Page 1

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INDICATION AND IMPORTANT LIMITATIONS OF USE JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin. IMPORTANT SAFETY INFORMATION WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately. CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: • Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance). •A  cute or chronic metabolic acidosis, including diabetic ketoacidosis. •H  istory of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS Lactic Acidosis • Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. • T he reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. • Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

• The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. • Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Monitoring of Renal Function Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. Impaired Hepatic Function Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Vitamin B12 Levels Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually. Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. Hypoxic States Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug. ADVERSE REACTIONS • In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea. • In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%). • Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator). DRUG INTERACTIONS • B ecause cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. • The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended. • T he concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase. USE IN SPECIFIC POPULATIONS • As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed. • It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. • T he safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established. • J ENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

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JD PROF ISI MAR152012


Focus on what matters Improving glycemic control for adult patients with type 2 diabetes

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Please see Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information. www.tradjenta.com

TRADJENTA is now covered for 90% of commercially insured patients without prior authorization* *Formulary covered commercial lives data provided by Fingertip Formulary as of December 2012. The formulary information should not be seen as making any claim regarding efficacy or safety. Please see additional formulary information on page 17.

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In addition to diet and exercise, when metformin alone is no longer enough... There are underlying concerns facing every uncontrolled patient

Tom:

Long-haul truck driver

Pam: 

Struggles to control her A1C, diet, and exercise

Patient Portrayal

Patient Portrayal

Patient Portrayal

Patient Portrayal

Teresa:

Elderly and lives alone

Jason:

Newly diagnosed with a high baseline A1C

Please see additional Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information.

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PATIENT PROFILE/ CORE EFFICACY

"I have a goal and I am determined to reach it" Patient Portrayals

Significant reductions in A1C, FPG, and PPG Placebo-adjusted difference in A1C with oral mono, dual, and triple therapy (linagliptin 5 mg) at 24 weeks1-4* BASELINE A1C 8.0%

BASELINE A1C 8.1%

BASELINE A1C 8.2%

BASELINE A1C 8.3%

TRADJENTA

TRADJENTA

TRADJENTA

TRADJENTA

MONOTHERAPY 1,2†

ADD-ON TO

ADD-ON TO

ADD-ON TO

-0.7%‡ (n=333) P<0.0001

METFORMIN1,3

METFORMIN + SU

-0.6%§

-0.6%

(n=513) P<0.0001

BASAL INSULIN1

1,4†

-0.7%¶ (n=618) P<0.0001

(n=778) P<0.0001

*Prespecified primary analysis of primary endpoint. Full analysis set (FAS; defined as all randomized, treated with at least 1 dose of study drug, with a baseline A1C value and at least 1 on-treatment A1C value). The FAS is the basis for the intention-to-treat (ITT) analysis. † Model includes continuous baseline A1C and treatment. ‡ 0.3% adjusted mean increase from baseline A1C 8.0% with placebo (n=163).1 20.9% of patients in the placebo group required use of rescue therapy vs 10.2% of patients in the TRADJENTA group. § 0.15% adjusted mean increase from baseline A1C 8.0% with placebo plus metformin (n=175).1 18.9% of patients in the placebo group required use of rescue therapy vs 7.8% of patients in the TRADJENTA group.  0.1% adjusted mean decrease from baseline A1C 8.1% with placebo plus metformin and sulfonylurea (SU) (n=262).1 13% of patients in the placebo group required use of rescue therapy vs 5.4% of patients in the TRADJENTA group. ¶ 0.1% adjusted mean increase from baseline A1C 8.3% with placebo plus basal insulin (n=617). 50.4% of patients in the placebo group required use of rescue therapy vs 38.2% of patients in the TRADJENTA group. PPG=postprandial glucose. FPG=fasting plasma glucose.

Secondary endpoints: difference from placebo in FPG and 2hPPG at 24 weeks Treatment

Difference from placebo in FPG#

Difference from placebo in 2hPPG#

TRADJENTA monotherapy1

–23 mg/dL**

­–58 mg/dL‡‡

Add-on to metformin1

–21 mg/dL††

–67 mg/dL§§

P<0.0001 # Placebo-adjusted mean. Full analysis set (ITT), last observation carried forward (LOCF).

