August 2014

TRAJENTA DUO
Film Coated Tablets

2.5mg/500mg
2.5mg/850mg
2.5mg/1,000mg
PRESCRIBING INFORMATION

NAME OF THE MEDICINAL PRODUCT: Trajenta Duo 2.5mg/500mg,

Trajenta Duo 2.5mg/850mg,
Trajenta Duo 2.5mg/1000mg

COMPOSITION: see section 10 ("Description")

WARNING: RISK OF LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk
increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic
impairment, and acute congestive heart failure.
The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory
distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If acidosis is suspected, TRAJENTA-DUO should be discontinued and the patient hospitalized immediately.
[See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE

1.1 Indication
TRAJENTA-DUO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type
2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate [see Dosage and Administration
(2.1) and Clinical Studies (14.1)].

1.2 Important Limitations of Use

TRAJENTA-DUO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it
would not be effective in these settings. TRAJENTA-DUO has not been studied in patients with a history of pancreatitis.
It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis
while using TRAJENTA-DUO [see Warnings and Precautions (5.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The dosage of TRAJENTA-DUO should be individualized on the basis of both effectiveness and tolerability, while not
exceeding the maximum recommended dose of 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily.
TRAJENTA-DUO should be given twice daily with meals. Dose escalation should be gradual to reduce the
gastrointestinal (GI) side effects associated with metformin use. For available dosage forms and strengths see [Dosage
Forms and Strengths (3)].

Recommended starting dose:

 In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin
hydrochloride twice daily
 In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at
each of the two daily meals (e.g., a patient on metformin 1000 mg twice daily would be started on 2.5 mg
linagliptin/1000 mg metformin hydrochloride twice daily with meals).
 Patients already treated with linagliptin and metformin individual components may be switched to TRAJENTA-DUO
containing the same doses of each component.

No studies have been performed specifically examining the safety and efficacy of TRAJENTA-DUO in patients
previously treated with other oral antihyperglycemic agents and switched to TRAJENTA-DUO. Any change in therapy of
type 2 diabetes mellitus should be undertaken with care and appropriate monitoring as changes in glycemic control can
occur.

2.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
When TRAJENTA-DUO is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower
dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and
Precautions (5.5)].

3 DOSAGE FORMS AND STRENGTHS

TRAJENTA-DUO is a combination of linagliptin and metformin hydrochloride. TRAJENTA-DUO tablets are available
in the following dosage forms and strengths:
 2.5 mg linagliptin/500 mg metformin hydrochloride tablets are light yellow, oval, biconvex tablets debossed with
“D2/500” on one side and the Boehringer Ingelheim logo on the other side
 2.5 mg linagliptin/850 mg metformin hydrochloride tablets are light orange, oval, biconvex tablets debossed with
“D2/850” on one side and the Boehringer Ingelheim logo on the other side
 2.5 mg linagliptin/1000 mg metformin hydrochloride tablets are light pink, oval, biconvex tablets debossed with
“D2/1000” on one side and the Boehringer Ingelheim logo on the other side

4 CONTRAINDICATIONS
TRAJENTA-DUO is contraindicated in patients with:
 Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine
clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial
infarction, and septicemia [see Warnings and Precautions (5.1, 5.3)]
 Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with
insulin [see Warnings and Precautions (5.1)]
 A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions,
urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]
 Hypersensitivity to metformin
 Type 1 diabetes

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5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Metformin
Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with
TRAJENTA-DUO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a
number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue
hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased
blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin
is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years,
(with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in
clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with
significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of
multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart
failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to
unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of
renal impairment and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular
monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied
by careful monitoring of renal function. Metformin treatment should not be initiated in any patient unless measurement of
creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld
in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function
may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory
evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin,
since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily
discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of
food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-
dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions
(7.1) and Clinical Pharmacology (11.3)].

The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias,
respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated
with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize
and promptly report these symptoms. If present, TRAJENTA-DUO should be discontinued until lactic acidosis is ruled
out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently
observed in subjects on a chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable,
dose of metformin could be caused by lactic acidosis or other serious disease.

To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin
levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in
patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such
as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis
(ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient
with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures
promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and
prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such
management often results in prompt reversal of symptoms and recovery [see Boxed Warning].

5.2 Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin.
Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue
TRAJENTA-DUO and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are
at increased risk for the development of pancreatitis while using TRAJENTA-DUO.
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5.3 Monitoring of Renal Function
Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney.
The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore,
TRAJENTA-DUO is contraindicated in patients with renal impairment.

Before initiation of therapy with TRAJENTA-DUO and at least annually thereafter, renal function should be assessed and
verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function
should be assessed more frequently and TRAJENTA-DUO discontinued if evidence of renal impairment is present.

Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if TRAJENTA-DUO is
discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with
renal impairment.

Use of concomitant medications that may affect renal function or metformin disposition:
Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with
the disposition of metformin should be used with caution [see Drug Interactions (7.1) and Clinical Pharmacology (11.3)].

