TRADJENTA- linagliptin tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LINAGLIPTIN (UNII: 3X29ZEJ4R2) (LINAGLIPTIN - UNII:3X29ZEJ4R2)
Available from:
A-S Medication Solutions
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14.1)]. Limitations of Use TRADJENTA 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. TRADJENTA 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 TRADJENTA [see Warnings and Precautions (5.1)]. TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. Risk Summary The limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for ma
Product summary:
Product: 50090-4383 NDC: 50090-4383-0 90 TABLET, FILM COATED in a BOTTLE
Authorization status:
New Drug Application
Authorization number:
50090-4383-0

A-S Medication Solutions

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This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: July

2019

MEDICATION GUIDE

TRADJENTA® (TRAD gen ta)

(linagliptin)

Tablets

Read this Medication Guide carefully before you start taking TRADJENTA and each time you get a refill.

There may be new information. This information does not take the place of talking to your doctor about your

medical condition or your treatment. If you have any questions about TRADJENTA, ask your doctor or

pharmacist.

What is the most important information I should know about TRADJENTA?

Serious side effects can happen to people taking TRADJENTA, including:

Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical

problems make you more likely to get pancreatitis.

Before you start taking TRADJENTA, tell your doctor if you have ever had:

inflammation of your pancreas (pancreatitis)

a history of alcoholism

stones in your gallbladder

(gallstones)

high blood triglyceride levels

Stop taking TRADJENTA and call your doctor right away if you have pain in your stomach area (abdomen)

that is severe and will not go away. The pain may be felt going from your abdomen through to your back.

The pain may happen with or without vomiting. These may be symptoms of pancreatitis.

Heart failure. Heart failure means your heart does not pump blood well enough.

Before you start taking TRADJENTA, tell your doctor if you have ever had heart failure or have

problems with your kidneys. Contact your doctor right away if you have any of the following

symptoms:

increasing shortness of breath or trouble breathing, especially when you lie down

swelling or fluid retention, especially in the feet, ankles or legs

an unusually fast increase in weight

unusual tiredness

These may be symptoms of heart failure.

What is TRADJENTA?

TRADJENTA is a prescription medicine used along with diet and exercise to lower blood sugar in

adults with type 2 diabetes.

TRADJENTA is not for people with type 1 diabetes.

TRADJENTA is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).

If you have had pancreatitis in the past, it is not known if you have a higher chance of getting

pancreatitis while you take TRADJENTA.

It is not known if TRADJENTA is safe and effective in children under 18 years of age.

Who should not take TRADJENTA?

Do not take TRADJENTA if you:

are allergic to linagliptin or any of the ingredients in TRADJENTA. See the end of this Medication

Guide for a complete list of ingredients in TRADJENTA.

Symptoms of a serious allergic reaction to TRADJENTA may include:

skin rash, itching, flaking or peeling

raised red patches on your skin (hives)

swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowing

difficulty with swallowing or breathing

If you have any of these symptoms, stop taking TRADJENTA and contact your doctor or go to the nearest

hospital emergency room right away.

What should I tell my doctor before using TRADJENTA?

Before you take TRADJENTA, tell your doctor about all of your medical conditions, including if you:

have or have had inflammation of your pancreas (pancreatitis).

are pregnant or plan to become pregnant. It is not known if TRADJENTA will harm your unborn

baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while

you are pregnant.

are breastfeeding or plan to breastfeed. It is not known if TRADJENTA passes into your breast milk.

Talk with your doctor about the best way to feed your baby if you take TRADJENTA.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,

vitamins, and herbal supplements.

TRADJENTA may affect the way other medicines work, and other medicines may affect how TRADJENTA

works.

Especially tell your doctor if you take

other medicines that can lower your blood sugar

rifampin (Rifadin®, Rimactane®, Rifater®, Rifamate®)*, an antibiotic that is used to treat

tuberculosis

Ask your doctor or pharmacist for a list of these medicines if you are not sure if your medicine is one that is

listed above. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist

when you get a new medicine.

How should I take TRADJENTA?

Take 1 tablet 1 time each day with or without food.

Your doctor will tell you when to take TRADJENTA.

Talk with your doctor if you do not understand how to take TRADJENTA.

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your

next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of

TRADJENTA at the same time.

Your doctor may tell you to take TRADJENTA along with other diabetes medicines. Low blood

sugar can happen more often when TRADJENTA is taken with certain other diabetes medicines. See

"What are the possible side effects of TRADJENTA?"

If you take too much TRADJENTA, call your doctor or Poison Control Center at 1-800-222-1222 or

go to the nearest hospital emergency room right away.

When your body is under some types of stress, such as fever, trauma (such as a car accident),

infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor

right away if you have any of these conditions and follow your doctor's instructions.

Check your blood sugar as your doctor tells you to.

Stay on your prescribed diet and exercise program while taking TRADJENTA.

Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and

your hemoglobin A1C.

What are the possible side effects of TRADJENTA?

TRADJENTA may cause serious side effects, including:

See "What is the most important information I should know about TRADJENTA?"

Low blood sugar (hypoglycemia). If you take TRADJENTA with another medicine that can cause

low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The

dose of your sulfonylurea medicine or insulin may need to be lowered while you take TRADJENTA.

Signs and symptoms of low blood sugar may include:

headache

irritability

drowsiness

hunger

weakness

fast heart

beat

dizziness

sweating

confusion

feeling jittery

Allergic (hypersensitivity) reactions. Serious allergic reactions can happen after your first dose or up

to 3 months after starting TRADJENTA. Symptoms may include:

swelling of your face, lips, throat, and other areas on your

skin

raised, red areas on your skin (hives)

difficulty with swallowing or

breathing

skin rash, itching, flaking, or

peeling

If you have these symptoms, stop taking TRADJENTA and call your doctor or go to the nearest hospital

emergency room right away.

