AstraZeneca and Bristol-Myers Squibb to Present New Data at American Diabetes Association 73rd Scien

AstraZeneca and Bristol-Myers Squibb to Present New Data at American Diabetes Association 73rd Scientific Sessions^®

• 33 abstracts have been accepted for presentation, including data from four different classes of diabetes agents

• Breadth of data underscores Alliance commitment to advancing research in type 1 and type 2 diabetes

PRINCETON, N.J. & WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca (NYS: AZN) and Bristol-Myers Squibb Company (NYS: BMY) announced today that 33 abstracts on the companies' research in diabetes have been accepted for presentation at the 73rd Scientific Sessions^® of the American Diabetes Association (ADA) in Chicago, June 21-25. The data include studies from five marketed products as well as dapagliflozin, an investigational compound in the U.S., currently approved for use in the European Union, Australia, New Zealand and Mexico. In addition to blood glucose control, studies presented at the meeting examine impact on cardiovascular risk factors such as weight and blood pressure, which are important to overall disease management in people with diabetes.

"The AstraZeneca and Bristol-Myers Squibb Alliance will present data on a broad, versatile portfolio including Onglyza, Kombiglyze XR, Symlin, Byetta and Bydureon, as well as the investigational compound dapagliflozin," said John Yee, MD, MPH, vice president, head of Medical Affairs, AstraZeneca/Bristol-Myers Squibb U.S. Diabetes Alliance. "The diversity of data reflects our joint commitment to researching and delivering innovative medicines and treatment options to help patients overcome the burdens of diabetes."

Key presentations include:

• The first presentation of Phase IIa pilot data exploring the use of dapagliflozin in adult patients with type 1 diabetes (late-breaking poster, 70-LB)

• Four-year data examining the durability of dapagliflozin vs. glipizide as add-on therapies in patients with type 2 diabetes inadequately controlled on metformin (late-breaking poster, 62-LB)

• Study evaluating the efficacy and tolerability of saxagliptin in patients with type 2 diabetes and a history of cardiovascular disease (poster 1174-P)

• Three-year data from a study examining the effect of exenatide once weekly on sustained glycemic control and weight compared with insulin glargine (oral presentation, 67-OR)

• Phase IV study examining glycemic control, weight, and hypoglycemia with exenatide compared to mealtime administration of rapid-acting analog insulin (oral presentation, 70-OR)

The complete list of AstraZeneca and Bristol-Myers Squibb data presentations is below and can also be accessed on the ADA website.

INDICATION and IMPORTANT SAFETY INFORMATION for BYDUREON^®
(exenatide extended-release for injectable suspension)

Indication and Important Limitations of Use for BYDUREON:

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

• Because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans, prescribe only to patients for whom potential benefits are considered to outweigh potential risk.

• Not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

• Not a substitute for insulin, should not be used in patients with type 1 diabetes or diabetic ketoacidosis, and cannot be recommended for use with insulin.

• BYDUREON and BYETTA^® (exenatide) injection both contain the same active ingredient, exenatide, and should not be used together.

• Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYDUREON; consider other antidiabetic therapies for these patients.

Important Safety Information for BYDUREON:

BOXED WARNING: RISK OF THYROID C-CELL TUMORS

Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with BYDUREON. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

Contraindications

• Patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

• Patients with prior serious hypersensitivity reactions to exenatide or to any of the product components.

Warnings and Precautions

• Pancreatitis: Based on postmarketing data, exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, observe patients carefully for pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting). If pancreatitis is suspected, BYDUREON should be discontinued promptly and should not be restarted if pancreatitis is confirmed.

• Hypoglycemia: Increased risk of hypoglycemia when used in combination with a sulfonylurea (SFU). Clinicians may consider reducing the SFU dose to minimize risk of hypoglycemia. It is possible that use of BYDUREON with other glucose-independent insulin secretagogues (eg, meglitinides) could increase the risk of hypoglycemia.