Radiological studies and surgical procedures:

Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous
cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been
associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned,
TRAJENTA-DUO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours
subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

TRAJENTA-DUO should be temporarily discontinued for any surgical procedure (except minor procedures not associated
with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal
function has been evaluated as normal.

5.4 Impaired Hepatic Function

Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy,
TRAJENTA-DUO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see
Warnings and Precautions (5.1)].

5.5 Use with Medications Known to Cause Hypoglycemia

Linagliptin
Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin
secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical
trial [see Adverse Reactions (6.1)]. The use of linagliptin in combination with insulin in subjects with severe renal
impairment was associated with a higher rate of hypoglycemia [see Adverse Reactions (6.1)]. Therefore, a lower dose of
the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with
TRAJENTA-DUO [see Dosage and Administration (2.2)].

Metformin
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur
when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during
concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or
malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible
to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-
adrenergic blocking drugs.

5.6 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the
components of TRAJENTA DUO). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions.
Onset of these reactions occurred within the first 3 months after initiation of treatment with linagliptin, with some reports
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occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRAJENTA DUO, assess for
other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a
history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to
angioedema with TRAJENTA DUO.

5.7 Vitamin B12 Levels

In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12
levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease,
possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated
with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more
relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have
been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of
metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in
patients on TRAJENTA-DUO and any apparent abnormalities should be appropriately investigated and managed. Certain
individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing
subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be
useful.

5.8 Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned
against excessive alcohol intake while receiving TRAJENTA-DUO [see Warnings and Precautions (5.1)].

5.9 Hypoxic States

Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction,
and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal
azotemia. When such events occur in patients on TRAJENTA-DUO therapy, the drug should be promptly discontinued
[see Warnings and Precautions (5.1)].

5.10 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or
metformin or any other antidiabetic drug.

6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed
in practice.

Linagliptin/Metformin
The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately
1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials.

Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1
study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in ≥5% of
patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin
(n=539) included nasopharyngitis (5.7% vs 4.3%).

In a 24-week factorial design study, adverse events reported in ≥5% of patients receiving linagliptin + metformin and
were more common than in patients given placebo are shown in Table 1.

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Table 1 Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and
Greater than with Placebo in a 24-week Factorial-Design Study

Placebo Linagliptin Metformin Combination of

n=72 Monotherapy Monotherapy Linagliptin with
n=142 n=291 Metformin
n=286
n (%) n (%) n (%) n (%)
Nasopharyngitis 1 (1.4) 8 (5.6) 8 (2.7) 18 (6.3)
Diarrhea 2 (2.8) 5 (3.5) 11 (3.8) 18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g.,
urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and
pancreatitis.

Linagliptin
Adverse reactions reported in ≥2% of patients treated with linagliptin 5mg and more commonly than in patients treated
with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).

Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific
anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin
was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin
was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin
therapy.

Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g.,
urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program,
pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared
with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator,
sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Metformin
The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia,
indigestion, abdominal discomfort, and headache.

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely
result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.5)].

Hypoglycemia
Linagliptin/Metformin
In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin +
metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When
linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported
hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and
sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose
measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that
all these reports reflect true hypoglycemia.

Linagliptin
In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no
significant difference in the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic
episodes with a self measured blood glucose ≤70 mg/dL, was noted between the linagliptin- (31.4%) and placebo-
(32.9%) treated groups.

6
Use in Renal Impairment
Linagliptin was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with
severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic
therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose
adjustments in antidiabetic background therapy were allowed.

In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other
linagliptin trials. The observed incidence of hypoglycemia was higher (linagliptin, 63% compared to placebo, 49%) due to
an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic
therapies were kept stable. Ten linagliptin-treated patients (15%) and 11 placebo-treated patients (17%) reported at least
one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same
time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively
administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) linagliptin-treated patients and
3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in
2 (2.9%) patients on linagliptin and 1 (1.5%) patient on placebo.

Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to
placebo.

Laboratory Tests
Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated
with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin
group and 1% more than in the placebo group were not detected.

No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of linagliptin. Because these reactions are
reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
・ Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]
・ Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see Warnings and
Precautions (5.6)]
・ Rash

7 DRUG INTERACTIONS
7.1 Drug Interactions with Metformin
Cationic Drugs
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene,
trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction
with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical
(except for cimetidine), careful patient monitoring and dose adjustment of TRAJENTA-DUO and/or the interfering drug
is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory
system [see Warnings and Precautions (5.3) and Clinical Pharmacology (11.3)].

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently
decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these
drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with TRAJENTA-DUO, as the risk
of lactic acidosis may increase [see Warnings and Precautions (5.1) and Clinical Pharmacology (11.3)].
7.2 Drug Interactions With Linagliptin
Inducers of P-glycoprotein and CYP3A4 Enzymes

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Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in
combination with a strong P-gp inducer or CYP 3A4 inducer. As TRAJENTA-DUO is a fixed-dose combination of
linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when
concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary [see Clinical Pharmacology (11.3)].