Joint pain. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may

develop joint pain that can be severe. Call your doctor if you have severe joint pain.

Skin reaction. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may

develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your

doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion).

Your doctor may tell you to stop taking TRADJENTA.

The most common side effects of TRADJENTA include stuffy or runny nose and sore throat, cough, and

diarrhea

These are not all the possible side effects of TRADJENTA. For more information, ask your doctor or

pharmacist.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

How should I store TRADJENTA?

Store TRADJENTA at room temperature between 68°F and 77°F (20°C and 25°C).

Keep TRADJENTA and all medicines out of the reach of children.

General information about the safe and effective use of TRADJENTA.

Medicines are sometimes prescribed for purposes other than those listed in Medication Guides. Do not use

TRADJENTA for a condition for which it was not prescribed. Do not give TRADJENTA to other people,

even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about TRADJENTA. If you would like

more information, talk with your doctor. You can ask your pharmacist or doctor for information about

TRADJENTA that is written for health professionals.

For more information about TRADJENTA, including current prescribing information and Medication

Guide, go to www.TRADJENTA.com, or scan the code below, or call Boehringer Ingelheim

Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in TRADJENTA?

Active Ingredient: linagliptin

Inactive Ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. The

film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene

glycol, and red ferric oxide.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and/or the insulin that your

body produces does not work as well as it should. Your body can also make too much sugar. When this

happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be

lowered by diet and exercise, and by certain medicines when necessary.

Talk to your doctor about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high

blood sugar (hyperglycemia), and other problems you have because of your diabetes.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA.

Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and

Company, Indianapolis, IN 46285 USA.

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany.

*The brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim

Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Boehringer

Ingelheim Pharmaceuticals, Inc., or its products.

TRADJENTA is a registered trademark of and used under license from Boehringer Ingelheim International

GmbH

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the CARMELINA® trademark under

license.

Copyright © 2019 Boehringer Ingelheim International GmbH.

ALL RIGHTS RESERVED

IT6174JG122019

Revised: 7/2019

Document Id: 5e9e8353-ce09-4675-b171-300d9019fda8

34391-3

Set id: b1da67d4-51e0-41b7-9fe1-7f38c0d1baa1

Version: 3

Effective Time: 20190726

A-S Medication Solutions

TRADJENTA- linagliptin tablet, film coated

A-S Medication Solutions

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TRADJENTA safely and effectively. See full

prescribing information for TRADJENTA.

TRADJENTA® (linagliptin) tablets, for oral use

Initial U.S. Approval: 2011

RECENT MAJOR CHANGES

Warnings and Precautions

Pancreatitis (5.1)

7/2019

Bullous Pemphigoid (5.6)

7/2019

Macrovascular Outcomes- Removed

7/2019

INDICATIONS AND USAGE

TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic

control in adults with type 2 diabetes mellitus (1)

Limitations of Use

Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (1)

Has not been studied in patients with a history of pancreatitis (1)

DOSAGE AND ADMINISTRATION

The recommended dose of TRADJENTA is 5 mg once daily (2.1)

TRADJENTA can be taken with or without food (2.1)

DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg (3)

CONTRAINDICATIONS

Hypersensitivity to linagliptin or any excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative

skin conditions, urticaria, or bronchial hyperreactivity have occurred. (4)

WARNINGS AND PRECAUTIONS

Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected,

promptly discontinue TRADJENTA. (5.1)

Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and

benefits of TRADJENTA in patients who have known risk factors for heart failure. Monitor for signs and symptoms.

(5.2)

Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea (SU)) or insulin, consider lowering the dose

of the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.3)

Hypersensitivity reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients

treated with TRADJENTA including anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly

discontinue TRADJENTA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate

alternative treatment for diabetes. (5.4)

Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible

cause for severe joint pain and discontinue drug if appropriate. (5.5)

Bullous pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report

development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA. (5.6)

ADVERSE REACTIONS

Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with

placebo included nasopharyngitis (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-

542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong P-glycoprotein/CYP3A4 inducer: The efficacy of TRADJENTA may be reduced when administered in combination

(e.g., with rifampin). Use of alternative treatments is strongly recommended. (7.1)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

5.2 Heart Failure

5.3 Use with Medications Known to Cause Hypoglycemia

5.4 Hypersensitivity Reactions

5.5 Severe and Disabling Arthralgia

5.6 Bullous Pemphigoid

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes

7.2 Insulin Secretagogues or Insulin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Glycemic Control Trials

14.2 Cardiovascular Safety Trial

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with

type 2 diabetes mellitus [see Clinical Studies (14.1)].

Limitations of Use

TRADJENTA 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.

TRADJENTA 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 TRADJENTA [see Warnings and Precautions (5.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended dose of TRADJENTA is 5 mg once daily.

TRADJENTA tablets can be taken with or without food.

3 DOSAGE FORMS AND STRENGTHS

TRADJENTA (linagliptin) 5 mg tablets are light red, round, biconvex, bevel-edged, film-coated tablets

with "D5" debossed on one side and the Boehringer Ingelheim logo debossed on the other side.

4 CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients

in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or

bronchial hyperreactivity have occurred [see Warnings and Precautions (5.4) and Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with TRADJENTA.

In the CARMELINA trial [see Clinical Studies (14.2)], acute pancreatitis was reported in 9 (0.3%)

patients treated with TRADJENTA and in 5 (0.1%) patients treated with placebo. Two patients treated

with TRADJENTA in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have

been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with

TRADJENTA.

Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected,

promptly discontinue TRADJENTA 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

TRADJENTA.

5.2 Heart Failure

An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular

outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with

type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart

failure, such as those with a prior history of heart failure and a history of renal impairment, and observe

these patients for signs and symptoms of heart failure during therapy. Advise patients of the

these patients for signs and symptoms of heart failure during therapy. Advise patients of the

characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure

develops, evaluate and manage according to current standards of care and consider discontinuation of

TRADJENTA.

