥7%2 Difference from -28.8* -28.8*
insulin or an insulin secretagogue may be required to reduce the Urinary tract infection1, 2 In Combination with m
­ etformin in drug-naïve patients (1276.12) other tissues is absent or very low. It is responsible as the pre-
risk of hypoglycaemia when used in combination with (24 weeks) dominant transporter for reabsorption of glucose from the glo- placebo1 (95% CI) (-34.2, -23.4) (-34.3, -23.3)
Baseline (mean) 165.9 [9.2] 163.7 [9.1] 170.0 [9.4] 172.6 [9.6] 169.0[9.4] Baseline (mean) 171.2 [9.5] 167.9 [9.3] 176.9 [9.8] 172.6 [9.6] 169.0 [9.4] N 207 216 213
­empagliflozin (see sections Dosage and Administration and Side Gastrointestinal Nausea3 merular filtrate back into the circulation. In patients with type 2 [-1.60* (-1.90, [-1.60* (-1.90,
Change from baseline1 -45.5 [-2.5] -47.8 [-2.7] -32.9 [-1.8] -17.2 [-1.0] -32.1 [-1.8] Change from baseline1 -44.0 [-2.4] -51.0 [-2.8] -28.0 [-1.6] -17.2 [-1.0] -32.1 [-1.8] effects). disorders5 Vomiting3 Met Empa 10/25 mg Empa diabetes mellitus (T2DM) and hyperglycaemia a higher amount of -1.30)] -1.29)]
FPG (mg/dL) [mmol/l]2
Diarrhoea3 500/1000 mg QD (5/12.5 mg) + glucose is filtered and reabsorbed.
Comparison vs. ­empagliflozin (95% CI) 1 -12.6** (-19.1, -6.0)b -14.8** (-21.4, -8.2)b Comparison vs. ­empagliflozin (95% CI) 1 -16.0** b (-22.8, -9.2) -23.0** b (-29.7, -16.3) Pharmacokinetic Interactions Abdominal pain3 BID Met N 225 225 216
Baseline (mean) 156.0 154.6 149.4
[-0.7 (-1.1, -0.3)] [-0.8 (-1.2, -0.5)] [-0.9 (-1.3,-0.5)] [-1.3 (-1.6, -0.9)] Loss of appetite3 (500/1000 mg) ­ mpagliflozin improves glycaemic control in patients with T2DM
E
[8.66] [8.58] [8.29] Body Weight (kg)
In vitro assessment of drug interactions BID by reducing renal glucose reabsorption. The amount of glucose
Comparison vs. ­metformin (95% CI) 1 -28.2** (-35.0, -21.5)b -15.6** (-22.3, -8.9)b Comparison vs. ­metformin (95% CI) 1 -26.7** b (-33.5, -20.0) -18.8** b (-25.5, -12.2) Metabolism and Hypoglycaemia (when used with sulpho- removed by the kidney through this glucuretic mechanism is
Change from baseline1 6.4 [0.35] -20.0 [-1.11] -22.3 [-1.24] Baseline (mean) 76.23 77.08 77.50
[-1.6 (-1.9, -1.2)] [-0.9 (-1.2, -0.5)] [-1.5 (-1.9, -1.1)] -1.0 (-1.4, -0.7)] ­ mpagliflozin does not inhibit, inactivate, or induce CYP450
E nutrition disorders nylurea or insulin)1 N 341 339 680 dependent upon the blood glucose concentration and GFR.
isoforms. In vitro data suggest that the primary route of metabo- Lactic acidosis3 Through inhibition of SGLT-2 in patients with T2DM and hyper- Difference from -26.4* -28.7*
lism of ­empagliflozin in humans is glucuronidation by the uridine Vitamin B12 absorption decrease3, 4 glycaemia, excess glucose is excreted in the urine. Change from -0.39 -2.16 -2.39
N 161 165 168 166 162 N 165 167 162 166 162 Overall 0.6% 0.6% 1.0% placebo1 (95% CI) (-31.3, -21.6) (-33.6, -23.8)
5‘-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, baseline1
confirmed (%) [-1.47* [-1.59*
Body Weight (kg) Body Weight (kg) UGT1A9, and UGT2B7. ­Empagliflozin does not inhibit UGT1A1, Hepatobiliary disorders Liver function tests abnormalities3, In patients with T2DM, urinary glucose excretion increased (-1.74, -1.20)] (-1.86, -1.32)] Difference from -1.76* -1.99*
UGT1A3, UGT1A8, UGT1A9, or UGT2B7. At therapeutic doses, the Hepatitis3 Major (%) 0% 0% 0% immediately following the first dose of e
­ mpagliflozin and is
Baseline (mean) 82.3 83.0 83.9 82.9 83.8 Baseline (mean) 82.9 83.7 83.4 82.9 83.8 placebo1(97.5% CI) (-2.25, -1.28) (-2.48, -1.50)
potential for e
­ mpagliflozin to reversibly inhibit or inactivate the continuous over the 24-hour dosing interval. Increased urinary N 207 217 213
major CYP450 isoforms or UGT1A1 is remote. Drug-drug interac- Nervous system Taste disturbance3 In Combination with m
­ etformin and linagliptin (1275.9) glucose excretion was maintained at the end of 4-week treatment
% Change from baseline1 % Change from baseline1 N 225 225 216
-3.1 -4.1 -2.7 -0.4 -1.2 -3.6 -4.3 -2.8 -0.4 -1.2 tions involving the major CYP450 and UGT isoforms with disorders (24 weeks)3 period, averaging approximately 78 g/day with 25 mg Body Weight (kg)
­empagliflozin and concomitantly administered substrates of ­empagliflozin once daily. Increased urinary glucose excretion Patients (%) achiev- 5.8 27.6 23.6
Comparison vs. ­metformin (95% CI) 1 -2.7** (-3.6, -1.8)b -2.8** (-3.8, -1.9)b Comparison vs. ­metformin (95% CI) 1 -3.1** (-4.1, -2.2)b -3.1** (-4.1, -2.2)b these enzymes are therefore considered unlikely. Skin and subcutaneous Pruritus2, 3 N n=110 n=112 n=110 resulted in an immediate reduction in plasma glucose levels in Baseline (mean) 79.73 81.59 82.21
disorders Urticaria3 ing weight loss of
patients with T2DM. >5%2
a Given in two equally divided doses per day a Given in two equally divided doses per day ­ mpagliflozin is a substrate for P-glycoprotein (P-gp) and breast
E Erythema3 Overall 0.9% 0.0% 2.7% Change from baseline1 -0.45 -2.08 -2.46
b F ull analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by treat- b Full analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by treat- cancer resistance protein (BCRP), but it does not inhibit these confirmed (%) ­ mpagliflozin improves both fasting and post-prandial plasma
E
Vascular disorders Volume depletion2 N 225 225 216
ment interaction, and baseline HbA1c; FPG included baseline FPG in addition; weight included baseline weight in addition. ment interaction, and baseline HbA1c; FPG included baseline FPG in addition; weight included baseline weight in addition. efflux transporters at therapeutic doses. Based on in vitro stud- glucose levels. Difference from -1.63* -2.01*
1 mean adjusted for baseline value 1m ies, ­empagliflozin is considered unlikely to cause interactions Major (%) 0% 0% 0.9% placebo1 (97.5% CI) (-2.17, -1.08) (-2.56, -1.46)
 ean adjusted for baseline value Renal and urinary Increased urination2