7.3 Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides
and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic
acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient
receiving TRAJENTA-DUO, the patient should be closely observed to maintain adequate glycemic control [see Clinical
Pharmacology (11.3)]. When such drugs are withdrawn from a patient receiving TRAJENTA-DUO, the patient should be
observed closely for hypoglycemia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Pregnancy Category B
TRAJENTA-DUO
There are no adequate and well controlled studies in pregnant women with TRAJENTA-DUO or its individual
components, and some clinical data is available for metformin which indicate that the risk for major malformations was
not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated
with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm,
TRAJENTA-DUO should be used during pregnancy only if clearly needed.

TRAJENTA-DUO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses
similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the
metformin component of the combination was associated with an increased incidence of fetal rib and scapula
malformations.

Linagliptin
Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period
of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times
the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or
reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation
day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose, based on exposure.

Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.

Metformin Hydrochloride
Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in
Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body
surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on
exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain.
Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area).

Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2
times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of
offspring.

Metformin crosses the placenta into the fetus in rats and humans.

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8.2 Nursing Mothers
No studies in lactating animals have been conducted with the combined components of TRAJENTA-DUO. In studies
performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is
not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations.
Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Pediatric Use

Safety and effectiveness of TRAJENTA-DUO in pediatric patients under 18 years of age have not been established.

8.4 Geriatric Use

Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering
that aging can be associated with reduced renal function, TRAJENTA-DUO should be used with caution as age increases
[see Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (11.3)].

Linagliptin
There were 4040 type 2 diabetes treated with linagliptin 5 mg from 15 clinical trials of linagliptin; 1085 (27%) patients
were 65 years and over, while 131 (3%) patients were 75 years and over. Of these patients, 2566 were enrolled in 12
double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No
overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients.
Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not
identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals
cannot be ruled out.

Metformin
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they
respond differently from younger patients, although other reported clinical experience has not identified differences in
responses between the elderly and young patients. The initial and maintenance dosing of metformin should be
conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose
adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and
Precautions (5.3), and Clinical Pharmacology (11.3)].

9 OVERDOSAGE
In the event of an overdose with TRAJENTA-DUO, employ the usual supportive measures (e.g., remove unabsorbed
material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the
patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is
dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be
useful partly for removal of accumulated metformin from patients in whom TRAJENTA-DUO overdosage is suspected.

Linagliptin
During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120
times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience
with doses above 600 mg in humans.
Metformin
Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported
in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been
reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions (5.1)].

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10 DESCRIPTION
TRAJENTA-DUO tablets contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus:
linagliptin and metformin hydrochloride.

Linagliptin
Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-

3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-

The empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is:

O
N N
N
N
N
O N N
NH2

Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9
mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly
soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL).

Metformin Hydrochloride
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or
pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to
off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin
hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of
metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:

TRAJENTA-DUO
TRAJENTA-DUO is available for oral administration as tablets containing 2.5 mg linagliptin and 500 mg metformin
hydrochloride (TRAJENTA-DUO 2.5 mg/500 mg), 850 mg metformin hydrochloride (TRAJENTA-DUO 2.5 mg/850 mg)
or 1000 mg metformin hydrochloride (TRAJENTA-DUO 2.5 mg/1000 mg). Each film-coated tablet of TRAJENTA-DUO
contains the following inactive ingredients: arginine, corn starch, copovidone, colloidal silicon dioxide, magnesium
stearate, titanium dioxide, propylene glycol, hypromellose, talc, yellow ferric oxide (2.5 mg/500 mg; 2.5 mg/850 mg)
and/or red ferric oxide (2.5 mg/850 mg; 2.5 mg/1000 mg).

11 CLINICAL PHARMACOLOGY
11.1 Mechanism of Action
TRAJENTA-DUO
TRAJENTA-DUO combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic
control in patients with type 2 diabetes mellitus: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a
member of the biguanide class.

10
Linagliptin
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin
hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the
circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin
hormones 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.

Metformin
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus,
lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other
classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption
of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs,
metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in
special circumstances) [see Warnings and Precautions (5.9)] and does not cause hyperinsulinemia. With metformin
therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may
actually decrease.

11.2 Pharmacodynamics
Linagliptin
Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin
glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the
glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9
activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a
single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No
increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak
linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.

11.3 Pharmacokinetics
TRAJENTA-DUO
The results of a bioequivalence study in healthy subjects demonstrated that TRAJENTA-DUO (linagliptin/metformin
hydrochloride) 2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg combination tablets are bioequivalent to
coadministration of corresponding doses of linagliptin and metformin as individual tablets. Administration of linagliptin
2.5 mg/metformin hydrochloride 1000 mg fixed-dose combination with food resulted in no change in overall exposure of
linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was
decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed
for metformin under fed conditions. These changes are not likely to be clinically significant.