5.3 Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA 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

TRADJENTA 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 TRADJENTA.

5.4 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with

TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset

of these reactions occurred within the first 3 months after initiation of treatment with TRADJENTA,

with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected,

discontinue TRADJENTA, 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 TRADJENTA.

5.5 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4

inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to

years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of

patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4

inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if

appropriate.

5.6 Bullous Pemphigoid

Bullous pemphigoid was reported in 7 (0.2%) patients treated with TRADJENTA compared to none in

patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2)], and 3 of these

patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid

requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients

typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the

DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving

TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be discontinued and referral

to a dermatologist should be considered for diagnosis and appropriate treatment.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below or elsewhere in the prescribing

information:

Pancreatitis [see Warnings and Precautions (5.1)]

Heart Failure [see Warnings and Precautions (5.2)]

Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3)]

Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

Severe and Disabling Arthralgia [see Warnings and Precautions (5.5)]

Bullous Pemphigoid [see Warnings and Precautions (5.6)]

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.

The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14

placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal

impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated

with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with

TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.

TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and

24 weeks' duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of

TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-

controlled trials: two with metformin (12 and 24 weeks' treatment duration); one with a sulfonylurea (18

weeks' treatment duration); one with metformin and sulfonylurea (24 weeks' treatment duration); one with

pioglitazone (24 weeks' treatment duration); and one with insulin (primary endpoint at 24 weeks).

In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of

patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n =

2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar

to placebo.

Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with

TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical

Studies of TRADJENTA Monotherapy or Combination Therapy

Number (%) of Patients

TRADJENTA 5 mg

n = 3625

Placebo

n = 2176

Nasopharyngitis

254 (7.0)

132 (6.1)

Diarrhea

119 (3.3)

65 (3.0)

Cough

76 (2.1)

30 (1.4)

Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in

combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and

hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea;

hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as

add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal

insulin therapy.

Following 104 weeks' treatment in a controlled study comparing TRADJENTA with glimepiride in

which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated

with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775)

were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs

7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA 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 TRADJENTA 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.

Hypoglycemia

In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5

mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The

incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as

monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was

administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported

hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with

metformin and a 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.

In the study of patients receiving TRADJENTA 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 TRADJENTA- (31.4%) and placebo- (32.9%) treated groups. During the same

time period, severe hypoglycemic events, defined as requiring the assistance of another person to

actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of

TRADJENTA-treated patients and 7 (1.1%) of placebo-treated patients. Events that were considered

life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1

(0.2%) on placebo.

Use in Renal Impairment

TRADJENTA 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 TRADJENTA trials. The observed incidence of hypoglycemia was higher

(TRADJENTA, 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

TRADJENTA-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%) TRADJENTA-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

TRADJENTA 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 TRADJENTA 5 mg compared to

patients treated with placebo.

Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA

group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group,

2.7% in the TRADJENTA group).

Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus

patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from

baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the

placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7%

patients in the TRADJENTA and placebo arms, respectively.

Vital Signs

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

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of TRADJENTA. 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)]

Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

Severe and disabling arthralgia

Bullous pemphigoid

Rash

Mouth ulceration, stomatitis

Rhabdomyolysis

7 DRUG INTERACTIONS

7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes

Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced

when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative

treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or

CYP3A4 inducer [see Clinical Pharmacology (12.3)].

7.2 Insulin Secretagogues or Insulin

Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may

require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see

Warnings and Precautions (5.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-

associated risk for major birth defects and miscarriage. There are risks to the mother and fetus

associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal reproduction studies, no adverse developmental effects were observed when linagliptin was

administered to pregnant rats during the period of organogenesis at doses similar to the maximum

recommended clinical dose, based on exposure [see Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational

diabetes with a HbA1c>7 and has been reported to be as high as 20 to 25% in women with HbA1c>10.

The estimated background risk of miscarriage for the indicated population is unknown. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically

recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-

eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled

diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal Data

No adverse developmental outcome was observed when linagliptin was 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 (rats) and 1943 times (rabbits) the

5 mg clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome

was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day

6 to lactation day 21 at a dose 49 times the 5 mg clinical dose, based on exposure.

8.2 Lactation

Risk Summary

There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed

infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the

developmental and health benefits of breastfeeding should be considered along with the mother's

clinical need for TRADJENTA and any potential adverse effects on the breastfed child from

TRADJENTA or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been

established.

8.5 Geriatric Use

There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of

TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) 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.

8.6 Renal Impairment

No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology

(12.3)].

In the TRADJENTA treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2200 (63%)

patients had renal impairment (eGFR <60 mL/min/1.73 m ). Approximately 20% of the population had

eGFR ≥45 to <60 mL/min/1.73 m , 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m and

15% had eGFR <30 mL/min/1.73 m . The overall incidence of adverse reactions were generally similar

between the TRADJENTA and placebo treatment arms.

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology

(12.3)].

10 OVERDOSAGE

In the event of an overdose with TRADJENTA, contact the Poison Control Center. Removal of

linagliptin by hemodialysis or peritoneal dialysis is unlikely.

11 DESCRIPTION

TRADJENTA (linagliptin) tablets contain, as the active ingredient, 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 C

H N O and the molecular weight is 472.54 g/mol. The structural

formula is:

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).

Each film-coated tablet of TRADJENTA contains 5 mg of linagliptin free base and the following

inactive ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. In

addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide,

talc, polyethylene glycol, and red ferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin

hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion,

thus resulting in better regulation of 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.

12.3 Pharmacokinetics

The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2

diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations

of linagliptin occurred at approximately 1.5 hours post dose (T

); the mean plasma area under the

curve (AUC) was 139 nmol*h/L and maximum concentration (C

) was 8.9 nmol/L.