**9 mg/dL adjusted mean decrease from baseline FPG with TRADJENTA (n=318) vs 15 mg/dL mean increase with placebo (n=149).1 ††11 mg/dL adjusted mean decrease from baseline FPG with TRADJENTA (n=495) vs 11 mg/dL mean increase with placebo (n=159).1 ‡‡ 34 mg/dL adjusted mean decrease from baseline 2hPPG with TRADJENTA (n=67) vs 25 mg/dL mean increase with placebo (n=24).1 §§ 49 mg/dL adjusted mean decrease from baseline 2hPPG with TRADJENTA (n=78) vs 18 mg/dL mean increase with placebo (n=21).1

Please see study design information on page 16.

Important Safety Information CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

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In addition to diet and exercise, when metformin alone is no longer enough... Comparable efficacy to a sulfonylurea (SU) with lower rates of hypoglycemia and comparative weight difference Noninferiority study: 104-week head-to-head study vs glimepiride in patients receiving metformin1 Mean change over time in A1C from baseline to week 104*

Glimepiride (n=467 at week 104)

TRADJENTA (n=450 at week 104)

7.50

(n=764) (n=755)

7.25 7.00

Proportion of patients (%)

Mean (SE) of HbA1C (%)

7.75

LOCF Set

Per Protocol Analysis

8.00

3.3

30

2.2

0 4 8 12 16

28 40 52 65 78 Treatment duration (weeks)

91

104

104

Almost

5x

25

lower

20

10

–2.2

5

–3.3

Glimepiride (n=775)

7.5 TRADJENTA (n=776)

6 lb (2.7 kg)

2.8 lb (1.3 kg)

0 –1.1

36.1

Almost

1.1

15

0

6.75

Adjusted mean body weight (lb) change from baseline at 104 weeksठ4.4

Lower incidence of hypoglycemia (%)† 40 P<0.0001 35

difference§

–3.1 lb (–1.4 kg)

–4.4 Glimepiride (n=722)

TRADJENTA (n=733)

*Model

includes treatment, baseline A1C, and number of previous oral antihyperglycemic drugs (OADs). 24.7% of patients in the TRADJENTA group required use of rescue therapy vs 21.5% of patients in the glimepiride group. †Treated set. ‡Model includes baseline A1C, baseline weight, number of prior OADs, treatment, week repeated within patients, and week-by-treatment interaction. §Actual difference=5.9 lb.



Primary endpoint: Patients in the full analysis set (LOCF) population achieved an adjusted mean A1C reduction of 0.2% (n=764) from baseline at 104 weeks vs 0.4% with glimepiride (n=755; 1-sided noninferiority: P=0.0004)1 A conclusion in favor of the noninferiority of TRADJENTA to glimepiride may be limited to patients with baseline A1C comparable to those included in the study (66% of patients had baseline A1C <8%, and 91% had A1C <9%)1

STUDY DESIGN A 104-week, double-blind, glimepiride-controlled, noninferiority study in which adult patients with type 2 diabetes with insufficient glycemic control on metformin therapy were randomized to receive the addition of TRADJENTA 5 mg/day (n=777) or glimepiride, titrated as needed (n=775). Average dose of glimepiride in trial was 3 mg/day (initial dose 1 mg/day; maximum dose 4 mg/day). Primary endpoint in this analysis was the change from baseline in A1C after 52 and 104 weeks of treatment.

Important Safety Information WARNINGS AND PRECAUTIONS 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. 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.