2 Analyses were performed on the full analysis set (FAS) using an observed cases (OC) approach 2A nalyses were performed on the full analysis set (FAS) using an observed cases (OC) approach with drugs that are P- gp substrates. E­ mpagliflozin is a substrate The mechanism of action of ­empagliflozin is independent of beta
of the human uptake transporters OAT3, OATP1B1, and OATP1B3, disorders Dysuria2 cell function and insulin pathway and this contributes to a low N 207 217 213
*p≤0.0062 for HbA1c; *p≤0.0056 for HbA1c Confirmed: blood glucose ≤70 mL/dL or required assistance
**Analysis in an exploratory manner: p≤0.0002 for FPG and p<0.0001 for body weight ** Analysis in an exploratory manner: p<0.0001 for FPG and p<0.0001 for body weight but not OAT1 and OCT2. E ­ mpagliflozin does not inhibit any of Major: required assistance risk of hypoglycaemia. 309887-01
 ­ mpagliflozin plus linagliptin 5 mg provided statistically signifi-
e ­ mpagliflozin 2-year data, as add on to ­metformin in comparison
E or urine (54.4%). The majority of drug related radioactivity recov- Paediatric ­ etformin was observed in the rat which was mostly evident as
m
­ mpagliflozin as
E Placebo ­ mpagliflozin
E ­ mpagliflozin
E Pioglitazone Placebo ­ mpagliflozin
E ­ mpagliflozin
E Basal insulin +/- Placebo ­Empagliflozin ­ mpagliflozin
E ­ mpagliflozin as
E Placebo E
­ mpagliflozin ­ mpagliflozin
E Placebo E
­ mpagliflozin ­Empagliflozin
cant reductions in body weight and blood pressure. A greater to glimepiride ered in faeces was unchanged parent drug and approximately half an increase in the number of skeletal malformations.
add-on to ­metformin 10 mg 25 mg +/- ­metformin 10 mg 25 mg ­metformin or sulfonyl- 10 mg 25 mg add-on to insulin + 10 mg 25 mg 10 mg 25 mg
proportion of patients with a baseline HbA1c ≥7.0% and treated of drug related radioactivity excreted in urine was unchanged Single dose study: After single doses of ­metformin 500 mg, pae-
and a sulphonylurea add-on therapy urea add-on therapy ­metformin therapy
with e
­ mpagliflozin plus linagliptin achieved a target HbA1c of In a study comparing the efficacy and safety of ­empagliflozin parent drug. diatric patients, have shown a similar pharmacokinetic profile to Availability
therapy Change from baseline1 0.32 -1.04 -1.40
<7% compared to linagliptin 5 mg (Table 8). 25 mg versus glimepiride (4 mg) in patients with inadequate that observed in healthy adults. Tablets of 5/500 mg Alu/PVC blister pack of 10’s (Box of 30’s)
N 155 151 160 Change from baseline1 -0.01 -0.57 -0.71 Body Weight (kg) at week 52 3
glycaemic control on ­metformin alone, treatment with Difference from placebo1 Specific Populations Tablets of 5/850 mg Alu/PVC blister pack of 10’s (Box of 30’s)
SBP (mmHg)2 -1.36** -1.72*
Patients (%) achiev- 7.7 23.8 30.0 After 24 weeks’ treatment with e­ mpagliflozin+linagliptin, both ­empagliflozin daily resulted in superior reduction in HbA1c, and Difference from -0.56* -0.70* Baseline (mean) 96.34 96.47 95.37 (95% CI) (-2.15,-0.56) (-2.51, -0.93) Multiple dose study: After repeated doses of 500 mg twice daily Tablet of 5/1000 mg Alu/PVC blister pack of 10’s (Box of 30’s)
Baseline (mean) 128.8 128.7 129.3 ing HbA1c <7% with systolic and diastolic blood pressures were reduced, -5.6/ a clinically meaningful reduction in FPG, compared to glimepiride placebo1 (97.5% CI) (-0.78, -0.33) (-0.93, -0.47) Renal Impairment for 7 days in paediatric patients the peak plasma concentration Tablets of 12.5/500 mg Alu/PVC blister pack of 10’s (Box of 30’s)
baseline HbA1c ≥7%3 -3.6 mmHg (p<0.001 versus linagliptin 5 mg for SBP and DBP) for (Table 10). E­ mpagliflozin daily resulted in a statistically signifi- Change from baseline1 0.44 -1.95 -2.04 (Cmax) and systemic exposure (AUC0-t) were approximately 33% Tablets of 12.5/850 mg Alu/PVC blister pack of 10’s (Box of 30’s)
­empagliflozin 25 mg+linagliptin 5 mg and -4.1/-2.6 mmHg cant reduction in body weight, systolic and diastolic blood pres- 1 Mean adjusted for baseline value and stratification In patients with mild (eGFR: 60 - <90 mL/min/1.73 m2), moderate and 40% lower, respectively, compared to diabetic adults who Tablets of 12.5/1000 mg Alu/PVC blister pack of 10’s (Box of 30’s)
Change from -1.4 -4.1 -3.5 N 112 127 110 2 L ast observation (prior to antihypertensive rescue ) carried
baseline1 N 165 163 168 (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for sure (change from baseline in DBP of -1.8 mmHg for ­empagliflozin Difference from -2.39* -2.48* (eGFR: 30 - <60 mL/min/1.73 m2), severe (eGFR: <30 mL/min/ received repeated doses of 500 mg twice daily for 14 days. As the
­empagliflozin 10 mg+linagliptin 5 mg.Clinically meaningful and +0.9 mmHg for glimepiride, p<0.0001). HbA1c (%) at week 78 placebo1 (97.5% CI) (-3.54, -1.24) (-3.63, -1.33) forward (LOCF) LOCF, values after antihypertensive rescue 1.73 m2) renal impairment and patients with kidney failure/ESRD dose is individually titrated based on glycaemic control, this is of Caution: Foods, Drugs, Devices and Cosmetics Act prohibits
Difference from -2.7 -2.1 FPG (mg/dL) [mmol/L] reductions in blood pressure were maintained for 52 weeks, censored value patients, AUC of e­ mpagliflozin increased by approximately 18%, limited clinical relevance. dispensing without prescription
-3.8/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP and DBP) Treatment with ­empagliflozin resulted in statistically significantly 3 L ast observation (prior to glycemic rescue ) carried forward 20%, 66%, and 48%, respectively, compared to subjects with
placebo1 (-4.6, -0.8) (-4.0, -0.2) Baseline (mean) 8.09 8.27 8.29 N 188 186 189
(95% CI) Baseline (mean) 151.93 152.0 151.86 for e
­ mpagliflozin 25 mg/linagliptin 5 mg and -3.1/-1.6 mmHg lower proportion of patients with hypoglycaemic events com- (LOCF) normal renal function. Peak plasma levels of ­empagliflozin were Toxicology Store at temperatures not exceeding 30°C.