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. The prolonged elimination phase

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 C

and AUC increased by a factor of 1.3 at steady state compared

with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC

were small (12.6% and 28.5%, respectively). 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.

Absorption

The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced C

by 15%

and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered

with or without food.

Distribution

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%-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.

Metabolism

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.

Excretion

Following administration of an oral [

C]-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.

Specific Populations

Renal Impairment

An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and

female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects

with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal

impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50

mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and

11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured

by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the

Cockcroft-Gault formula.

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

increased (AUC

by 71% and C

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 C

by 35%). For both type 2 diabetes mellitus groups, renal

excretion was below 7% of the administered dose.

These findings were further supported by the results of population pharmacokinetic analyses.

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUC

) of

linagliptin was approximately 25% lower and C

was approximately 36% lower than in healthy

subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUC of linagliptin was

about 14% lower and C

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 AUC

and approximately 23% lower C

compared with healthy subjects. Reductions in the pharmacokinetic

parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

Body Mass Index (BMI)/Weight

No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect

on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Gender

No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the

pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Geriatric

Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a

population pharmacokinetic analysis.

Pediatric

Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been

performed.

Race

No dose adjustment is necessary based on race. 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.

Drug Interactions

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

τ,s s

τ,s s

τ,s s

max,ss

max,ss

0-24

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 organic cationic transporter

(OCT). No dose adjustment of TRADJENTA is recommended based on results of the described

pharmacokinetic studies.

Table 2 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

*Multiple dose (steady state) unless otherwise noted

**Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may

require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see

Warnings and Precautions (5.3) and Drug Interactions (7.2)].

***For information regarding clinical recommendations [see Drug Interactions (7.1)].

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

Coadminis tered

Drug

Dosing of

Coadminis tered

Drug*

Dosing of

Linagliptin*

Geometric Mean Ratio

(ratio with/without coadministered

drug)

No effect = 1.0

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

Rifampin***

600 mg QD

5 mg QD

0.60

0.56

Table 3 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Coadminis tered

Drug

Dosing of

Coadminis tered

Drug*

Dosing of

Linagliptin*

Geometric Mean Ratio

(ratio with/without coadministered

drug)

No effect = 1.0

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

45 mg QD

10 mg QD

pioglitazone

metabolite M-III

metabolite M-IV

0.94

0.98

1.04

0.86

0.96

1.05

Digoxin

0.25 mg QD

5 mg QD

digoxin

1.02

0.94

Simvastatin

40 mg QD

10 mg QD

simvastatin

simvastatin acid

1.34

1.33

1.10

1.21

R-warfarin

S-warfarin

0.99

1.03

1.00

1.01

*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 C

for pharmacodynamic end points

***Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may

require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see

Warnings and Precautions (5.3) and Drug Interactions (7.2)].

INR = International Normalized Ratio

PT = Prothrombin Time

QD = once daily

TID = three times daily

Warfarin

10 mg

5 mg QD

S-warfarin

1.03

0.93**

1.03**

1.01

1.04**

1.15**

Ethinylestradiol and

levonorgestrel

ethinylestradiol

0.03 mg and

levonorgestrel

0.150 mg QD

5 mg QD

ethinylestradiol

levonorgestrel

1.01

1.09

1.08

1.13

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

14 CLINICAL STUDIES

14.1 Glycemic Control Trials

TRADJENTA has been studied as monotherapy and in combination with metformin, sulfonylurea,

pioglitazone, and insulin. TRADJENTA has also been studied in patients with type 2 diabetes and

severe chronic renal impairment.

In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant

improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial

glucose (PPG) compared with placebo.

Monotherapy

A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies,

one of 18 weeks' and another of 24 weeks' duration, to evaluate the efficacy and safety of

TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic

agent discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks

that included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic

control (A1C 7% to 10%) after the washout period were randomized; patients not currently on

antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7%

to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-

week study, only patients ineligible for metformin were recruited. In the 18-week study, 76 patients

were randomized to placebo and 151 to TRADJENTA 5 mg; in the 24-week study, 167 patients were

randomized to placebo and 336 to TRADJENTA 5 mg. Patients who failed to meet specific glycemic

goals during the 18-week study received rescue therapy with pioglitazone and/or insulin; metformin

rescue therapy was used in the 24-week trial.

Treatment with TRADJENTA 5 mg daily provided statistically significant improvements in A1C, FPG,

and 2-hour PPG compared with placebo (Table 4). In the 18-week study, 12% of patients receiving

TRADJENTA 5 mg and 18% who received placebo required rescue therapy. In the 24-week study,

10.2% of patients receiving TRADJENTA 5 mg and 20.9% of patients receiving placebo required

rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race,

prior antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR).

As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with TRADJENTA

appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, the

changes from baseline in A1C were -0.4% and -0.4%, respectively, for those given TRADJENTA, and

0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not

differ significantly between the groups.

Table 4 Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRADJENTA*

*Full analysis population using last observation on study

18-Week Study

24-Week Study

TRADJENTA

5 mg

Placebo

TRADJENTA

5 mg

Placebo

A1C (%)

Number of patients

n = 147

n = 73

n = 333

n = 163

Baseline (mean)

Change from baseline (adjusted

mean***)

-0.4

-0.4

Difference from placebo (adjusted

mean) (95% CI)

-0.6 (-0.9, -0.3) --

-0.7 (-0.9, -0.5) --

Patients [n (%)] achieving A1C

<7%**

32 (23.5)

8 (11.8)

77 (25)

17 (12)

FPG (mg/dL)

Number of patients

n = 138

n = 66

n = 318

n = 149

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference from placebo (adjusted

mean) (95% CI)

-21 (-31, -10)

-23 (-30, -16)

2-hour PPG (mg/dL)

Number of patients

Data not

available

Data not

available

n = 67

n = 24

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference from placebo (adjusted

mean) (95% CI)

-58 (-82, -34)

**18-week study: Placebo, n=68; TRADJENTA, n=136

24-week study: Placebo, n=147; TRADJENTA, n=306

***18-week study. HbA1c: ANCOVA model included treatment, reason for metformin intolerance and

number of prior oral anti-diabetic medicine(s) (OADs) as class-effects, as well as baseline HbA1c as

continuous covariates. FPG: ANCOVA model included treatment, reason for metformin intolerance and

number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous

covariates.