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"I continue to struggle with diet and exercise, and controlling my blood sugar"

Prespecified subgroup analysis: placebo-adjusted difference in A1C at week 24 across all age groups studied (%)1*† BASELINE A1C 8.2%

BASELINE A1C 8.2%

BASELINE A1C 8.0%

BASELINE A1C 8.1%

≤50 YEARS

51 to 64 YEARS

65 to 74 YEARS

≥75 YEARS

-0.6%‡

-0.6%§

-0.6%

-0.8%¶

(n=442) P<0.0001

(n=970) P<0.0001

(n=398) P<0.0001

(n=66) P=0.0002

*Model includes baseline A1C, washout, treatment, study, BMI, subgroup, and treatment-by-subgroup interaction. † Full analysis set (ITT), last observation carried forward. ‡ 0.02% adjusted mean increase from baseline A1C 8.2% with placebo (n=194).1 § 0.02% adjusted mean decrease from baseline A1C 8.2% with placebo (n=363).1  0.09% adjusted mean decrease from baseline A1C 8.1% with placebo (n=152).1 ¶ 0.03% adjusted mean increase from baseline A1C 8.1% with placebo (n=19).1

Prespecified subgroup analysis on pooled data from the 4 pivotal phase III trials that demonstrated effectiveness of TRADJENTA in adult patients with type 2 diabetes is illustrated above. Since these studies had the same design and duration and comparable eligibility criteria, the data from these studies were pooled to provide supportive evidence of efficacy and to provide the basis for the evaluation of efficacy in subgroups. Adult patients across a broad range of ages achieved statistically significant A1C reductions1 Clinical experience with TRADJENTA has not identified differences in response between the elderly and younger patients; however, greater sensitivity of some older individuals cannot be ruled out Please see study design information on page 16.

Important Safety Information WARNINGS AND PRECAUTIONS Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug. Please see additional Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information.

7

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EFFICACY VS SU / EFFICACY BY AGE GROUP

Significant A1C reductions across all age groups studied


In addition to diet and exercise, when metformin alone is no longer enough... African American Study: The first published study evaluating the efficacy of a DPP-4 inhibitor exclusively in African American patients with type 2 diabetes Placebo-adjusted difference in A1C with TRADJENTA in African American patients at 24 weeks1*

BASELINE A1C 8.6%

TRADJENTA MONOTHERAPY OR ADD-ON THERAPY†

27% (n=98) of patients receiving TRADJENTA achieved A1C goal of <7% vs 9% (n=108) for those receiving placebo  t week 24, there was no difference A between the treatment groups in mean change from baseline for body weight

-0.6%

0.25% adjusted mean decrease from baseline A1C 8.7% with placebo (n=105)

(n=93) P=0.0005

P  rimary endpoint: change from baseline in A1C after 24 weeks of treatment* R  esults are consistent with those observed in previous studies with linagliptin in other patient populations Patient Portrayal *Patients had to be treatment-naïve or receiving a maximum of 1 oral antihyperglycemic drug (OAD) and have A1C ≥7.5% and ≤11.0% at screening. Patients who were on an antihyperglycemic drug were required to have a stable regimen with no changes for ≥10 weeks before screening. There was no washout of antihyperglycemic drug, and the drug was to be continued at the same dose throughout the trial. 15.5% of patients in the placebo group required use of rescue therapy vs 8.2% of patients in the TRADJENTA group. † Model includes treatment, number of OADs, and baseline A1C.

Please see study design information on page 16.

Important Safety Information ADVERSE REACTIONS

Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo.

8

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 Safety evaluated up to 2 years in clinical trials Patient Portrayals

A demonstrated safety profile evaluated in more than 6000 patients Adverse reactions reported in â&#x2030;Ľ2% of adult patients treated with TRADJENTA and greater than placebo in placebo-controlled clinical studies of TRADJENTA monotherapy or combination therapy Placebo n (%) n=2176

Nasopharyngitis

254 (7.0)

132 (6.1)

Diarrhea

119 (3.3)

65 (3.0)

76 (2.1)

30 (1.4)

Cough

Incidence of Hypoglycemia In the placebo-controlled studies, hypoglycemia was reported in 6.6% of patients treated with linagliptin vs 3.6% of patients treated with placebo. When linagliptin was administered in combination with metformin and an SU, 22.9% of patients reported hypoglycemia vs 14.8% of patients administered placebo in combination with metformin and an SU In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks, no significant difference in the incidence of investigator-reported hypoglycemia was noted compared with placebo (31.4% vs 32.9%, respectively) In patients with severe renal impairment, the incidence of hypoglycemia was higher in patients treated with linagliptin (63%) vs in patients treated with placebo (49%). Severe hypoglycemic events were reported in 4.4% of patients treated with linagliptin vs 4.6% of patients treated with placebo in this trial

Important Safety Information ADVERSE REACTIONS (continued)

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

Please see additional Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information.