[8.43] [8.44] [8.43] (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for pared to glimepiride (2.5% for e
­ mpagliflozin, 24.2% for Change from baseline1 -0.02 -0.48 -0.64 SBP (mmHg)5 * p-value <0.0001 similar in subjects with moderate renal impairment and kidney
­empagliflozin 10 mg/linagliptin 5 mg. glimepiride, p<0.0001). ** p-value =0.0008 failure/ESRD compared to patients with normal renal function. ­ mpagliflozin and m
E ­ etformin Manufactured by
1 mean adjusted for baseline value and stratification
Change from 6.47 [0.37] -17.0 [-0.94] -21.99 [-1.23] Difference from -0.46* -0.62* Baseline (mean) 132.6 134.2 132.9 Peak plasma levels of ­empagliflozin were roughly 20% higher in General toxicity studies in rats up to 13 weeks were performed Boehringer Ingelheim
2 not evaluated for statistical significance; not part of the In a pre-specified pooled analysis of 4 placebo-controlled stud-
baseline1 After 24 weeks, rescue therapy was used in 1 (0.7%) patient Table 10 Results at 104 week (LOCF)4 in an active controlled placebo1 (97.5% CI) (-0.73, -0.19) (-0.90, -0.34) subjects with mild and severe renal impairment as compared to with the combination of e ­ mpagliflozin and m­ etformin. In Pharma GmbH & Co. KG
sequential testing procedure for the secondary endpoints treated with e
­ mpagliflozin 25 mg/linagliptin 5 mg and in 3 (2.2%) study comparing ­empagliflozin to glimepiride as add on Change from baseline1 -2.6 -3.9 -4.0 ies, treatment with e­ mpagliflozin (68% of all patients were on subjects with normal renal function. In line with the Phase I a 13 week combination study with e ­ mpagliflozin and m­ etformin Binger Strasse 173
3 L ast observation (prior to glycemic rescue) carried forward N 112 127 110 ­metformin background) resulted in a reduction in systolic blood
Difference from -23.5* (-31.8, -28.5* (-36.7, patients treated with ­empagliflozin 10 mg/linagliptin 5 mg, com- to m
­ etformin (Full Analysis Set) study, the population pharmacokinetic analysis showed that the in rats the No-observed-adverse-effect-level (NOAEL) was based D-55216 Ingelheim am Rhein
(LOCF) placebo1 (97.5% CI) -15.1) [-1.32 -20.2) [-1.61 pared to 4 (3.1%) patients treated with linagliptin 5 mg and Difference from -1.4 (-3.6, 0.9) -1.4(-3.7, 0.8) pressure (­empagliflozin 10 mg -3.9 mmHg, e ­ mpagliflozin 25 mg apparent oral clearance of ­empagliflozin decreased with on hypochloremia seen at exposures of approximately 24- and Germany
*p-value <0.0001 (-1.72, -0.91)] (-2.01, -1.21)] 6 (4.3%) patients treated with e
­ mpagliflozin 25 mg and 1 (0.7%) Basal insulin dose (IU/day) at week 78 placebo1,4 (95% CI) -4.3 mmHg) compared with placebo (-0.5 mmHg), and in diastolic a decrease in eGFR leading to an increase in drug exposure. Based 9-times the clinical AUC exposure of e ­ mpagliflozin associated Imported by
­ mpagliflozin as add-on to m
E ­ etformin ­Empagliflozin Glimepiride
patient treated with e
­ mpagliflozin 10 mg. blood pressure (­empagliflozin 10 mg -1.8 mmHg, e ­ mpagliflozin on pharmacokinetics, no dosage adjustment is recommended in with the 10 and 25 mg doses, respectively. Boehringer Ingelheim (Phil.) Inc.
­ mpagliflozin as add on to a combination of pioglitazone therapy
E therapy in comparison to glimepiride 25 mg (up to 4 mg)
N 165 165 168 Baseline (mean) 47.84 45.13 48.43 1 mean adjusted for baseline value and stratification 25 mg -2.0 mmHg) compared with placebo (-0.5 mmHg), at week patients with renal insufficiency. 23rd Floor Citibank Tower
(+/- ­metformin ) [3] 24, that were maintained up to week 76. An embryofetal development study in pregnant rats did not indi- 8741 Paseo de Roxas
N 765 780 2 Week 18: FAS; week 52: PPS-Completers-52
Body Weight (kg) Change from baseline1 5.45 -1.21 -0.47 Hepatic Impairment cate a teratogenic effect attributed to the co-administration of Salcedo Village, Makati City
3W  eek 19-40: treat-to-target regimen for insulin dose adjust-
The efficacy and safety of ­empagliflozin in combination with ­ mpagliflozin in patients inadequately controlled on m
E ­ etformin Cardiovascular safety ­empagliflozin and m­ etformin at exposures of approximately
HbA1c (%) ment to achieve pre-defined glucose target levels (pre-prandial
pioglitazone, with or without ­metformin (75.5% of all patients Baseline (mean) 78.1 77.97 78.93 and linagliptin Difference from -6.66*** -5.92*** In subjects with mild, moderate, and severe hepatic impairment 35- and 14-times the clinical AUC exposure of e­ mpagliflozin 1500903
were on ­metformin background) was evaluated in a double- placebo1 (97.5% CI) (-11.56, -1.77) (-11.00, -0.85) <100 mg/dl (5.5 mmol/l), post-prandial <140 mg/dl (7.8 mmol/l)
Baseline (mean) 7.92 7.92 4n In a prospective, pre-specified meta-analysis of independently according to the Child-Pugh classification, AUC of ­empagliflozin associated with the 10 and 25 mg doses, respectively, and
blind, placebo-controlled study of 24 weeks duration. Change from 0.34 -1.62 -1.47  ot evaluated for statistical significance; not part of the
In patients inadequately controlled on ­metformin and linagliptin adjudicated cardiovascular events from 12 phase 2 and 3 clinical increased approximately by 23%, 47%, and 75% and Cmax by 4-times the clinical AUC exposure of m­ etformin associated with
­Empagliflozin in combination with pioglitazone (dose ≥30 mg) baseline1 sequential testing procedure for the secondary endpoints
5 mg, 24-weeks treatment with both GLYXAMBI 10 mg/5mg and Change from baseline1 -0.66 -0.55 1 mean adjusted for baseline value and stratification 5 L ast observation (prior to glycemic rescue ) carried forward studies involving 10036 patients with type 2 diabetes, approximately 4%, 23%, and 48%, respectively, compared to the 2000 mg dose. At dose levels of 600 mg/kg/day, associated
with or without ­metformin resulted in statistically significant GLYXAMBI 25 mg/5 mg provided statistically significant 2 L ast observation (prior to glycemic rescue) carried forward ­empagliflozin did not increase cardiovascular risk. subjects with normal hepatic function. Based on pharmacokinet- with 8-times the maximum recommended human dose (MRHD)
reductions in HbA1c, fasting plasma glucose, and body weight Difference from -1.95* -1.81* (LOCF)
improvements in HbA1c, FPG and body weight compared to Difference from glimepiride1 -0.11* (LOCF) 6 Week 52: FAS ics, no dosage adjustment is recommended in patients with of ­metformin in humans, teratogenicity of ­metformin was
and clinically meaningful reductions in blood pressure compared placebo1 (97.5% CI) (-2.64, -1.27) (-2.49, -1.13) placebo+linagliptin 5 mg. A statistically significantly greater (97.5%) CI) (-0.20, -0.01) In a randomized, placebo-controlled, active-comparator, cross- hepatic impairment. observed.