24-week 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. 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.

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 TRADJENTA 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 TRADJENTA 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, TRADJENTA provided statistically significant improvements in A1C,

FPG, and 2-hour PPG compared with placebo (Table 5). Rescue glycemic therapy was used in 7.8% of

patients treated with TRADJENTA 5 mg and in 18.9% of patients treated with placebo. A similar

decrease in body weight was observed for both treatment groups.

Table 5 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in

Combination with Metformin*

TRADJENTA 5 mg +

Metformin

Placebo + Metformin

A1C (%)

Number of patients

n = 513

n = 175

Baseline (mean)

Change from baseline (adjusted

mean***)

-0.5

0.15

Difference from placebo +

metformin (adjusted mean) (95% CI)

-0.6 (-0.8, -0.5)

Patients [n (%)] achieving A1C

<7%**

127 (26.2)

15 (9.2)

FPG (mg/dL)

Number of patients

n = 495

n = 159

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference from placebo +

metformin (adjusted mean) (95% CI)

-21 (-27, -15)

2-hour PPG (mg/dL)

Number of patients

n = 78

n = 21

*Full analysis population using last observation on study

**TRADJENTA 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.

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference from placebo +

metformin (adjusted mean) (95% CI)

-67 (-95, -40)

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 TRADJENTA 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 TRADJENTA 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).

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 linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000

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 TRADJENTA 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 TRADJENTA 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**

TRADJENTA

Metformin

500 mg

Linagliptin

2.5 mg

Twice

Daily*

Metformin

1000 mg

Linagliptin

2.5 mg

Twice

Daily*

*Total daily dose of TRADJENTA 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.

Placebo

5 mg Once

Daily*

500 mg

Twice

Daily

+

Metformin

500 mg

Twice

Daily

1000 mg

Twice

Daily

+

Metformin

1000 mg

Twice

Daily

A1C (%)

Number of patients

n = 65

n = 135

n = 141

n = 137

n = 138

n = 140

Baseline (mean)

Change from baseline

(adjusted mean****)

-0.5

-0.6

-1.2

-1.1

-1.6

Difference from placebo

(adjusted mean) (95% CI)

-0.6 (-0.9, -

0.3)

-0.8 (-1.0, -

0.5)

-1.3 (-1.6, -

1.1)

-1.2 (-1.5, -

0.9)

-1.7 (-2.0, -

1.4)

Patients [n (%)] achieving

A1C <7%***

7 (10.8)

14 (10.4)

26 (18.6)

41 (30.1)

42 (30.7)

74 (53.6)

Patients (%) receiving

rescue medication

29.2

11.1

13.5

FPG (mg/dL)

Number of patients

n = 61

n = 134

n = 136

n = 135

n = 132

n = 136

Baseline (mean)

Change from baseline

(adjusted mean****)

Difference from placebo

(adjusted mean) (95% CI)

-19 (-31, -6)

-26 (-38, -

-43 (-56, -

-42 (-55, -

-60 (-72, -

Active-Controlled Study vs Glimepiride in Combination with Metformin

The efficacy of TRADJENTA was evaluated in a 104-week, double-blind, glimepiride-controlled,

non-inferiority study in patients with type 2 diabetes 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/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 TRADJENTA 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 and 104 weeks, TRADJENTA and glimepiride both had reductions from baseline in A1C (52

weeks: -0.4% for TRADJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4%

for glimepiride) from a baseline mean of 7.7% (Table 7). 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.

Table 7 Glycemic Parameters at 52 and 104 Weeks in Study Comparing TRADJENTA to

Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin**

*p<0.0001 vs glimepiride;

p=0.0012 vs glimepiride

**Full analysis population using last observation on study

***Hypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms

and plasma glucose concentration of ≤70 mg/dL) and symptomatic events with typical symptoms of

hypoglycemia and plasma glucose concentration of ≤70 mg/dL.

****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.

Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient population

contained in the treated set, to compare the proportion of patients with hypoglycemic events between

patients treated with linagliptin and patients treated with glimepiride.

Week 52

Week 104

TRADJENTA

5 mg +

Metformin

Glimepiride +

Metformin

(mean

Glimepiride

dose 3 mg)

TRADJENTA

5 mg +

Metformin

Glimepiride +

Metformin

(mean

Glimepiride

dose 3 mg)

A1C (%)

Number of patients

n = 764

n = 755

n = 764

n = 755

Baseline (mean)

Change from baseline (adjusted

mean****)

-0.4

-0.6

-0.2

-0.4

Difference from glimepiride

(adjusted mean) (97.5% CI)

0.2 (0.1, 0.3)

0.2 (0.1, 0.3)

FPG (mg/dL)

Number of patients

n = 733

n = 725

n = 733

n = 725

Baseline (mean)

Change from baseline (adjusted

mean****)

Hypoglycemia incidence (%)***

Number of patients

n = 776

n = 775

n = 776

n = 775

Incidence****

5.3 *

31.1

7.5 *

36.1

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).

Add-On Combination Therapy with Pioglitazone

A total of 389 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with

pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for a period of 6

weeks (4 weeks followed by a 2-week, open-label, placebo run-in period). Drug-naïve patients entered

directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to

receive either TRADJENTA 5 mg or placebo, both in addition to pioglitazone 30 mg daily. Patients

who failed to meet specific glycemic goals during the studies were treated with metformin rescue.