Absorption
Linagliptin
The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, plasma concentrations of
linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding
of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulation of the drug. The
effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5
mg, is approximately 12 hours. After once-daily dosing, steady state plasma concentrations of linagliptin 5 mg are reached
by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady-state compared with the first dose. Plasma
AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The
pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes.

Metformin
11
The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately
50% to 60%. Studies using single oral doses of metformin tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate
that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an
alteration in elimination.

Distribution
Linagliptin
The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to
healthy subjects is approximately 1110 L, 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% to 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% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma.
Plasma binding is not altered in patients with renal or hepatic impairment.

Metformin
The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin
hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to SUs,
which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At
usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations of metformin are
reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum
metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism
Linagliptin
Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism
represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically
inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.

Metformin
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and
does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion
Linagliptin
Following administration of an oral [14C]linagliptin dose to healthy subjects, approximately 85% of the administered
radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at
steady state was approximately 70 mL/min.

Metformin
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the
major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is
eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In
blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment
of distribution.

Specific Populations
Renal Impairment
TRAJENTA-DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of
TRAJENTA-DUO in renally impaired patients have not been performed. Since metformin is contraindicated in patients
with renal impairment, use of TRAJENTA-DUO is also contraindicated in patients with renal impairment (e.g., serum
creatinine ≥1.5 mg/dL [males] or ≥1.4 mg/dL [females], or abnormal creatinine clearance) [see Contraindications (4) and
Warnings and Precautions (5.3)].

Linagliptin: Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to
healthy subjects. In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin

12
increased (AUC,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a
prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin
was below 5% of the administered dose and was not affected by decreased renal function.

Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40%
higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUC by 42% and Cmax by
35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

Metformin: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-
life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance
[see Contraindications (4) and Warnings and Precautions (5.3)].

Hepatic Impairment
TRAJENTA-DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of
TRAJENTA-DUO in hepatically impaired patients have not been performed. However, use of metformin alone in patients
with hepatic impairment has been associated with some cases of lactic acidosis. Therefore, use of TRAJENTA-DUO is
not recommended in patients with hepatic impairment [see Warnings and Precautions (5.4)].

Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,ss) of linagliptin
was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with
moderate hepatic impairment (Child-Pugh class B), AUCss, of linagliptin was about 14% lower and Cmax,ss was
approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had
comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy
subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in
reductions in DPP-4 inhibition.

Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic
impairment.

Body Mass Index (BMI)/Weight

Linagliptin: BMI/Weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population
pharmacokinetic analysis.

Gender
Linagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population
pharmacokinetic analysis.

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects
and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in
patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.

Geriatric
TRAJENTA-DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of
TRAJENTA-DUO in geriatric patients have not been performed. Based on the metformin component, TRAJENTA-DUO
treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates
that renal function is not reduced [see Warnings and Precautions (5.1, 5.3) and Use in Specific Populations (8.5)].

Linagliptin: Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population
pharmacokinetic analysis.

Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects
suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared
with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is
primarily accounted for by a change in renal function.

13
Pediatric
Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of TRAJENTA-DUO in
pediatric patients have not yet been performed.

Race
Linagliptin: Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available
pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups.

Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed.
In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was
comparable in Caucasians (n=249), Blacks (n=51), and Hispanics (n=24).

Drug Interactions
Pharmacokinetic drug interaction studies with TRAJENTA-DUO have not been performed; however, such studies have
been conducted with the individual components of TRAJENTA-DUO (linagliptin and metformin hydrochloride).

Linagliptin
In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not
an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.

Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations.
Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with
other P-gp substrates at therapeutic concentrations.

In vivo Assessment of Drug Interactions

Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely
ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9,
CYP2C8, P-gp, and OCT. No dose adjustment of linagliptin is recommended based on results of the described
pharmacokinetic studies.

Table 2 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

Geometric Mean Ratio

Coadministered Dosing of (ratio with/without coadministered
Dosing of Linagliptin*
Drug Coadministered Drug* drug)
No effect=1.0
AUC† Cmax
No dosing adjustments required for linagliptin when given with following coadministered drugs:
Metformin 850 mg TID 10 mg QD 1.20 1.03
#
Glyburide 1.75 mg 5 mg QD 1.02 1.01
Pioglitazone 45 mg QD 10 mg QD 1.13 1.07
#
Ritonavir 200 mg BID 5 mg 2.01 2.96
The efficacy of TRAJENTA-DUO may be reduced when administered in combination with strong inducers of
CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatments is strongly recommended [see Drug Interactions
(7.2)].
Rifampin 600 mg QD 5 mg QD 0.60 0.56
*Multiple dose (steady state) unless otherwise noted
#
Single dose
†AUC = AUC(0 to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments
QD = once daily
BID = twice daily
TID = three times daily