*p-value <0.0001 * p-value <0.0001
to placebo (Table 7). number of patients with a baseline HbA1c ≥7.0% and treated with ***p-value <0.01 over study of 30 healthy subjects no increase in QTc was
N 165 165 168 ** p-value <0.001
both doses of ­empagliflozin achieved a target HbA1c of <7% N 690 715 observed with either 25 mg or 200 mg ­empagliflozin. Body Mass Index (BMI) The following data are findings in studies performed with
In the double-blind placebo-controlled extension of this study, compared to placebo+linagliptin 5 mg (Table 9). After 24 weeks’ ­Empagliflozin as add on to MDI insulin therapy and m
­ etformin ­empagliflozin or ­metformin individually.
reductions of HbA1c (change from baseline of -0.61% for Patients(%) achiev- 5.5 18.8 13.7 ­ mpagliflozin twice daily versus once daily as add on to ­metformin
E
treatment with e­ mpagliflozin, both systolic and diastolic blood Patients (%) achieving HbA1c <7% 33.6 Pharmacokinetics No dosage adjustment is necessary based on BMI. Body mass
ing weight loss of therapy
­empagliflozin 10 mg, -0.70% for e ­ mpagliflozin 25 mg and -0.01% pressures were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for with baseline HbA1c ≥7%2 30.9 The efficacy and safety of ­empagliflozin as add-on to multiple index had no clinically relevant effect on the pharmacokinetics of ­Empagliflozin
for placebo), body weight (change from baseline of -1.47 kg for >5%3 ­ mpagliflozin + M
E ­ etformin HCl (­JARDIANCE DUO)
SBP and DBP) for e ­ mpagliflozin 25 mg+linagliptin 5 mg and -1.3/ daily insulin with or without concomitant ­metformin therapy The efficacy and safety of ­empagliflozin twice daily versus once ­empagliflozin based on the population pharmacokinetic analysis.
­empagliflozin 10 mg, -1.21 kg for e­ mpagliflozin 25 mg and -0.1 mmHg (n.s. versus placebo for SBP and DBP) for N (71.0% of all patients were on m­ etformin background) was evalu- The results of bioequivalence studies in healthy subjects demon- In general toxicity studies in rodents and dogs, signs of toxicity
+0.50 kg for placebo) and blood pressure (SBP: change from N 165 165 168 daily (daily dose of 10 mg and 25 mg) as add-on therapy in
­empagliflozin 10 mg+linagliptin 5 mg. ated in a double-blind, placebo-controlled trial of 52 weeks strated that E
­ mpagliflozin + ­Metformin HCl (­JARDIANCE DUO) Gender were observed at exposures greater than or equal to 10-times the
baseline of -1.7 mmHg for ­empagliflozin 10 mg, -3.4 mmHg for FPG (mg/dL) [mmol/L] patients with insufficient glycaemic control on m ­ etformin mono-
duration. During the initial 18 weeks and the last 12 weeks, the 5 mg/500 mg, 5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/500 mg, No dosage adjustment is necessary based on gender. Gender had clinical dose of 25 mg. Most toxicity was consistent with second-
­empagliflozin 25 mg and +0.3 mmHg for placebo, DBP: change SBP (mmHg)2, 3 therapy was evaluated in a double blind placebo-controlled study
After 24 weeks, rescue therapy was used in 4 (3.6%) patients insulin dose was kept stable, but was adjusted to achieve pre- 12.5 mg/850 mg, and 12.5 mg/1000 mg combination tablets are no clinically relevant effect on the pharmacokinetics of ary pharmacology related to urinary glucose loss and included
from baseline of -1.3 mmHg for ­empagliflozin 10 mg, -2.0 mmHg Baseline (mean) 150.00 149.82 of 16 weeks duration. All treatments with e ­ mpagliflozin resulted
Baseline (mean) 125.7 126.5 125.9 treated with e
­ mpagliflozin 25 mg+linagliptin 5 mg and in 2 (1.8%) prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-pran- bioequivalent to co-administration of corresponding doses of ­empagliflozin based on the population pharmacokinetic analysis. decreased body weight and body fat, increased food consump-
for e
­ mpagliflozin 25 mg and +0.2 mmHg for placebo) were sus- in significant reductions in HbA1c from baseline (total mean
patients treated with ­empagliflozin 10 mg+linagliptin 5 mg, com- dial glucose levels <140 mg/dl [7.8 mmol/l] between Weeks 19 ­empagliflozin and m
­ etformin as individual tablets. tion, diarrhoea, dehydration, decreased serum glucose and
tained up to Week 76. Change from baseline1 -15.36 -2.98 7.8%) after 16 weeks of treatment compared with placebo.