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AFRICAN AMERICAN STUDY/ ADVERSE REACTIONS

TRADJENTA 5 mg n (%) n=3625


Indication, Important Limitations of Use, and Important Safety Information Indication and Important Limitations of Use

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS 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. 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.

Macrovascular Outcomes

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

ADVERSE REACTIONS

Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

DRUG INTERACTIONS

The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI SEPT 28 2012 Please see accompanying full Prescribing Information, including Patient Information.

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Improving glycemic control for adult patients with type 2 diabetes Proven glycemic control across a broad range of adult patients

Patient Portrayal

Patient Portrayal

Patient Portrayal

3 3

When metformin alone is no longer enough...

Significant A1C reductions Safety evaluated in more than 6000 patients

3 3

Formulary access for the majority of patients Savings Card program

In a noninferiority study, efficacy comparable to sulfonylurea...

Lower rates of hypoglycemia and comparative weight difference

5 mg

A Single-Strength DPP-4 Inhibitor  o dose adjustment required* N  inimal renal excretion† M

*One 5-mg dose, once daily, for adults with type 2 diabetes. † Primarily

nonrenal excretion: 80% excreted via the bile and gut and 5% eliminated via the kidney within 4 days of dosing.

Indication and Important Limitations of Use

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. Please see additional Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information.

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IMPORTANT SAFETY INFORMATION/SUMMARY

Patient Portrayal


References

1. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. 2. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13(3):258-267. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(1):65-74. 4. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28(11):1352-1361. Erratum in: Diabet Med. 2012;29(1):158. 5. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929-2940. 6. Rosenstock J, Zinman B. Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2007;14(2):98-107.

Please see additional Important Safety Information on page 8 and accompanying full Prescribing Information, including Patient Information.

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A mechanism of action (MOA) that works 5,6 in 2 ways to improve glycemic control TRADJENTA, a DPP-4 inhibitor, 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 to regulate glucose homeostasis1

NUTRIENTS

GLUCAGON

INSULIN

Glucose-dependent

Glucose-dependent

GLP-1 and GIP are released from the duodenum and intestine and are vulnerable to cleavage by DPP-4

DPP-4

DPP-4 inhibitor acts here

Important Safety Information DRUG INTERACTIONS

The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

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MOA

REGULATED GLUCOSE HOMEOSTASIS


"When I need more significant A1C reductions" Significant A1C reductions Placebo-adjusted difference in A1C at 24 weeks in patients receiving linagliptin and metformin, alone or in combination (%)1*†‡ BASELINE A1C 8.7%

BASELINE A1C 8.7%

TRADJENTA 5 mg

METFORMIN 500 mg

ONCE DAILY

TWICE DAILY

-0.6% (n=135)

-0.8% (n=141)

BASELINE A1C 8.7%

JENTADUETO LINAGLIPTIN 2.5 mg METFORMIN 500 mg

TWICE DAILY§

-1.3%

BASELINE A1C 8.5% METFORMIN 1000 mg

TWICE DAILY

-1.2% (n=138)

(n=137)

BASELINE A1C 8.7%

JENTADUETO LINAGLIPTIN 2.5 mg METFORMIN 1000 mg

TWICE DAILY §

-1.7% (n=140)

P<0.0001 Results are adjusted for a 0.1% mean A1C increase for placebo (n=65).

P<0.0001

*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) patients with type 2 diabetes with insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C after 24 weeks of treatment. Secondary endpoints included change from baseline in FPG and in 2-hour postprandial glucose after 24 weeks of treatment. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study. † Superiority

of both free combination therapies, consisting of the twice-daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both twice daily) and over linagliptin 5 mg once daily for the change in A1C from baseline at week 24. Linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily was superior to metformin 1000 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to metformin 500 mg twice daily (P<0.0001); linagliptin 2.5 mg twice daily + metformin 500 mg twice daily was superior to linagliptin 5 mg once daily (P<0.0001).