• Renal Impairment: Should not be used in patients with severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or moderate renal failure. Postmarketing reports of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation.

• Gastrointestinal Disease: Because exenatide is commonly associated with gastrointestinal adverse reactions, BYDUREON is not recommended in patients with severe gastrointestinal disease (eg, gastroparesis).

• Immunogenicity: Patients may develop antibodies to exenatide. In 5 registration trials, attenuated glycemic response was associated in 6% of BYDUREON-treated patients with antibody formation. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy.

• Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYDUREON and other suspect medications and promptly seek medical advice.

• Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with BYDUREON or any other antidiabetic drug.

Withdrawals

• In 5 comparator-controlled, 24- to 30-week BYDUREON trials, the incidence of withdrawal due to adverse events was 4.9% for BYDUREON, 4.9% for BYETTA, and 2.0% for other comparators. The most common adverse reactions leading to withdrawal for BYDUREON, BYETTA, and comparators respectively were nausea (0.5%, 1.5%, 0.3%), injection-site nodule (0.5%, 0.0%, 0.0%), diarrhea (0.3%, 0.4%, 0.3%), injection-site reaction (0.2%, 0.0%, 0.0%), and headache (0.2%, 0.0%, 0.0%). One percent of BYDUREON patients withdrew due to injection-site adverse reactions.

Most Common Adverse Reactions (≥5%)

• BYDUREONvs BYETTA:

  • 24-week trial: nausea (14% vs 35%), diarrhea (9.3% vs 4.1%), injection-site erythema (5.4% vs 2.4%).

  • 30-week trial: nausea (27% vs 33.8%), diarrhea (16.2% vs 12.4%), vomiting (10.8% vs 18.6%), injection-site pruritus (18.2% vs 1.4%), constipation (10.1% vs 6.2%), gastroenteritis viral (8.8% vs 5.5%), gastroesophageal reflux disease (7.4% vs 4.1%), dyspepsia (7.4% vs 2.1%), injection-site erythema (7.4% vs 0.0%), fatigue (6.1% vs 3.4%), headache (6.1% vs 4.8%), injection-site hematoma (5.4% vs 11.0%).

• BYDUREON vs titrated insulin glargine: nausea (12.9% vs 1.3%), headache (9.9% vs 7.6%), diarrhea (9.4% vs 4.0%), injection-site nodule (6.0% vs 0.0%).

• Combination trial vs sitagliptin and pioglitazone: nausea (24.4% vs 9.6% and 4.8%), diarrhea (20.0% vs 9.6% and 7.3%), vomiting (11.3% vs 2.4% and 3.0%), headache (9.4% vs 9.0% and 5.5%), constipation (6.3% vs 3.6% and 1.2%), fatigue (5.6% vs 0.6% and 3.0%), dyspepsia (5.0% vs 3.6% and 2.4%), decreased appetite (5.0% vs 1.2% and 0.0%), injection-site pruritus (5.0% vs 4.8% and 1.2%).

• Monotherapy trial vs sitagliptin, pioglitazone, and metformin: nausea (11.3% vs 3.7%, 4.3%, and 6.9%), diarrhea (10.9% vs 5.5%, 3.7%, and 12.6%), injection-site nodule (10.5% vs 6.7%, 3.7%, and 10.2%), constipation (8.5% vs 2.5%, 1.8%, and 3.3%), headache (8.1% vs 9.2%, 8.0%, and 12.2%), dyspepsia (7.3% vs 1.8%, 4.9%, and 3.3%).

• Hypoglycemia: No major hypoglycemia was reported for BYDUREON- or comparator-treated patients in five 24- to 30-week trials. Minor hypoglycemia incidences for BYDUREON vs comparator-treated patients were as follows: 24-week trial vs BYETTA: with SFU, 12.5% vs 11.8%; without SFU, 0.0% for both; 30-week trial vs BYETTA: with SFU, 14.5% vs 15.4%; without SFU, 0.0% vs 1.1%; monotherapy trial vs sitagliptin, pioglitazone, and metformin: 2.0% vs 0.0% (all comparators); combination trial vs sitagliptin and pioglitazone: 1.3% vs 3.0% and 1.2%; vs titrated insulin glargine, with SFU, 20.0% vs 43.9%; without SFU, 3.7% vs 19.1%.