Change from 0.7 -3.1 -4.0 pared to 13 (12.0%) patients treated with placebo+linagliptin and 40. ­Empagliflozin twice daily dose regimens led to comparable Race increases in other serum parameters reflective of increased pro-
baseline1 5 mg. Administration of 12.5 mg e ­ mpagliflozin/1000 mg ­metformin tein metabolism, gluconeogenesis and electrolyte imbalances,
Table 7 Results of a 24-week (LOCF)3 placebo-controlled study Difference from glimepiride1 (95% CI) -12.37** reductions in HbA1c versus once daily dose regimens with
At Week 18, ­empagliflozin provided statistically significant under fed conditions resulted in a 9% decrease in AUC and a 28% No dosage adjustment is necessary based on race. Based on the urinary changes such as polyuria and glucosuria, and microscopic
of e
­ mpagliflozin as add-on to pioglitazone with or (-15.47,-9.27) a treatment difference in HbA1c reductions from baseline to week
Difference from -3.9 (-6.2, -1.5) -4.7 (-7.1, -2.4) Table 9 Efficacy Parameters Comparing ­Empagliflozin to Pla- improvement in HbA1c compared with placebo (Table 12). decrease in Cmax for e ­ mpagliflozin, when compared to fasted population pharmacokinetic analysis, AUC was estimated to be changes in kidney.
without m
­ etformin (Full Analysis Set) 16 of -0.02% (95% CI -0.16, 0.13) for e
­ mpagliflozin 5 mg twice
placebo1 (95% CI) cebo as Add-on Therapy in Patients Inadequately Con- A greater proportion of patients with a baseline HbA1c ≥7.0% conditions. For m ­ etformin, AUC decreased by 12% and Cmax 13.5% higher in Asian patients with a BMI of 25 kg/m2 compared
N 765 780 daily vs. 10 mg once daily, and -0.11% (95% CI -0.26, 0.03) for
trolled on Metformin and Linagliptin 5 mg (19.5% e
­ mpagliflozin 10 mg, 31.0% e­ mpagliflozin 25 mg) decreased by 26% compared to fasting conditions. The observed to non-Asian patients with a BMI of 25 kg/m2. Carcinogenicity
­empagliflozin 12.5 mg twice daily vs. 25 mg once daily.
Pioglitazone Placebo ­ mpagliflozin
E ­ mpagliflozin
E Body Weight (kg) achieved a target HbA1c of <7% compared with placebo (15.1%). effect of food on e ­ mpagliflozin and m
­ etformin is not considered
1 mean adjusted for baseline value and stratification to be clinically relevant. However, as ­metformin is recommended
+/- ­metformin 10 mg 25 mg 2 not evaluated for statistical significance; not part of the Metformin + Linagliptin 5 mg 2-hour postprandial glucose Geriatric ­ mpagliflozin did not increase the incidence of tumours in female
E
add-on therapy Baseline (mean) 82.52 83.03 At Week 52, treatment with e ­ mpagliflozin resulted in a statisti- to be given with meals, E ­ mpagliflozin + ­Metformin HCl rats at doses up to the highest dose of 700 mg/kg/day, which
sequential testing procedure for the secondary endpoints Treatment with ­empagliflozin as add-on to ­metformin or
­ mpagliflozin ­Empagliflozin Placebo2
E cally significant decrease in HbA1c and insulin sparing compared (­JARDIANCE DUO) is also proposed to be given with food. Age did not have a clinically meaningful impact on the pharmaco- corresponds to approximately 72- and 182- times the clinical AUC
3 L ast observation (prior to glycemic rescue) carried forward ­metformin plus sulfonylurea resulted in clinically meaningful
N 165 165 168 10 mg1 25 mg1 Change from baseline1 -3.12 1.34 with placebo and a reduction in FPG (change from baseline of improvement of 2-hour post-prandial glucose (meal tolerance kinetics of e
­ mpagliflozin based on the population pharmacoki- exposure associated with the 25 mg and 10 mg doses, respec-
(LOCF) The following data are findings in studies performed with
-0.3 mg/dl [-0.02 mmol/l] for placebo, -19.7 mg/dl [-1.09 mmol/l] test) at 24 weeks (add-on to ­metformin, placebo (n=57): +5.9 mg/ netic analysis. tively. In male rats, treatment-related benign vascular prolifera-
HbA1c (%) *p-value <0.0001 ­empagliflozin or ­metformin individually.
HbA1c (%) - 24 weeks3 Difference from glimepiride1 -4.46** for e­ mpagliflozin 10 mg, and -23.7 mg/dl [-1.31 mmol/l] for dL, ­empagliflozin 10 mg (n=52): -46.0 mg/dl, ­empagliflozin 25 mg tive lesions (hemangiomas) of the mesenteric lymph node were
(97.5% CI) (-4.87, -4.05) ­empagliflozin 25 mg), body weight, and blood pressure (SBP: (n=58): -44.6 mg/dL; add-on to m­ etformin plus sulphonylurea, Paediatric observed at 700 mg/kg/day, which corresponds to approximately
Baseline (mean) 8.16 8.07 8.06 ­Empagliflozin and linagliptin as add on therapy to m
­ etformin ­Empagliflozin
N 109 110 106 change from baseline of -2.6 mmHg for placebo, -3.9 mmHg for placebo (n=35): -2.3 mg/dL, ­empagliflozin 10 mg (n=44): 42- and 105-times the clinical exposure associated with the
N 765 780 ­empagliflozin 10 mg and 4.0 mmHg for ­empagliflozin 25 mg, DBP: -35.7 mg/dl, ­empagliflozin 25 mg (n=46): -36.6 mg/dL). Studies characterizing the pharmacokinetics of ­empagliflozin in 25 mg and 10 mg doses, respectively. These tumours are common
Change from -0.11 -0.59 -0.72 In a factorial design study, patients inadequately controlled on Absorption
Baseline (mean) 7.97 7.97 7.96 change from baseline of -1.0 mmHg for placebo, -1.4 mmHg for paediatric patients have not been performed. in rats and are unlikely to be relevant to humans. ­Empagliflozin
baseline1 ­metformin, 24-weeks treatment with both doses of e ­ mpagliflozin Patients(%) achieving weight loss of 27.5 ­empagliflozin 10 mg and -2.6 mmHg for e ­ mpagliflozin 25 mg). did not increase the incidence of tumours in female mice at doses
10 mg and 25 mg administered together with linagliptin 5 mg Patients with baseline HbA1c ≥9%
Change from baseline -0.65 -0.56 0.14 >5%2 3.8% The pharmacokinetics of ­empagliflozin have been extensively Metformin up to 1000 mg/kg/day, which corresponds to approximately
Difference from -0.48* -0.61* provided statistically significant improvements in HbA1c and FPG In a pre-specified analysis of subjects with baseline HbA1c
(adjusted mean) Table 12 Results at 18 and 52 (LOCF)5 weeks in a placebo-con- characterized in healthy volunteers and patients with T2DM. 62- and 158-times the clinical exposure associated with the
placebo1 (97.5% CI) (-0.69, -0.27) (-0.82, -0.40) compared to linagliptin 5 mg and also compared to ­empagliflozin ≥9.0%, treatment with e ­ mpagliflozin 10 mg or 25 mg as add-on to
N 765 780 trolled study of e
­ mpagliflozin as add on to multiple After oral administration, e
­ mpagliflozin was rapidly absorbed Absorption 25 mg and 10 mg doses, respectively. E ­ mpagliflozin induced renal
10 or 25 mg. Compared to linagliptin 5 mg, both doses of ­metformin resulted in statistically significant reductions in HbA1c
Comparison vs. placebo -0.79 -0.70 daily doses of insulin with metformin2 with peak plasma concentrations occurring at a median tmax tumours in male mice at 1000 mg/kg/day, which corresponds to
SBP (mmHg)3 at Week 24 (adjusted mean change from baseline of -1.49% for
(adjusted mean) (95% CI)2 (-1.02, -0.55) (-0.93, -0.46) 1.5 h post-dose. Thereafter, plasma concentrations declined in After an oral dose of m
­ etformin, Tmax is reached in 2.5 hours. approximately 45- and 113-times the clinical exposure associated
­empagliflozin 25 mg, -1.40% for ­empagliflozin 10 mg, and -0.44%
[3] P<0.0001 P<0.0001 a biphasic manner with a rapid distribution phase and a relatively Absolute bioavailability of a 500 mg or 850 mg ­metformin hydro- with the 25 mg and 10 mg doses, respectively. The mode of action
Baseline (mean) 133.4 133.5 ­ mpagliflozin as
E Placebo E
­ mpagliflozin ­ mpagliflozin
E for placebo).