§ JENTADUETO

studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO with coadministered linagliptin and metformin tablets was demonstrated in healthy subjects.

INDICATION AND IMPORTANT LIMITATIONS OF USE JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin. CONTRAINDICATIONS JENTADUETO is contraindicated in patients with:  Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).  Acute or chronic metabolic acidosis, including diabetic ketoacidosis.  History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

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"I'm worried about my future, and I need greater control" A fixed dose with flexibility In patients receiving JENTADUETO as coadministered linagliptin 2.5 mg/metformin 1000 mg twice daily as initial therapy:

Placebo-adjusted A1C reduction at 24 weeks (n=140)*

Percent of patients who achieved A1C <7%

54%

A1C -1.7%

vs

JENTADUETO

placebo (7 of 65 patients)

(76 of 140 patients) *Results are adjusted for a 0.1% mean A1C increase for placebo (n=65).

11%

Please see page 12 for study design.

JENTADUETO is available in 3 dosage strengths taken twice daily

 2.5 mg linagliptin/ 500 mg metformin HCl

 2.5 mg linagliptin/ 850 mg metformin HCl

 2.5 mg linagliptin/ 1000 mg metformin HCl

IMPORTANT SAFETY INFORMATION WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

Lactic Acidosis  Lactic acidosis is a serious metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.  The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Please see additional Important Safety Information on pages 14 and 15 and accompanying full Prescribing Information, including Boxed Warning regarding the risk of lactic acidosis, and Patient Information.

15

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JENTADUETO

WARNINGS AND PRECAUTIONS


Important Safety Information WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately. CONTRAINDICATIONS JENTADUETO is contraindicated in patients with:  Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).  Acute or chronic metabolic acidosis, including diabetic ketoacidosis.  History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin. WARNINGS AND PRECAUTIONS Lactic Acidosis (continued) Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Monitoring of Renal Function Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: Use of JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. Impaired Hepatic Function Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.

Please see accompanying full Prescribing Information, including Boxed Warning regarding the risk of lactic acidosis, and Patient Information.

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Important Safety Information WARNINGS AND PRECAUTIONS (continued) Vitamin B12 Levels Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually. Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. Hypoxic States Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug. ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in â&#x2030;Ľ5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo are nasopharyngitis and diarrhea. In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%). Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator). DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended. The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase. USE IN SPECIFIC POPULATIONS

JD PROF ISI MAR152012

17

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JENTADUETO IMPORTANT SAFETY INFO

As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established. JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.


Study design TRADJENTA Monotherapy A randomized, multicenter, double-blind, placebo-controlled study of treatment-naïve and treatment-experienced adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336) or placebo (n=167) for 24 weeks. Primary endpoint was change in A1C at 24 weeks. Secondary endpoints included change in FPG and 2-hour postprandial glucose. TRADJENTA Add-on to Metformin A randomized, double-blind, placebo-controlled, parallel-group study of TRADJENTA in adult patients with type 2 diabetes with insufficient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524) or placebo (n=177) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at study endpoint. Secondary endpoints included change from baseline in FPG and 2hPPG. TRADJENTA Add-on to Metformin + SU A randomized, double-blind, placebo-controlled, parallel-group study of TRADJENTA vs placebo in adult patients with type 2 diabetes with insufficient glycemic control despite treatment with metformin in combination with a SU who were randomized to TRADJENTA 5 mg/day (n=793) or placebo (n=265) as an add-on to existing metformin + SU therapy. Primary endpoint was change from baseline A1C at 24 weeks. Secondary endpoints included change from baseline in FPG. TRADJENTA + Basal Insulin A 52-week, randomized, double-blind, placebo-controlled, parallel-group study of TRADJENTA vs placebo in adult patients with type 2 diabetes with insufficient glycemic control despite treatment with basal insulin therapy who were randomized to TRADJENTA 5 mg/day (n=633) or placebo (n=630) as an add-on to existing basal insulin therapy with or without metformin +/– pioglitazone. Primary endpoint was change from baseline A1C at 24 weeks. Secondary endpoints included change from baseline in fasting plasma glucose (FPG). TRADJENTA in African American Patients A randomized, double-blind, placebo-controlled, efficacy and safety study of TRADJENTA in African American patients with type 2 diabetes. Patients were randomized to TRADJENTA 5 mg/day (n=106) or placebo (n=120) as monotherapy or an add-on to pre-existing antihyperglycemic therapy. Primary endpoint was change from baseline A1C at 24 weeks. Secondary endpoints included change from baseline in FPG.