Glycemic endpoints measured were A1C and FPG.

In initial combination with pioglitazone 30 mg, TRADJENTA 5 mg provided statistically significant

improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was

used in 7.9% of patients treated with TRADJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients

treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with

an adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRADJENTA 5 mg/pioglitazone 30

mg and placebo/pioglitazone 30 mg groups, respectively (p = 0.0141).

Table 8 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in

Combination Therapy with Pioglitazone*

*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.

TRADJENTA 5 mg

+ Pioglitazone

Placebo +

Pioglitazone

A1C (%)

Number of patients

n = 252

n = 128

Baseline (mean)

Change from baseline (adjusted mean**)

-1.1

-0.6

Difference from placebo + pioglitazone

(adjusted mean) (95% CI)

-0.5 (-0.7, -0.3)

Patients [n (%)] achieving A1C <7%

108 (42.9)

39 (30.5)

FPG (mg/dL)

Number of patients

n = 243

n = 122

Baseline (mean)

Change from baseline (adjusted mean**)

Difference from placebo + pioglitazone

(adjusted mean) (95% CI)

-14 (-21, -7)

Add-On Combination with Sulfonylureas

A total of 245 patients with type 2 diabetes participated in an 18-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with

sulfonylurea (SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a

2-week, single-blind, placebo run-in period. Patients on a sulfonylurea plus one additional oral

antihyperglycemic agent (n = 103) were randomized after a wash-out period of 4 weeks and a 2-week,

single-blind, placebo run-in period. Patients were randomized to the addition of TRADJENTA 5 mg or

to placebo, each administered once daily. Patients who failed to meet specific glycemic goals during

the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and FPG.

In combination with a sulfonylurea, TRADJENTA provided statistically significant improvements in

A1C compared with placebo following 18 weeks' treatment; the improvements in FPG observed with

TRADJENTA were not statistically significant compared with placebo (Table 9). Rescue therapy was

used in 7.6% of patients treated with TRADJENTA 5 mg and 15.9% of patients treated with placebo.

There was no significant difference between TRADJENTA and placebo in body weight.

Table 9 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in

Combination with Sulfonylurea*

SU = sulfonylurea

*Full analysis population using last observation on study

**TRADJENTA 5 mg + SU, n=156; Placebo + SU, n=82

***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

TRADJENTA 5 mg

+ SU

Placebo + SU

A1C (%)

Number of patients

n = 158

n = 82

Baseline (mean)

Change from baseline (adjusted mean***)

-0.5

-0.1

Difference from placebo + SU (adjusted

mean) (95% CI)

-0.5 (-0.7, -0.2)

Patients [n (%)] achieving A1C <7%**

23 (14.7)

3 (3.7)

FPG (mg/dL)

Number of patients

n = 155

n = 78

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo + SU (adjusted

mean) (95% CI)

-6 (-17, 4)

Add-On Combination Therapy with Metformin and a Sulfonylurea

A total of 1058 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of TRADJENTA 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 TRADJENTA 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 endpoints measured included A1C and FPG.

In combination with a sulfonylurea and metformin, TRADJENTA provided statistically significant

improvements in A1C and FPG compared with placebo (Table 10). In the entire study population

(patients on TRADJENTA in combination with 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 TRADJENTA 5 mg and in 13% of patients treated with placebo.

Change from baseline in body weight did not differ significantly between the groups.

Table 10 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in

Combination with Metformin and Sulfonylurea*

TRADJENTA 5 mg

+ Metformin + SU

Placebo + Metformin

+ SU

A1C (%)

Number of patients

n = 778

n = 262

Baseline (mean)

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)

SU = sulfonylurea

*Full analysis population using last observation on study

**TRADJENTA 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 class-effects, as well as

baseline HbA1c and baseline FPG as continuous covariates.

FPG (mg/dL)

Number of patients

n = 739

n = 248

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo (adjusted mean)

(95% CI)

-13 (-18, -7)

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 TRADJENTA 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 TRADJENTA 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.

TRADJENTA 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 TRADJENTA 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 TRADJENTA 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% TRADJENTA;

22.9% placebo) in the first 24 weeks of the study.

Table 11 Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in

Combination with Insulin*

TRADJENTA 5 mg

+ Insulin

Placebo + Insulin

A1C (%)

Number of patients

n = 618

n = 617

Baseline (mean)

Change from baseline (adjusted mean***)

-0.6

Difference from placebo (adjusted mean)

-0.7 (-0.7, -0.6)

*Full analysis population using last observation carried forward (LOCF) method on study

**TRADJENTA + 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.

(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)

Change from baseline (adjusted mean***)

Difference from placebo (adjusted mean)

(95% CI)

-11 (-16, -6)

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 (eGFR ≥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).

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 TRADJENTA 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, TRADJENTA 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.

14.2 Cardiovascular Safety Trial

The cardiovascular risk of TRADJENTA was evaluated in CARMELINA, a multi-national, multi-

center, placebo-controlled, double-blind, parallel group trial comparing TRADJENTA (N=3494) to

placebo (N=3485) in adult patients with type 2 diabetes mellitus and a history of established

macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events

(MACE) between TRADJENTA and placebo when these were added to standard of care treatments for

diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of

follow-up was 2.2 years and vital status was obtained for 99.7% of patients.

Patients were eligible to enter the trial if they were adults with type 2 diabetes, with HbA1c of 6.5% to

10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or

evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria

(42% of enrolled population), or both (18% of enrolled population).

At baseline the mean age was 66 years and the population was 63% male, 80% Caucasian, 9% Asian,

and 6% Black. Mean HbA1c was 8.0% and mean duration of type 2 diabetes mellitus was 15 years. The

trial population included 17% patients ≥75 years of age and 62% patients with renal impairment defined

as eGFR <60 mL/min/1.73m . The mean eGFR was 55 mL/min/1.73m and 27% of patients had mild renal

impairment (eGFR 60 to 90 mL/min/1.73m ), 47% of patients had moderate renal impairment (eGFR 30

to <60 mL/min/1.73 m ) and 15% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m ).