slow terminal phase. The steady state mean plasma AUC and chloride tablet is approximately 50-60% in healthy subjects. After for these tumours is dependent on the natural predisposition of
FPG ( mg/dL) – 24 weeks3 add-on to insulin + 10 mg 25 mg
Table 8 Results of a 24 week (OC) placebo-controlled study of ­empagliflozin and linagliptin as fixed dose combination as add-on Cmax were 1870 nmol.h and 259 nmol/l with e ­ mpagliflozin 10 mg an oral dose, the non-absorbed fraction recovered in faeces was the male mouse to renal pathology and a metabolic pathway not
Change from baseline1 -3.1 2.5 ­metformin therapy Body weight
therapy to ­metformin (Full Analysis Set) and 4740 nmol.h/L and 687 nmol/L with ­empagliflozin 25 mg 20-30%. reflective of humans. The male mouse renal tumours are consid-
N 109 109 106 In a pre-specified pooled analysis of 4 placebo controlled stud-
once daily, respectively. Systemic exposure of e ­ mpagliflozin ered not relevant to humans.
Difference from glimepiride1 -5.6** N 188 186 189 ies, treatment with e­ mpagliflozin (68% of all patients were on
­ mpagliflozin/linagliptin ­Empagliflozin/linagliptin ­Empagliflozin
E ­ mpagliflozin
E Linagliptin increased in a dose-proportional manner. The single-dose and After oral administration, m
­ etformin hydrochloride absorption is
Baseline (mean) 167.9 170.1 162.9 (97.5% CI) (-7.0,-4.2) ­metformin background) resulted in body weight reduction com-
(25 mg/5 mg) (10 mg/5 mg) 25 mg 10 mg 5 mg HbA1c (%) at week 18 steady-state pharmacokinetics parameters of ­empagliflozin were saturable and incomplete. It is assumed that the pharmacokinet- Genotoxicity
pared to placebo at week 24 (-2.04 kg for ­empagliflozin 10 mg,
similar suggesting linear pharmacokinetics with respect to time. ics of ­metformin hydrochloride absorption are non-linear.
Change from baseline -26.3 -31.6 6.1 -2.26 kg for e
­ mpagliflozin 25 mg and -0.24 kg for placebo) that
N 134 135 140 137 128 1 Mean adjusted for baseline value and stratification Baseline (mean) 8.33 8.39 8.29 There were no clinically relevant differences in e­ mpagliflozin ­Empagliflozin is not genotoxic.
(adjusted mean) was maintained up to week 52 (-1.96 kg for ­empagliflozin 10 mg,
2N  ot evaluated for statistical significance; not part of the pharmacokinetics between healthy volunteers and patients with At the recommended m ­ etformin hydrochloride doses and dosing
-2.25 kg for e
­ mpagliflozin 25 mg and -0.16 kg for placebo).
HbA1c (%) – 24 weeks sequential testing procedure for the secondary endpoints Change from baseline1 -0.50 -0.94 -1.02 type 2 diabetes mellitus. schedules, steady state plasma concentrations are reached Reproduction Toxicity
Comparison vs. placebo -32.4 -37.7 3 LOCF, values after antihypertensive rescue censored
Blood pressure within 24 to 48 hours and are generally less than 1 µg/mL.
(adjusted mean) (95% CI) (-41.7, -23.0) (-47.0, -28.3) 4 L ast observation (prior to glycemic rescue) carried forward The pharmacokinetics of 5 mg ­empagliflozin twice daily and
Baseline (mean) 7.9 8.0 8.0 8.0 8.0 Difference from -0.44* -0.52* The efficacy and safety of ­empagliflozin was evaluated in a dou- Nonclinical studies show that ­empagliflozin crosses the placenta
p<0.0001 p<0.0001 10 mg e­ mpagliflozin once daily were compared in healthy sub-
(LOCF) placebo1 (97.5% CI) (-0.61, -0.27) (-0.69, -0.35) ble-blind, placebo-controlled study of 12 weeks duration in In controlled clinical trials, maximum ­metformin hydrochloride during late gestation to a very limited extent but do not indicate
Change from baseline -1.2 -1.1 -0.6 -0.7 -0.7 * p-value <0.0001 for non-inferiority, and p-value = 0.0153 for jects. Overall exposure (AUCss) of e
­ mpagliflozin over a 24- hour plasma levels (Cmax) did not exceed 5 µg/mL, even at maximum direct or indirect harmful effects with respect to early embryonic
Body Weight-24 weeks3 patients with type 2 diabetes and high blood pressure on differ-
(adjusted mean) superiority N 115 119 118 period with 5 mg administered twice daily was similar to 10 mg doses. development. ­Empagliflozin administered during the period of
ent antidiabetic (67.8% treated with m ­ etformin with or without
** p-value <0.0001 administered once daily. As expected, e­ mpagliflozin 5 mg admin- organogenesis was not teratogenic at doses up to 300 mg/kg in
N 109 110 106 other antidiabetic drugs including insulin) and up to 2 antihyper-
Comparison vs. linagliptin 5 mg -0.5 (-0.7, -0.3)* -0.4 (-0.6, -0.2)* HbA1c (%) at week 52 3 istered twice daily compared with 10 mg e ­ mpagliflozin once daily Food decreases the extent and slightly delays the absorption of the rat or rabbit, which corresponds to approximately 48- and
tensive therapies (Table 13). Treatment with e ­ mpagliflozin once
(adjusted mean) (95% CI)2 ­Empagliflozin as add on to basal insulin therapy resulted in lower Cmax and higher trough plasma e ­ mpagliflozin ­metformin hydrochloride. Following administration of a dose of 122- times or 128- and 325- times the clinical dose of
Baseline (mean) in kg 88.4 84.4 82.3 daily resulted in statistically significant improvement in HbA1c,
Baseline (mean) 8.25 8.40 8.37 concentrations (Cmin). 850 mg, a 40% lower plasma peak concentration, a 25% decrease ­empagliflozin based on AUC exposure associated with the 25 mg
N 134 135 140 137 128 24 hour mean systolic and diastolic blood pressure as determined