18

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Expanding formulary access TRADJENTA is now covered for 90% of commercially insured patients without prior authorization*

Talk to your sales representative about what this may mean for your patients *Source: formulary covered commercial lives data provided by Fingertip Formulary as of December 2012. Intended for provider communication only, not a guarantee of coverage or payment (full or partial). Actual benefits are determined by plan. Formulary information herein does not establish clinical comparability of products, and should not be seen as making a claim regarding efficacy or safety. Patients should consider formulary status of all medications they may be taking. Lilly and BI do not sponsor or endorse any particular plan.

Eligible patients may pay as little as $10 per month. Patients must pay for any additional cost beyond the $150 maximum covered by this offer for each monthly prescription.† E ligible patients who are at least 18 years of age may pay as little as $10 per month with savings up to $150 per monthly prescription. Eligible patients must pay for any additional cost beyond the $150 maximum covered by this offer for each monthly prescription. If activated by May 31, 2012, card expires 24 consecutive months after activation date. If activated between June 1, 2012 and May 31, 2013, card expires 12 consecutive months after activation date. If you live in Massachusetts, card expires on whichever date comes first: expiration date described above or date that AB-rated generic equivalent becomes available. Limit one offer per patient. May not be combined with any other offer. Only valid in the U.S., including D.C. and Puerto Rico. This program is not health insurance. You are not eligible if your prescriptions are paid for in part, or in whole, by a state or federally funded program, such as, Medicare Part D, Medicaid, Tricare, Vet. Aff., or Dept. of Def. Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company reserve the right to change this offer at any time, without notice.

Please see Indication, Limitations of Use, and Important Safety Information for TRADJENTA and JENTADUETO. Please see accompanying full Prescribing Information on pages 8 and 14, including Boxed Warning for JENTADUETO regarding the risk of lactic acidosis.

19

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In addition to diet and exercise, when metformin alone is no longer enough... TOM

Tom: 52 years old

Continues to work hard, both at home and at his job as a long-haul truck driver. With so many hours spent on the road, he needs a treatment that won't get in the way. Medical history: 4 years since type 2 diabetes diagnosis; hyperglycemia inadequately controlled on metformin A1C: 8.0% BMI: 29 kg/m2 Hypertension: YES Dyslipidemia: YES Current medications: Metformin; ACE inhibitor

Patient Portrayal

When metformin alone is no longer enough...

3 3

Significant A1C reductions Safety evaluated in more than 6000 patients

In a noninferiority study, efficacy comparable to sulfonylurea...

5 mg

3 3

Formulary access for the majority of patients Savings Card program

Lower rates of hypoglycemia and comparative weight difference

A Single-Strength DPP-4 Inhibitor No dose adjustment required*

 inimal renal excretion† M

*One 5-mg dose, once daily, for adults with type 2 diabetes. † Primarily 

nonrenal excretion: 80% excreted via the bile and gut and 5% eliminated via the kidney within 4 days of dosing.

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. Please see additional Important Safety Information on reverse side and accompanying full Prescribing Information, including Patient Information.

20

Copyright © 2013 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (06/13) TJ562715PROF


Important Safety Information WARNINGS AND PRECAUTIONS 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. 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.

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

ADVERSE REACTIONS Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI SEPT 28 2012

Please see accompanying full Prescribing Information, including Patient Information.

21

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In addition to diet and exercise, when metformin alone is no longer enough...

Pam: 47 years old

Struggles with her diet, exercise, and controlling A1C. Always busy taking care of everyone else, she needs a treatment that she can rely on. Ethnicity: African American Medical history: 2 years since type 2 diabetes diagnosis; inadequately controlled on the maximum dose of metformin plus diet and exercise A1C: 7.5% BMI: 33 kg/m2 Dyslipidemia: YES Current medications: Metformin; ACE inhibitor

Patient Portrayal

When metformin alone is no longer enough...