Patients were taking at least one antidiabetic drug (97%), and the most common were insulin and

analogues (57%), metformin (54%) and sulfonylurea (32%). Patients were also taking antihypertensives

(96%), lipid lowering drugs (76%) with 72% on statin, and aspirin (62%).

The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes

which included cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. The study was

designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE.

The results of CARMELINA, including the contribution of each component to the primary composite

endpoint, are shown in Table 12. The estimated hazard ratio for MACE associated with TRADJENTA

relative to placebo was 1.02 with a 95% confidence interval of (0.89, 1.17). The upper bound of this

confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve depicting time to

first occurrence of MACE is shown in Figure 1.

Table 12 Major Adverse Cardiovascular Events (MACE) by Treatment Group in the

CARMELINA Trial

*PY=patient years

**A patient may have experienced more than one component; therefore, the sum of the components is

larger than the number of patients who experienced the composite outcome.

TRADJENTA 5 mg

n = 3494

Placebo

n = 3485

Hazard Ratio

Number of

Subjects (%)

Incidence

Rate per 1000

PY*

Number of

Subjects (%)

Incidence

Rate per 1000

PY*

(95% CI)

Composite of first event

of CV death, non-fatal

myocardial infarction

(MI), or non-fatal stroke

(MACE)

434 (12.4)

57.7

420 (12.1)

56.3

1.02 (0.89,

1.17)

CV death**

255 (7.3)

32.6

264 (7.6)

34.0

0.96 (0.81,

1.14)

Non-fatal MI**

156 (4.5)

20.6

135 (3.9)

18.0

1.15 (0.91,

1.45)

Non-fatal stroke**

65 (1.9)

73 (2.1)

0.88 (0.63,

1.23)

Figure 1 Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4383

NDC: 50090-4383-0 90 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Pancreatitis

Inform patients that acute pancreatitis has been reported during use of TRADJENTA. Inform patients

that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be

accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue

TRADJENTA promptly and contact their physician if persistent severe abdominal pain occurs [see

Warnings and Precautions (5.1)].

Heart Failure

Inform patients of the signs and symptoms of heart failure. Before initiating TRADJENTA, patients

should be asked about a history of heart failure or other risk factors for heart failure including

moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as

possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid

increase in weight or swelling of the feet [see Warnings and Precautions (5.2)].

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when TRADJENTA is added to a

sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce

the risk of hypoglycemia [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin

conditions, have been reported during postmarketing use of TRADJENTA. If symptoms of allergic

reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face,

lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop

taking TRADJENTA and seek medical advice promptly [see Warnings and Precautions (5.4)].

Severe and Disabling Arthralgia

Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset

of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint

pain occurs [see Warnings and Precautions (5.5)].

Bullous Pemphigoid

Inform patients that bullous pemphigoid has been reported during use of TRADJENTA. Instruct patients

to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.6)].

Missed Dose

Instruct patients to take TRADJENTA only as prescribed. If a dose is missed, advise patients not to

double their next dose.

Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Marketed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Eli Lilly and Company

Indianapolis, IN 46285 USA

Licensed from:

Boehringer Ingelheim International GmbH, Ingelheim, Germany

TRADJENTA is a registered trademark of and used under license from Boehringer Ingelheim

International GmbH

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the CARMELINA® trademark under

license.

Copyright © 2019 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

IT6174JG122019

MEDICATION GUIDE

TRADJENTA (TRAD gen ta)

(linagliptin)

Tablets

Read this Medication Guide carefully before you start taking TRADJENTA and each time you get a

refill. There may be new information. This information does not take the place of talking to your doctor

about your medical condition or your treatment. If you have any questions about TRADJENTA, ask

your doctor or pharmacist.

What is the most important information I should know about TRADJENTA?

Serious side effects can happen to people taking TRADJENTA, including:

Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain

medical problems make you more likely to get pancreatitis.

®

Before you start taking TRADJENTA, tell your doctor if you have ever had:

inflammation of your pancreas (pancreatitis)

a history of alcoholism

stones in your gallbladder

(gallstones)

high blood triglyceride levels

Stop taking TRADJENTA and call your doctor right away if you have pain in your stomach area

(abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through

to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.

Heart failure. Heart failure means your heart does not pump blood well enough.

Before you start taking TRADJENTA, tell your doctor if you have ever had heart failure or have

problems with your kidneys. Contact your doctor right away if you have any of the following

symptoms:

increasing shortness of breath or trouble breathing, especially when you lie down

swelling or fluid retention, especially in the feet, ankles or legs

an unusually fast increase in weight

unusual tiredness

These may be symptoms of heart failure.

What is TRADJENTA?

TRADJENTA is a prescription medicine used along with diet and exercise to lower blood sugar in

adults with type 2 diabetes.

TRADJENTA is not for people with type 1 diabetes.

TRADJENTA is not for people with diabetic ketoacidosis (increased ketones in the blood or

urine).

If you have had pancreatitis in the past, it is not known if you have a higher chance of getting

pancreatitis while you take TRADJENTA.

It is not known if TRADJENTA is safe and effective in children under 18 years of age.

Who should not take TRADJENTA?

Do not take TRADJENTA if you:

are allergic to linagliptin or any of the ingredients in TRADJENTA. See the end of this Medication

Guide for a complete list of ingredients in TRADJENTA.

Symptoms of a serious allergic reaction to TRADJENTA may include:

skin rash, itching, flaking or peeling

raised red patches on your skin (hives)

swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowing

difficulty with swallowing or breathing

If you have any of these symptoms, stop taking TRADJENTA and contact your doctor or go to the

nearest hospital emergency room right away.