14
Table 3 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Geometric Mean Ratio

Coadministered Dosing of (ratio with/without coadministered
Dosing of Linagliptin*
Drug Coadministered Drug* drug)
No effect=1.0
AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Metformin 850 mg TID 10 mg QD metformin 1.01 0.89
Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86
pioglitazone
metabolite M- 0.94 0.86
Pioglitazone 45 mg QD 10 mg QD III 0.98 0.96
metabolite M- 1.04 1.05
IV
Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94
simvastatin 1.34 1.10
Simvastatin 40 mg QD 10 mg QD
simvastatin acid 1.33 1.21
R-warfarin 0.99 1.00
S-warfarin 1.03 1.01
Warfarin 10 mg# 5 mg QD
INR 0.93** 1.04**
PT 1.03** 1.15**
ethinylestradiol 0.03 mg
Ethinylestradiol and ethinylestradiol 1.01 1.08
and levonorgestrel 0.150 5 mg QD
levonorgestrel levonorgestrel 1.09 1.13
mg QD
* Multiple dose (steady state) unless otherwise noted
#
Single dose
†AUC = AUC(INF) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments
**AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points
INR = International Normalized Ratio
PT = Prothrombin Time
QD = once daily
BID = twice daily
TID = three times daily

15
Metformin hydrochloride

Table 4 Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Geometric Mean Ratio

Coadministered Dosing of (ratio with/without coadministered
Dose of Metformin*
Drug Coadministered Drug* drug)
No effect=1.0
AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡
Nifedipine 10 mg 850 mg metformin 1.16 1.21
Propranolol 40 mg 850 mg metformin 0.90 0.94
Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution [see
Warnings and Precautions (5.9) and Drug Interactions (7.1)].
Cimetidine 400 mg 850 mg metformin 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution [see Warnings and Precautions
(5.1) and Drug Interactions (7.1)].
Topiramate** 100 mg 500 mg metformin 1.25 1.17
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF)
‡ Ratio of arithmetic means
**At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 5 Effect of Metformin on Coadministered Drug Systemic Exposure

Geometric Mean Ratio

Coadministered Dosing of
Dose of Metformin* (ratio with/without metformin)
Drug Coadministered Drug*
No effect=1.0
AUC† Cmax
No dosing adjustments required for the following coadministered drugs:
Glyburide 5 mg 500 mg§ glyburide 0.78‡ 0.63‡
Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡
Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08
Propranolol 40 mg 850 mg propranolol 1.01§ 0.94
Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF) unless otherwise noted
‡ Ratio of arithmetic means, p-value of difference <0.05
§ AUC(0-24 hr) reported
¶ Ratio of arithmetic means

12 NONCLINICAL TOXICOLOGY
12.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
TRAJENTA-DUO
No animal studies have been conducted with the combined products in TRAJENTA-DUO to evaluate carcinogenesis,
mutagenesis, or impairment of fertility. General toxicity studies in rats up to 13 weeks were performed with TRAJENTA-
DUO.

16
The following data are based on the findings in studies with linagliptin and metformin individually.

Linagliptin
Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60
mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of 5 mg/day based on AUC exposure.
Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25
mg/kg (females), or approximately 35 and 270 times the clinical dose based on AUC exposure. Higher doses of linagliptin
in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215 times the clinical dose based on
AUC exposure.

Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity
assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.

In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing
live young up to the highest dose of 240 mg/kg (approximately 943 times the clinical dose based on AUC exposure).

Metformin Hydrochloride
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration
of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both
approximately 4 times the maximum recommended human daily dose of 2000 mg/kg/day based on body surface area
comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there
was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of
benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (Salmonella
typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes).
Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which
is approximately 2 times the MRHD based on body surface area comparisons.

13 CLINICAL STUDIES
The coadministration of linagliptin and metformin has been studied in patients with type 2 diabetes mellitus inadequately
controlled on diet and exercise and in combination with sulfonylurea.

There have been no clinical efficacy studies conducted with TRAJENTA-DUO; however, bioequivalence of TRAJENTA-
DUO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

13.1 Initial Combination Therapy With Metformin

A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in
the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy
of linagliptin as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout
period of 4 weeks’ duration. After the washout period and after completing a 2-week single-blind placebo run-in period,
patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized. Patients with inadequate glycemic
control (A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week
single-blind placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs
≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to
either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive
initial therapy with 5 mg of linagliptin once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin
twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific
glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.

Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C, and fasting
plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 6, Figure 1). The adjusted
mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for
17
linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000 mg twice daily; -1.1% (95% CI -1.4, -0.9;
p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to linagliptin 5 mg once daily; -0.6% (95% CI
-0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily;
and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to linagliptin 5
mg once daily.

Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the 6 treatment groups.