3 3

Significant A1C reductions Safety evaluated in more than 6000 patients

In a noninferiority study, efficacy comparable to sulfonylurea...

5 mg

3 3

Formulary access for the majority of patients Savings Card program

Lower rates of hypoglycemia and comparative weight difference

A Single-Strength DPP-4 Inhibitor No dose adjustment required*  inimal renal excretion† M

*One 5-mg dose, once daily, for adults with type 2 diabetes. † Primarily 

nonrenal excretion: 80% excreted via the bile and gut and 5% eliminated via the kidney within 4 days of dosing.

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. Please see additional Important Safety Information on reverse side and accompanying full Prescribing Information, including Patient Information.

22

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PAM

Hypertension: YES


Important Safety Information WARNINGS AND PRECAUTIONS 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. 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.

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

ADVERSE REACTIONS Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI SEPT 28 2012

Please see accompanying full Prescribing Information, including Patient Information.

23

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In addition to diet and exercise, when metformin alone is no longer enough...

Teresa: 71 years old

Lives alone and has type 2 diabetes; therefore, taking care of her glycemic control is a growing concern. Ethnicity: Hispanic Medical history: 5 years since type 2 diabetes diagnosis; inadequately controlled on metformin A1C: 8.3% BMI: 28 kg/m2 Hypertension: YES Dyslipidemia: YES Current medications: Metformin; ACE inhibitor

Patient Portrayal

When metformin alone is no longer enough...

3 3

Significant A1C reductions Safety evaluated in more than 6000 patients

In a noninferiority study, efficacy comparable to sulfonylurea...

Savings Card program

Lower rates of hypoglycemia and comparative weight difference

A Single-Strength DPP-4 Inhibitor No dose adjustment required* Minimal renal excretion†

*One 5-mg dose, once daily, for adults with type 2 diabetes. † Primarily 

nonrenal excretion: 80% excreted via the bile and gut and 5% eliminated via the kidney within 4 days of dosing.

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Important Safety Information CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. Please see additional Important Safety Information on reverse side and accompanying full Prescribing Information, including Patient Information.

24

Copyright © 2013 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (06/13) TJ562715PROF

TERESA

5 mg

3 3

Formulary access for the majority of patients


Important Safety Information WARNINGS AND PRECAUTIONS 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. 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.

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

ADVERSE REACTIONS Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI SEPT 28 2012

Please see accompanying full Prescribing Information, including Patient Information.

25

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When patients need a powerful first option...

Jason: 40 years old

Newly diagnosed with a high baseline A1C, Jason is worried about his future and is eager to start treatment to help reduce his high A1C Medical history: Newly diagnosed with a high baseline A1C, treatment naïve A1C: 8.7% BMI: 30 kg/m2 Hypertension: YES Dyslipidemia: YES Current medications: None

Patient Portrayal

3 3

Significant A1C reductions Safety evaluated in more than 6000 patients

3 3

In a noninferiority study, efficacy comparable to sulfonylurea...

5 mg

Formulary access for the majority of patients Savings Card program

Lower rates of hypoglycemia and comparative weight difference

A Single-Strength DPP-4 Inhibitor No dose adjustment required*  inimal renal excretion† M

*One 5-mg dose, once daily, for adults with type 2 diabetes. † Primarily 

nonrenal excretion: 80% excreted via the bile and gut and 5% eliminated via the kidney within 4 days of dosing.

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. Please see additional Important Safety Information on reverse side and accompanying full Prescribing Information, including Patient Information.

26

Copyright © 2013 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (06/13) TJ562715PROF

JASON

Important Safety Information CONTRAINDICATIONS


Important Safety Information WARNINGS AND PRECAUTIONS 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. 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.

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

ADVERSE REACTIONS Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. 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. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of 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.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI SEPT 28 2012

Please see accompanying full Prescribing Information, including Patient Information.

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Copyright Š 2013 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (06/13) TJ562715PROF


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Copyright Š 2013 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (06/13) TJ562715PROF

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