Change from baseline -3.1 -2.5 -0.3 The efficacy and safety of ­empagliflozin as add on to basal insulin by ambulatory blood pressure monitoring. Treatment with in AUC (area under the curve) and a 35 minute prolongation of the and 10 mg doses, respectively. Doses of e ­ mpagliflozin causing
with or without concomitant ­metformin and/or sulfonylurea Change from baseline1 -0.81 -1.18 -1.27 Administration of 25 mg e ­ mpagliflozin after intake of a high-fat time to peak plasma concentration were observed. The clinical maternal toxicity in the rat also caused the malformation of bent
(adjusted mean) ­empagliflozin provided reductions in seated SBP (change from
HbA1c (%) – 52 weeks1 therapy (79.8% of all patients were on m­ etformin background) and high calorie meal resulted in slightly lower exposure; AUC relevance of these decreases is unknown. limb bones at exposures approximately 155- and 393- times the
Difference from -0.38** -0.46* baseline of -0.67 mmHg for placebo, -4.60 mmHg for
Comparison vs. placebo -2.8 -2.2 was evaluated in a double-blind, placebo-controlled trial of decreased by approximately 16% and Cmax decreased by approx- clinical dose associated with the 25 mg and 10 mg doses, respec-
Baseline (mean) 7.9 8.0 8.0 8.0 8.0 placebo1 (97.5% CI) (-0.62, -0.13) (-0.70, -0.22) ­empagliflozin 10 mg and -5.47 mmHg for ­empagliflozin 25 mg)
(adjusted mean) (95% CI)1 (-3.5, -2.1) (-2.9, -1.5) 78 weeks duration. During the initial 18 weeks the insulin dose imately 37%, compared to fasted condition. The observed effect Distribution tively. Maternally toxic doses in the rabbit also caused increased
and seated DBP (change from baseline of -1.13 mmHg for pla-
P<0.0001 P<0.0001 was to be kept stable, but was adjusted to achieve a FPG <110 mg/ of food on e ­ mpagliflozin pharmacokinetics was not considered embryofetal loss at doses approximately 139- and 353- times the
Change from baseline -1.2 -1.0 -0.7 -0.7 -0.5 N 113 118 118 cebo, -3.06 mmHg for ­empagliflozin 10 mg and -3.02 mmHg for
dL in the following 60 weeks. clinically relevant and e­ mpagliflozin may be administered with or Plasma protein binding is negligible. Metformin hydrochloride clinical dose associated with the 25 mg and 10 mg doses,
(adjusted mean) ­empagliflozin 25 mg).
Patients (%) achieving HbA1c <7% with baseline HbA1c ≥7% without food. partitions into erythrocytes. The blood peak is lower than the respectively.
Patients (%) achieving 26.5 39.8 45.8
Comparison vs. linagliptin 5 mg -0.8 (-1.0, -0.6)* -0.60 (-0.8, -0.4)* - 24 weeks4 At week 18, e ­ mpagliflozin provided statistically significant Table 13 Results at 12 week (LOCF)3 in a placebo-controlled plasma peak and appears at approximately the same time. The
HbA1c <7% with base- Distribution
improvement in HbA1c compared to placebo. A greater propor- red blood cells most likely represent a secondary compartment of In pre- and postnatal toxicity studies in rats, reduced weight gain
(adjusted mean) (95% CI)2 line HbA1c ≥7% at study of ­empagliflozin in patients with type 2 diabetes
N 100 107 100 tion of patients with a baseline HbA1c ≥7.0% achieved a target and uncontrolled blood pressure (Full Analysis Set) distribution. The mean volume of distribution (Vd) ranged in offspring was observed at maternal exposures approximately
week 524 The apparent steady-state volume of distribution was estimated
N 134 135 140 137 128 HbA1c of <7% compared to placebo. At 78 weeks, ­empagliflozin between 63-276 L. 4- and 11-times the clinical dose associated with the 25 mg and
Patients (%) achieving 37.0 32.7 17.0 resulted in a statistically significant decrease in HbA1c and insu- to be 73.8 L, based on a population pharmacokinetic analysis. 10 mg doses, respectively.
N 188 186 189 Placebo E
­ mpagliflozin ­Empagliflozin
Body Weight - 24 weeks A1C <7% lin sparing compared to placebo (Table 11). Following administration of an oral [14C]-­empagliflozin solution Metabolism
At week 78, ­empagliflozin resulted in a reduction in FPG 10 mg 25 mg to healthy subjects, the red blood cell partitioning was approxi- In a juvenile toxicity study in the rat, when ­empagliflozin was
FPG (mg/dL) [mmol/L] at week 525
Baseline (mean) in kg 85 87 88 86 85 Comparison vs. placebo 4.0 2.9 -10.51 mg/dl [-0.58 mmol/l] for e­ mpagliflozin 10 mg, -17.43 mg/ mately 36.8% and plasma protein binding was 86.2%. Metformin hydrochloride is excreted unchanged in the urine. No administered from postnatal day 21 until postnatal day 90, non-
(odds ratio) (95% CI)5 (1.9, 8.7) (1.4, 6.1) dL [0.3 mmol/L] for e ­ mpagliflozin 25 mg and -5.48 mg/dL N 271 276 276
Baseline (mean) 151.6 159.1 [8.83] 150.3 [8.34] metabolites have been identified in humans. adverse, minimal to mild renal tubular and pelvic dilation in
Change from baseline -3.0 -2.6 -3.2 -2.5 -0.7 P=0.0004 p=0.0061 [-0.97 mmol/L] for placebo), body weight (-2.47 kg for Metabolism juvenile rats was seen only at 100 mg/kg/day, which approxi-
[8.41] HbA1c (%) at week 12
(adjusted mean) ­empagliflozin 10 mg, -1.96 kg for e ­ mpagliflozin 25 mg and No major metabolites of ­empagliflozin were detected in human Elimination mates 11-times the maximum clinical dose of 25 mg. These find-
1Patients randomized to the e ­ mpagliflozin 10 mg or 25 mg groups +1.16 kg for placebo, p< 0.0001), blood pressure (SBP: -4.1 mmHg Change from baseline1 -0.3 -19.7 [-1.09] -23.7 [-1.31] plasma and the most abundant metabolites were three glucuro- Renal clearance of ­metformin hydrochloride is >400 mL/min, ings were absent after a 13 weeks drug-free recovery period.