Table 6 Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin, Alone and in
Combination in Randomized Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and
Exercise**

Placebo Linagliptin Metformin Linagliptin Metformin Linagliptin 2.5

5 mg Once 500 mg 2.5 mg 1000 mg mg Twice
Daily* Twice Daily Twice Daily* Twice Daily Daily* +
+ Metformin Metformin
500 mg 1000 mg
Twice Daily Twice Daily
A1C (%)
Number of patients n=65 n=135 n=141 n=137 n=138 n=140
Baseline (mean) 8.7 8.7 8.7 8.7 8.5 8.7
Change from baseline
0.1 -0.5 -0.6 -1.2 -1.1 -1.6
(adjusted mean****)
Difference from placebo -- -0.6 (-0.9, - -0.8 (-1.0, - -1.3 (-1.6, - -1.2 (-1.5, - -1.7 (-2.0, -1.4)
(adjusted mean) (95% 0.3) 0.5) 1.1) 0.9)
CI)
Patients (%) achieving
7 (10.8) 14 (10.4) 26 (18.6) 41 (30.1) 42 (30.7) 74 (53.6)
A1C <7% ***
Patients (%) receiving
29.2 11.1 13.5 7.3 8.0 4.3
rescue medication
FPG (mg/dL)
Number of patients n=61 n=134 n=136 n=135 n=132 n=136
Baseline (mean) 203 195 191 199 191 196
Change from baseline
10 -9 -16 -33 -32 -49
(adjusted mean****)
Difference from placebo -- -19 (-31, -6) -26 (-38, -14) -43 (-56, -31) -42 (-55, -30) -60 (-72, -47)
(adjusted mean) (95%
CI)
* Total daily dose of linagliptin is equal to 5 mg
** Full analysis population using last observation on study
*** Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily + Metformin 500 twice daily, n=136;
Metformin 1000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily + Metformin 1000 mg twice daily, n=138.
**** HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c
as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well
as baseline HbA1c and baseline FPG as continuous covariates.

18
Figure 1 Adjusted Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin and
Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled
with Diet and Exercise - FAS completers.

13.2 Initial Combination Therapy with Linagliptin and Metformin vs Linagliptin in Treatment-Naïve Patients
A total of 316 patients with type 2 diabetes diagnosed within the previous 12 months and treatment-naïve (no antidiabetic
therapy for 12 weeks prior to randomization) and inadequate glycemic control (A1C ≥8.5% to ≤12.0%) participated in a
24-week, randomized, double-blind, study designed to assess the efficacy of linagliptin in combination with metformin vs
linagliptin. Patients were randomized (1:1), after a 2-week run-in period, to either linagliptin 5 mg plus metformin (1500
to 2000 mg per day, n=159) or linagliptin 5 mg plus placebo, (n=157) administered once daily. Patients in the linagliptin
and metformin treatment group were up-titrated to a maximum tolerated dose of metformin (1000 to 2000 mg per day)
over a three-week period.
Initial therapy with the combination of linagliptin and metformin provided statistically significant improvements in A1C
compared to linagliptin (Table 7). The mean difference between groups in A1C change from baseline was -0.8% with 2-
sided 95% confidence interval (-1.23%, -0.45%).

19
Table 7 Glycemic Parameters at 24 Weeks in Study Comparing Linagliptin in Combination with Metformin to
Linagliptin in Treatment-Naïve Patients*

Linagliptin 5 mg + Linagliptin 5 mg +
Metformin Placebo
A1C (%) *
Number of patients n=513 n=150
Baseline (mean) 9.8 9.9
Change from baseline (adjusted mean) -2.9 -2
Difference from linagliptin (adjusted mean**) -0.84† (-1.23, -0.45) --
(95% CI)
Patients [n (%)] achieving A1C <7% * 82 (53.6) 45 (30)
FPG (mg/dL) *
Number of patients n=153 n=150
Baseline (mean) 196 198
Change from baseline (adjusted mean) -54 -35
Difference from linagliptin (adjusted mean**) -18†† (-31, -5.5) --
(95% CI)
†p<0.0001 compared to linagliptin, ††p=0.0054 compared to linagliptin
*Full analysis set population
**A1C: MMRM model included treatment, continuous baseline A1C, baseline A1C by visit interaction, visit by treatment
interaction, baseline renal impairment by treatment interaction and baseline renal impairment by treatment by visit
interaction. FPG: MMRM model included treatment, continuous baseline A1C, continuous baseline FPG, baseline FPG
by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal
impairment by treatment by visit interaction.

The adjusted mean changes for A1C (%) from baseline over time for linagliptin and metformin as compared to linagliptin
alone were maintained throughout the 24 week treatment period. Using the completers analysis the respective adjusted
means for A1C (%) changes from baseline for linagliptin and metformin as compared to linagliptin alone were -1.9 and -
1.3 at week 6, -2.6 and -1.8 at week 12, -2.7 and -1.9 at week 18, and -2.7 and -1.9 at week 24.

Changes in body weight from baseline were not clinically significant in either treatment group.

13.3 Add-On Combination Therapy With Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study
designed to assess the efficacy of linagliptin in combination with metformin. Patients already on metformin (n=491) at a
dose of at least 1500 mg per day were randomized after completing a 2-week open-label placebo run-in period. Patients
on metformin and another antihyperglycemic agent (n=207) were randomized after a run-in period of approximately 6
weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of
either linagliptin 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the
studies were treated with glimepiride rescue.

