RIDGEFIELD, Conn. and INDIANAPOLIS, June 4, 2019 /PRNewswire/ -- The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for the investigational fixed-dose combination tablet of empagliflozin, linagliptin and metformin extended release (XR) for the treatment of adults with type 2 diabetes, Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced.

"Millions of adults with type 2 diabetes take multiple medicines to control their condition," said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "If approved by the FDA, the combination tablet would be one of the first single-pill options with three complementary mechanisms of action to help manage blood glucose in adults with type 2 diabetes who could benefit from having empagliflozin and linagliptin as part of their treatment regimen, in addition to metformin."

Empagliflozin, marketed as Jardiance® in the U.S., is a sodium glucose co-transporter-2 (SGLT-2) inhibitor, which removes excess glucose through the urine by blocking glucose re-absorption in the kidney. Jardiance is a once-daily tablet used along with diet and exercise to lower blood sugar in adults with type 2 diabetes and is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes and known cardiovascular disease. Jardiance is not for people with type 1 diabetes or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

Linagliptin, marketed as Tradjenta® tablets in the U.S., is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which controls glucose by increasing hormones that stimulate the pancreas to secrete insulin and stimulate the liver to produce less glucose. Tradjenta is a once-daily, 5 mg tablet used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. The long-term cardiovascular safety profile of Tradjenta has been studied in two separate cardiovascular outcomes trials of adults with type 2 diabetes and increased cardiovascular risk. Tradjenta should not be used in people with type 1 diabetes or for the treatment of diabetic ketoacidosis. Tradjenta has not been studied in people with a history of pancreatitis.

Metformin, which decreases the production of glucose in the liver and its absorption in the intestine and improves the body's sensitivity to insulin and ability to utilize glucose, is the most commonly prescribed initial treatment for type 2 diabetes.

"Boehringer Ingelheim and Lilly continue to provide a range of treatment options to help improve overall care and outcomes for adults with type 2 diabetes," said Sherry Martin, M.D., vice president, Medical Affairs, Lilly. "We look forward to working with the FDA to make this combination tablet of empagliflozin, linagliptin and metformin XR available in hopes that it may help adults with type 2 diabetes better manage their condition with their healthcare providers."

The NDA is based on two randomized open-label trials that assessed the bioequivalence of empagliflozin, linagliptin and metformin XR investigational fixed-dose combination tablets and their individual components in healthy adults. Boehringer Ingelheim and Lilly plan to present results from the trials at a medical congress later this year.

About DiabetesApproximately 30 million Americans and an estimated 425 million people worldwide have diabetes, and nearly 24% of Americans with diabetes—or more than 7 million people—are undiagnosed. In the U.S., approximately 12% of those aged 18 and older have diabetes. Type 2 diabetes is the most common type, accounting for an estimated 90 to 95% of all diagnosed adult diabetes cases in the U.S. Diabetes is a chronic condition that occurs when the body does not properly produce or use the hormone insulin.

What is JARDIANCE? (www.jardiance.com) JARDIANCE is a prescription medicine used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

JARDIANCE is also used to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease.

JARDIANCE is not for people with type 1 diabetes or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

IMPORTANT SAFETY INFORMATIONDo not take JARDIANCE if you are allergic to empagliflozin or any of the ingredients in JARDIANCE.

Do not take JARDIANCE if you have severe kidney problems or are on dialysis.

JARDIANCE can cause serious side effects, including:

• Dehydration. JARDIANCE can cause some people to have dehydration (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up.You may be at a higher risk of dehydration if you:
• have low blood pressure
• take medicines to lower your blood pressure, including water pills (diuretics)
• are on a low salt diet
• have kidney problems
• are 65 years of age or older.

• Vaginal yeast infection. Women who take JARDIANCE may get vaginal yeast infections. Talk to your doctor if you experience vaginal odor, white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese), and/or vaginal itching.

• Yeast infection of the penis. Men who take JARDIANCE may get a yeast infection of the skin around the penis, especially uncircumcised males and those with chronic infections. Talk to your doctor if you experience redness, itching or swelling of the penis, rash of the penis, foul smelling discharge from the penis, and/or pain in the skin around penis.

• Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis is a serious condition and may need to be treated in the hospital. Ketoacidosis may lead to death. Ketoacidosis occurs in people with type 1 diabetes and can also occur in people with type 2 diabetes taking JARDIANCE, even if blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you get any of the following symptoms, and if possible, check for ketones in your urine:
• nausea
• vomiting
• stomach-area (abdominal) pain
• tiredness
• trouble breathing

• Kidney problems. Sudden kidney injury has happened in people taking JARDIANCE. Talk to your doctor right away if you reduce the amount you eat or drink, or if you lose liquids; for example, from vomiting, diarrhea, or being in the sun too long.

• Serious urinary tract infections. Serious urinary tract infections can occur in people taking JARDIANCE and may lead to hospitalization. Tell your doctor if you have symptoms of a urinary tract infection, such as a burning feeling when passing urine, a need to urinate often or right away, pain in the lower part of your stomach or pelvis, or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.

• Low blood sugar (hypoglycemia): If you take JARDIANCE with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of low blood sugar is higher. The dose of your sulfonylurea or insulin may need to be lowered. Symptoms of low blood sugar may include:
• headache
• drowsiness
• weakness
• dizziness
• confusion
• irritability
• hunger
• fast heartbeat
• sweating
• shaking or feeling jittery

• Necrotizing fasciitis. A rare but serious bacterial infection that causes damage to the tissue under the skin in the area between and around your anus and genitals (perineum). This bacterial infection has happened in women and men who take JARDIANCE, and may lead to hospitalization, multiple surgeries, and death. Seek medical attention immediately if you have fever or are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals: pain or tenderness, swelling, and redness of skin (erythema).

• Allergic (hypersensitivity) reactions. Symptoms of serious allergic reactions to JARDIANCE may include:
• swelling of your face, lips, throat and other areas of your skin
• difficulty with swallowing or breathing
• raised, red areas on your skin (hives)If you have any of these symptoms, stop taking JARDIANCE and contact your doctor or go to the nearest emergency room right away.
• Increased fats in your blood (cholesterol).

The most common side effects of JARDIANCE include urinary tract infections and yeast infections in females.

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

Before taking JARDIANCE, tell your doctor if you:

• have kidney problems. Your doctor may do blood tests to check your kidneys before and during your treatment with JARDIANCE
• have liver problems
• have a history of urinary tract infections or problems with urination
• are going to have surgery
• are eating less due to illness, surgery, or a change in your diet
• have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas
• drink alcohol very often, or drink a lot of alcohol in the short term ("binge" drinking)
• have any other medical conditions
• are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. Tell your doctor right away if you become pregnant during treatment with JARDIANCE.
• are breastfeeding or are planning to breastfeed. JARDIANCE may pass into your breast milk and may harm your baby. Do not breastfeed while taking JARDIANCE.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take water pills (diuretics) or medicines that can lower your blood sugar, such as insulin.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. For more information, please see Prescribing Information and Medication Guide.

CL-JAR-100026 10.30.18

What is TRADJENTA?

TRADJENTA is a prescription medicine that is 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 or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

If you have had inflammation of the pancreas (pancreatitis) in the past, it is not known if you have a higher chance of getting pancreatitis while you take TRADJENTA.

IMPORTANT SAFETY INFORMATION

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. Before you start taking TRADJENTA, tell your doctor if you have ever had pancreatitis, gallstones, a history of alcoholism, or high 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 or unusual tiredness. These may be symptoms of heart failure.

Who should not take TRADJENTA?

Do not take TRADJENTA if you are allergic to linagliptin or any of the ingredients in TRADJENTA.

Symptoms of a serious allergic reaction to TRADJENTA may include rash, itching, flaking or peeling; raised red patches on your skin (hives); swelling of your face, lips, tongue, and throat that may cause difficulty breathing or swallowing. If you have any of these symptoms, stop taking TRADJENTA and call your doctor or go to the emergency room right away.