What should I tell my doctor before using TRADJENTA?

Before you take TRADJENTA, tell your doctor about all of your medical conditions, including if

you:

have or have had inflammation of your pancreas (pancreatitis).

are pregnant or plan to become pregnant. It is not known if TRADJENTA will harm your unborn

baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar

while you are pregnant.

are breastfeeding or plan to breastfeed. It is not known if TRADJENTA passes into your breast

milk. Talk with your doctor about the best way to feed your baby if you take TRADJENTA.

Tell your doctor about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

TRADJENTA may affect the way other medicines work, and other medicines may affect how

TRADJENTA works.

Especially tell your doctor if you take

other medicines that can lower your blood sugar

rifampin (Rifadin®, Rimactane®, Rifater®, Rifamate®)*, an antibiotic that is used to treat

tuberculosis

Ask your doctor or pharmacist for a list of these medicines if you are not sure if your medicine is one

that is listed above. Know the medicines you take. Keep a list of them and show it to your doctor and

pharmacist when you get a new medicine.

How should I take TRADJENTA?

Take 1 tablet 1 time each day with or without food.

Your doctor will tell you when to take TRADJENTA.

Talk with your doctor if you do not understand how to take TRADJENTA.

If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your

next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of

TRADJENTA at the same time.

Your doctor may tell you to take TRADJENTA along with other diabetes medicines. Low blood

sugar can happen more often when TRADJENTA is taken with certain other diabetes medicines.

See "What are the possible side effects of TRADJENTA?"

If you take too much TRADJENTA, call your doctor or Poison Control Center at 1-800-222-1222

or go to the nearest hospital emergency room right away.

When your body is under some types of stress, such as fever, trauma (such as a car accident),

infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor

right away if you have any of these conditions and follow your doctor's instructions.

Check your blood sugar as your doctor tells you to.

Stay on your prescribed diet and exercise program while taking TRADJENTA.

Your doctor will check your diabetes with regular blood tests, including your blood sugar levels

and your hemoglobin A1C.

What are the possible side effects of TRADJENTA?

TRADJENTA may cause serious side effects, including:

See "What is the most important information I should know about TRADJENTA?"

Low blood sugar (hypoglycemia). If you take TRADJENTA with another medicine that can cause

low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher.

The dose of your sulfonylurea medicine or insulin may need to be lowered while you take

TRADJENTA. Signs and symptoms of low blood sugar may include:

headache

irritability

drowsiness

hunger

weakness

fast heart beat

dizziness

sweating

confusion

feeling jittery

Allergic (hypersensitivity) reactions. Serious allergic reactions can happen after your first dose

or up to 3 months after starting TRADJENTA. Symptoms may include:

swelling of your face, lips, throat, and other areas on your

skin

raised, red areas on your skin (hives)

difficulty with swallowing or

breathing

skin rash, itching, flaking, or peeling

If you have these symptoms, stop taking TRADJENTA and call your doctor or go to the nearest

hospital emergency room right away.

Joint pain. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may

develop joint pain that can be severe. Call your doctor if you have severe joint pain.

Skin reaction. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may

develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your

doctor right away if you develop blisters or the breakdown of the outer layer of your skin

(erosion). Your doctor may tell you to stop taking TRADJENTA.

The most common side effects of TRADJENTA include stuffy or runny nose and sore throat,

cough, and diarrhea

These are not all the possible side effects of TRADJENTA. For more information, ask your doctor or

pharmacist.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store TRADJENTA?

Store TRADJENTA at room temperature between 68°F and 77°F (20°C and 25°C).

Keep TRADJENTA and all medicines out of the reach of children.

General information about the safe and effective use of TRADJENTA.

Medicines are sometimes prescribed for purposes other than those listed in Medication Guides. Do not

use TRADJENTA for a condition for which it was not prescribed. Do not give TRADJENTA to other

people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about TRADJENTA. If you would

like more information, talk with your doctor. You can ask your pharmacist or doctor for information

about TRADJENTA that is written for health professionals.

For more information about TRADJENTA, including current prescribing information and Medication

Guide, go to www.TRADJENTA.com, or scan the code below, or call Boehringer Ingelheim

Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in TRADJENTA?

Active Ingredient: linagliptin

Inactive Ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate.

The film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc,

polyethylene glycol, and red ferric oxide.

What is type 2 diabetes?

Type 2 diabetes is a condition in which your body does not make enough insulin, and/or the insulin that

your body produces does not work as well as it should. Your body can also make too much sugar.

When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar

can be lowered by diet and exercise, and by certain medicines when necessary.

Talk to your doctor about how to prevent, recognize, and take care of low blood sugar (hypoglycemia),

high blood sugar (hyperglycemia), and other problems you have because of your diabetes.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA.

Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and

Company, Indianapolis, IN 46285 USA.

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany.

*The brands listed are trademarks of their respective owners and are not trademarks of Boehringer

Ingelheim Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse

Boehringer Ingelheim Pharmaceuticals, Inc., or its products.

This Medication Guide has been approved by the U.S. Food and Drug

Administration.

Revised: July

2019

TRADJENTA is a registered trademark of and used under license from Boehringer Ingelheim

International GmbH

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the CARMELINA® trademark under

license.

Copyright © 2019 Boehringer Ingelheim International GmbH.

ALL RIGHTS RESERVED

IT6174JG122019

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room

Temperature].

linagliptin

TRADJENTA

linagliptin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 0 9 0 -438 3(NDC:0 59 7-0 140 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LINAGLIPTIN (UNII: 3X29 ZEJ4R2) (LINAGLIPTIN - UNII:3X29 ZEJ4R2)

LINAGLIPTIN

5 mg

Product Characteristics

Color

RED (Light Red)

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

A-S Medication Solutions

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 0 9 0 -438 3-0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /24/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA20 128 0

0 5/0 9 /20 11

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -438 3)

Revised: 7/2019

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