In combination with metformin, linagliptin provided statistically significant improvements in A1C, FPG, and 2-hour PPG
compared with placebo (Table 8). Rescue glycemic therapy was used in 7.8% of patients treated with linagliptin 5 mg
and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

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Table 8 Glycemic Parameters (in Placebo-Controlled Study) for Linagliptin in Combination with Metformin*

Linagliptin 5 mg + Placebo + Metformin

Metformin
A1C (%)
Number of patients n=513 n=175
Baseline (mean) 8.1 8.0
Change from baseline (adjusted mean***) -0.5 0.15
Difference from placebo + metformin (adjusted -0.6 (-0.8, -0.5) --
mean) (95% CI)
Patients [n (%)] achieving A1C <7% ** 127 (26.2) 15 (9.2)
FPG (mg/dL)
Number of patients n=495 n=159
Baseline (mean) 169 164
Change from baseline (adjusted mean***) -11 11
Difference from placebo + metformin (adjusted -21 (-27, -15) --
mean) (95% CI)
2-hour PPG (mg/dL)
Number of patients n=78 n=21
Baseline (mean) 270 274
Change from baseline (adjusted mean***) -49 18
Difference from placebo + metformin (adjusted -67 (-95, -40) --
mean) (95% CI)
* Full analysis population using last observation on study
** Linagliptin 5 mg + Metformin, n=485; Placebo + Metformin, n=163.
*** HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline
HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects,
as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and
number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as
covariate.

13.4 Active-Controlled Study vs Glimepiride in Combination With Metformin

The efficacy of linagliptin was evaluated in a 104-week double-blind, glimepiride-controlled non-inferiority study in type
2 diabetic patients with insufficient glycemic control despite metformin therapy. Patients being treated with metformin
only entered a run-in period of 2 weeks’ duration, whereas patients pretreated with metformin and one additional
antihyperglycemic agent entered a run-in treatment period of 6 weeks’ duration with metformin monotherapy (dose of
≥1500 mg per day) and washout of the other agent. After an additional 2-week placebo run-in period, those with
inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of linagliptin 5 mg once daily or
glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic
drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of 1
mg/day and then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize
glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent
hypoglycemia.

After 52 weeks and 104 weeks, linagliptin and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4%
for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for linagliptin, -0.4% for glimepiride) from a baseline mean of
7.7% (Table 9). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5%
confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results
were consistent with the completers analysis.

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Table 9 Glycemic Parameters at 52 and 104 Weeks in Study Comparing Linagliptin to Glimepiride as Add-On
Therapy in Patients Inadequately Controlled on Metformin**

Week 52 Week 104

Linagliptin 5 mg Glimepiride + Linagliptin Glimepiride +
+ Metformin Metformin 5 mg + Metformin
(mean Metformin (mean
glimepiride glimepiride
dose 3 mg) dose 3 mg)
A1C (%)
Number of patients n=764 n=755 n=764 n=755
Baseline (mean) 7.7 7.7 7.7 7.7
Change from baseline (adjusted -0.4 -0.6 -0.2 -0.4
mean****)
Difference from glimepiride (adjusted 0.2 (0.1, 0.3) -- 0.2 (0.1, 0.3) --
mean) (97.5% CI)
FPG (mg/dL)
Number of patients n=733 n=725 n=733 n=725
Baseline (mean) 164 166 164 166
Change from baseline (adjusted 8* -15 -2† -9
mean****)
* p<0.0001 vs glimepiride †p=0.0012 vs glimepiride
** Full analysis population using last observation on study
**** HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c
as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well
as baseline HbA1c and baseline FPG as continuous covariates.
Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean
decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body
weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks
and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints).

13.5 Add-On Combination Therapy With Metformin and a Sulfonylurea

A total of 1058 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-
controlled study designed to assess the efficacy of linagliptin in combination with a sulfonylurea and metformin. The most
common sulfonylureas used by patients in the study were glimepiride (31%), glibenclamide (26%), and gliclazide (26%
[not available in the United States]). Patients on a sulfonylurea and metformin were randomized to receive linagliptin 5
mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were
treated with pioglitazone rescue. Glycemic end points measured included A1C and FPG.

In combination with a sulfonylurea and metformin, linagliptin provided statistically significant improvements in A1C and
FPG compared with placebo (Table 10). In the entire study population (patients on linagliptin in combination with a
sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of
-0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with linagliptin 5 mg and
in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the
groups.

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Table 10 Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin in Combination With Metformin and
Sulfonylurea*

Linagliptin 5 mg + Placebo + Metformin +

Metformin + SU SU
A1C (%)
Number of patients n=778 n=262
Baseline (mean) 8.2 8.1
Change from baseline (adjusted mean***) -0.7 -0.1
Difference from placebo (adjusted mean) (95% CI) -0.6 (-0.7, -0.5) --
Patients [n (%)] achieving A1C <7% ** 217 (29.2) 20 (8.1)
FPG (mg/dL)
Number of patients n=739 n=248
Baseline (mean) 159 163
Change from baseline (adjusted mean***) -5 8
Difference from placebo (adjusted mean) (95% CI) -13 (-18, -7) --
SU=sulfonylurea
* Full analysis population using last observation on study
** Linagliptin 5 mg + Metformin + SU, n=742; Placebo + Metformin + SU, n=247
*** HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous covariates. FPG:
ANCOVA model included treatment as classeffects, as well as baseline HbA1c and baseline FPG as continuous
covariates.