What should I tell my doctor before using TRADJENTA? Tell your doctor about all your medical conditions, including if you have or have had inflammation of your pancreas (pancreatitis). Tell your doctor about all the medicines you take, including prescription and non-prescription 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. If you take TRADJENTA with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea or insulin may need to be lowered while you take TRADJENTA.

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

*These trademarks are owned by third parties not affiliated with TRADJENTA.

Tell your doctor if you are pregnant or planning to become pregnant or are breastfeeding or plan to breastfeed.

What are the possible side effects of TRADJENTA?

TRADJENTA may cause serious side effects, including

• Inflammation of the pancreas (pancreatitis).

• Low blood sugar (hypoglycemia), especially if you take TRADJENTA with another medicine that can cause low blood sugar. Signs and symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, sweating, or feeling jittery.

• Allergic (hypersensitivity) 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; difficulty with swallowing or breathing; raised, red areas on your skin (hives); skin rash, itching, flaking, or peeling.

• Joint pain. Some people who take medicines called dipeptidyl peptidase-4 (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 which can be serious and may need to be treated in a hospital. Tell your doctor right away if you develop blisters.

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

These are not all the possible side effects of TRADJENTA. For more information, ask your doctor or pharmacist. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. For more information, please see Prescribing Information and Medication Guide.

CL-TJ-100000 8.21.17

Boehringer Ingelheim and Eli Lilly and CompanyIn January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an alliance in diabetes that centers on compounds representing several of the largest diabetes treatment classes. This alliance leverages the strengths of two of the world's leading pharmaceutical companies. By joining forces, the companies demonstrate commitment in the care of patients with diabetes and stand together to focus on patient needs. Find out more about the alliance at www.boehringer-ingelheim.com or www.lilly.com.

About Boehringer Ingelheim Pharmaceuticals, Inc.Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, Conn., is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world's top 20 pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with approximately 50,000 employees. Since its founding in 1885, the company has remained family-owned, and today our goal is to improve the lives of humans and animals through its three business areas: human pharmaceuticals, animal health and biopharmaceutical contract manufacturing.

Boehringer Ingelheim concentrates on developing innovative therapies that can improve and extend patients' lives. As a research-driven pharmaceutical company, it plans in generations for long-term success. Its research efforts are focused on diseases with high, unmet medical need. In animal health, the company stands for advanced prevention.

In 2018, Boehringer Ingelheim achieved net sales of around $20.7 billion (17.5 billion euros). R&D expenditure of almost $3.7 billion (3.2 billion euros) corresponded to 18.1 per cent of net sales.

Boehringer Ingelheim is committed to improving lives and strengthening our communities. Please visit www.boehringer-ingelheim.us/csr to learn more about Corporate Social Responsibility initiatives.

For more information, please visit www.boehringer-ingelheim.us, or follow us on Twitter @BoehringerUS.

About Lilly DiabetesLilly has been a global leader in diabetes care since 1923, when we introduced the world's first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research and collaboration, a wide range of therapies and a continued determination to provide real solutions—from medicines to support programs and more—we strive to make life better for all those affected by diabetes around the world. For more information, visit www.lillydiabetes.com.

About Eli Lilly and CompanyLilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and newsroom.lilly.com/social-channels.

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about an investigational fixed-dose combination of empagliflozin, linagliptin and metformin XR and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug development and commercialization. Among other things, there can be no guarantee that future study results will be consistent with the results to date or that the investigational fixed-dose combination of empagliflozin, linagliptin and metformin XR will receive regulatory approval. For a further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, please see Lilly's most recent Forms 10-K and 10-Q filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

Jardiance® and Tradjenta® are registered trademarks of Boehringer Ingelheim.

P-LLYMPR-US-100829

CONTACT:Jennifer ForsythDirector, Public RelationsBoehringer Ingelheim Pharmaceuticals, Inc.Email: [email protected] Phone: (203) 791-5889

Stephan Thalen Global Business CommunicationsLilly Diabetes and Lilly USAEmail: [email protected] Phone: (317) 903-5640

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