Baseline (mean) 7.90 7.87 7.92
Comparison vs. linagliptin 5 mg -2.3 (-3.2, -1.4)* -1.9 (-2.8, -1.1)* were receiving GLYXAMBI® 10 mg/5 mg or 25 mg/5 mg with for e
­ mpagliflozin 10 mg, -2.4 mmHg for e ­ mpagliflozin 25 mg and [-0.02] nide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic indicating that m
­ etformin hydrochloride is eliminated by glo-
(adjusted mean) (95% CI)4 +0.1 mmHg for placebo, DPB: -2.9 mmHg for ­empagliflozin 10 mg, exposure of each metabolite was less than 10% of total drug- merular filtration and tubular secretion. Following an oral dose, Metformin
background ­metformin Change from baseline1 0.03 -0.59 -0.62
2Patients randomized to the placebo group were receiving the -1.5 mmHg for e ­ mpagliflozin 25 mg and -0.3 mmHg for placebo). Difference from -19.3 (-27.9, -23.4 (-31.8, related material. In vitro studies suggested that the primary route the apparent terminal elimination half-life is approximately
N 123 128 132 125 119 placebo plus linagliptin 5 mg with background ­metformin placebo1(95% CI) -10.8) [-1.07 -14.9)[-1.30 Difference from placebo1 -0.62* -0.65* of metabolism of ­empagliflozin in humans is glucuronidation by 6.5 hours. When renal function is impaired, renal clearance is Non-clinical data reveal no special hazard for humans based on
3MMRM model on FAS (OC) includes baseline HbA1c, baseline Table 11 Results at 18, 78 week (LOCF)2 in a placebo-controlled (-1.55, -0.6)] (-1.77, -0.83)] (95% CI) (-0.72, -0.52) (-0.75, -0.55) the uridine 5‘-diphospho-glucuronosyltransferases, UGT1A3, decreased in proportion to that of creatinine and thus the elimi- conventional studies on safety pharmacology, genotoxicity, and
Patients (%) achieving HbA1c <7% 62 58 33 28 36 eGFR (MDRD), geographical region, visit treatment,and treat- study of ­empagliflozin as add on to basal insulin with or UGT1A8, UGT1A9, and UGT2B7. nation half-life is prolonged, leading to increased levels of carcinogenic potential. In a 2 week ­metformin only study and
with baseline HbA1c ≥7% - 24 weeks ment by visit interaction. For FPG, baseline FPG is also included. without m­ etformin and/or sulphonylurea (Full Analysis N 115 118 117 24 hour SBP at week 122 ­metformin hydrochloride in plasma. 2 and 13-week toxicity e­ mpagliflozin/­metformin studies in rats,
For weight, baseline weight is also included. Set -Completers) Elimination ­metformin related toxicity was seen in heart, liver, kidneys, sali-
Comparison vs. linagliptin 5 mg 3.5 (1.9, 6.4)* 2.8 (1.6, 5.0)** 4not evaluated for statistical significance; not part of sequential Insulin dose (IU/day) at week 52 3 Baseline (mean) 131.72 131.34 131.18 Special populations vary glands, ovaries, gastrointestinal tract and adrenal glands at
(odds ratio) (95% CI)3 testing procedure for the secondary endpoints Basal insulin +/- Placebo ­Empagliflozin ­ mpagliflozin
E The apparent terminal elimination half-life of ­empagliflozin was dosages associated with a systemic exposure of 5 times the
5Logistic regression on FAS (NCF) includes baseline HbA1c, base- ­metformin or sulfonyl- 10 mg 25 mg Baseline (mean) 89.94 88.57 90.38 Change from baseline1 0.48 -2.95 -3.68 estimated to be 12.4 h and apparent oral clearance was 10.6 L/h Renal impairment MRHD or higher.
1 not evaluated for statistical significance as a result of the sequential confirmatory testing procedure line eGFR (MDRD), geographical region, and treatment; based urea add-on therapy based on the population pharmacokinetic analysis. The inter-
2 Full analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by treat- on patients with HbA1c of 7% and above at baseline Change from baseline1 10.16 1.33 -1.06 Difference from placebo1 -3.44* -4.16* subject and residual variabilities for e
­ mpagliflozin oral clearance The available data in subjects with moderate renal insufficiency Metformin was not teratogenic in rats at a dose of 200 mg/kg/day
ment interaction, and baseline HbA1c. N 125 132 117 (95% CI) (-4.78, -2.09) (-5.50, -2.83) were 39.1% and 35.8%, respectively. With once-daily dosing, are scarce and no reliable estimation of the systemic exposure to associated with a systemic exposure of 4 times the MRHD
3 Full analysis population with non-completers considered failure. Logistic regression included treatment, baseline renal function, Difference from -8.83** -11.22** steady-state plasma concentrations of ­empagliflozin were ­metformin in this subgroup as compared to subjects with normal (2000 mg ­metformin). At higher doses (500 and 1000 mg/kg/day,
In a prespecified subgroup of patients with baseline HbA1c
HbA1c (%) at week 18 placebo1 (97.5% CI) (-15.69, -1.97) (-18.09, -4.36) 24 hour DBP at week 122 reached by the fifth dose. Consistent with the half-life, up to 22% renal function could be made. Therefore, the dose adaptation associated with 11 and 23 times the MRHD), teratogenicity of
geographical region and baseline HbA1c. greater or equal than 8.5% the reduction from baseline in HbA1c
4 Full analysis population using last observation carried forward. ANCOVA model included treatment, renal function, region, baseline with e ­ mpagliflozin 25 mg+linagliptin 5 mg was -1.3% at 24 weeks accumulation, with respect to plasma AUC, was observed at should be made upon clinical efficacy/tolerability considerations
Baseline (mean) 8.10 8.26 8.34 N 115 119 118 Baseline (mean) 75.16 75.13 74.64 steady-state. Following administration of an oral [14C]-­ (see section Dosage and administration).
weight, and baseline HbA1c. (p<0.0001 versus placebo+linagliptin 5 mg) and with
*P<0.0001 ­empagliflozin 10 mg+linagliptin 5 mg -1.3% at 24 weeks empagliflozin solution to healthy subjects, approximately 95.6%
of the drug related radioactivity was eliminated in faeces (41.2%) Store in a safe place out of the reach of children!
**P<0.001 (p<0.0001 versus placebo+linagliptin 5 mg).