13.6 Add-On Combination Therapy with Insulin

A total of 1261 patients with type 2 diabetes inadequately controlled on basal insulin alone or basal insulin in combination
with oral drugs participated in a randomized, double-blind placebo-controlled trial designed to evaluate the efficacy of
linagliptin as add-on therapy to basal insulin over 24 weeks. Randomization was stratified by baseline HbA1c (<8.5% vs
≥8.5%), renal function impairment status (based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none,
metformin only, pioglitazone only, metformin + pioglitazone). Patients with a baseline A1C of >7% and <10% were
included in the study including 709 patients with renal impairment (eGFR <90 mL/min), most of whom (n=575) were
categorized as mild renal impairment (eGFR 60 to <90 mL/min). Patients entered a 2-week placebo run-in period on basal
insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background
therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of either
5 mg of linagliptin or placebo, administered once daily. Patients were maintained on a stable dose of insulin prior to
enrollment, during the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific
glycemic goals during the double-blind treatment period were rescued by increasing background insulin dose.

Linagliptin used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically
significant improvements in A1C and FPG compared to placebo (Table 11) after 24 weeks of treatment. The mean total
daily insulin dose at baseline was 42 units for patients treated with linagliptin and 40 units for patients treated with
placebo. Background baseline diabetes therapy included use of: insulin alone (16.1%), insulin combined with metformin
only (75.5%), insulin combined with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only
(1%). The mean change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6
IU in the linagliptin group. The mean change in body weight from baseline to Week 24 was similar in the two treatment
groups. The rate of hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood
glucose was also similar in both groups (21.4% linagliptin; 22.9% placebo) in the first 24 weeks of the study.

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Table 11 Glycemic Parameters in Placebo-Controlled Study for Linagliptin in Combination with Insulin*
Linagliptin 5 mg + Insulin Placebo + Insulin
A1C (%)
Number of patients n=618 n=617
Baseline (mean) 8.3 8.3
Change from baseline (adjusted mean***) -0.6 0.1
Difference from placebo (adjusted mean) (95% CI) -0.7 (-0.7, -0.6) --
Patients [n (%)] achieving A1C <7% ** 116 (19.5) 48 (8.1)
FPG (mg/dL)
Number of patients n=613 n=608
Baseline (mean) 147 151
Change from baseline (adjusted mean***) -8 3
Difference from placebo (adjusted mean) (95% CI) -11 (-16, -6) --
* Full analysis population using last observation carried forward (LOCF) method on study
** Linagliptin + Insulin, n=595; Placebo + Insulin, n=593
*** HbA1c: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as
class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, categorical
renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c and baseline FPG as
continuous covariates.
The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c
after 24 weeks was comparable for patients with no renal impairment (eGRF ≥90 mL/min, n=539), with mild renal
impairment (eGFR 60 to <90 mL/min, n=565), or with moderate renal impairment (eGFR 30 to <60 mL/min, n=124).

13.7 Renal Impairment

A total of 133 patients with type 2 diabetes participated in a 52 week, double-blind, randomized, placebo-controlled trial
designed to evaluate the efficacy and safety of linagliptin in patients with both type 2 diabetes and severe chronic renal
impairment. Participants with an estimated (based on the four variables modified diet in renal disease [MDRD] equation)
GFR value of <30 mL/min were eligible to participate in the study. Randomization was stratified by baseline HbA1c
(≤8% and >8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as
monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks
of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and
pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. At
baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes therapy, and 12.5% were
receiving sulfonylurea alone.

After 12 weeks of treatment, linagliptin 5 mg provided statistically significant improvement in A1C compared to placebo,
with an adjusted mean change of -0.6% compared to placebo (95% confidence interval -0.9, -0.3) based on the analysis
using last observation carried forward (LOCF). With adjustments in antidiabetic background therapy after the initial 12
weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to
placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF.

14 HOW SUPPLIED/STORAGE AND HANDLING

Blister packs are available with 14 and 60 film-coated tablets.
Not all the pack sizes may be marketed.

Storage
Store below 25°C;

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15 MANUFACTURER

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Straße 173
55216 Ingelheim am Rhein
GERMANY

Or

Boehringer Ingelheim Ellas A.E., Koropi, Greece.

16 REGISTRATION HOLDER / NUMBER

Boehringer Inhelheim Israel Ltd.,

Medinat Ha-Yehudim 89 St.;
P.O.B 4124,
Herzeliya Pituach 4676672

Registration numbers:

Trajenta Duo Tablets 2.5mg/500mg 150-17-33739

Trajenta Duo Tablets 2.5mg/850mg 150-18-33740
Trajenta Duo Tablets 2.5mg/1,000mg 150-19-33741

This leaflet format has been determined by the Ministry of Health and the content thereof has been checked and approved. Date of
approval: August 2014.

25