• Injection-site reactions were observed more frequently in BYDUREON-treated patients (17.1%) vs patients treated with BYETTA (12.7%), titrated insulin glargine (1.8%), or placebo injection (6.4%-13.0%). Injection-site reactions were observed in 14.2% of antibody-positive patients vs 3.1% of antibody-negative patients, with higher incidence in those with higher-titer antibodies. BYETTA-treated patients had similar incidence between antibody-positive and antibody-negative patients (5.8% vs 7.0%). Small, asymptomatic, subcutaneous injection-site nodules are seen with the use of BYDUREON.

Drug Interactions

• Oral Medications: BYDUREON slows gastric emptying and can reduce the rate of absorption of orally administered drugs. Use with caution with oral medications.

• Warfarin: Postmarketing reports with exenatide of increased international normalized ratio (INR) sometimes associated with bleeding with concomitant use of warfarin. Monitor INR frequently until stable upon initiation or alteration of BYDUREON.

Use in Specific Populations

• Pregnant and Nursing Women: Based on animal data, BYDUREON may cause fetal harm and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081. When administered to a nursing woman, a decision should be made whether to discontinue nursing or to discontinue BYDUREON.

• Pediatric Patients: Use in pediatric patients is not recommended as safety and effectiveness have not been established.

Please click here for US Full Prescribing Information for BYDUREON (exenatide extended-release for injectable suspension) 2mg, including Boxed WARNINGregarding risk of thyroid C-cell tumors, and click here for Medication Guide.

INDICATION and IMPORTANT SAFETY INFORMATION for BYETTA^®(exenatide) Injection

Indication and Important Limitations of Use for BYETTA:

BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• Not a substitute for insulin and should not be used in patients with type 1 diabetes or diabetic ketoacidosis.

• Concurrent use with prandial insulin has not been studied and cannot be recommended.

• BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYETTA; consider other antidiabetic therapies for these patients.

Important Safety Information for BYETTA:

Contraindications

• BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to any of the product components.

Warnings and Precautions

• Pancreatitis: Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation and dose increases of BYETTA, observe patients carefully for pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting). If pancreatitis is suspected, BYETTA should be discontinued promptly and should not be restarted if pancreatitis is confirmed.

• Hypoglycemia: Increased risk of hypoglycemia when used in combination with a sulfonylurea (SU) or when used with a glucose-independent insulin secretagogues (eg, meglitinides). Clinicians may consider reducing the SU dose in patients receiving BYETTA to reduce the risk of hypoglycemia. When used with insulin, evaluate and consider reducing the insulin dose in patients at increased risk of hypoglycemia.

• Renal Impairment: Should not be used in patients with severe renal impairment or end-stage renal disease. Use with caution in patients with renal transplantation or when initiating or escalating the dose in patients with moderate renal failure. Postmarketing reports of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation.

• Gastrointestinal Disease: Because exenatide is commonly associated with gastrointestinal adverse reactions, BYETTA is not recommended in patients with severe gastrointestinal disease (eg, gastroparesis).

• Immunogenicity: Patients may develop antibodies to exenatide. In 3 registration trials, antibody levels were measured in 90% of patients, with up to 4% of patients having high-titer antibodies and attenuated glycemic response. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy.

• Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYETTA and other suspect medications and promptly seek medical advice.

• Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug.

Most Common Adverse Reactions (≥5%)

• 24-week monotherapy trial vs placebo (PBO): nausea (8% vs 0%).

• Three 30-week combination trials of BYETTA added to metformin (MET) and/or SU vs PBO: nausea (44% vs 18%), vomiting (13% vs 4%), and diarrhea (13% vs 6%), feeling jittery (9% vs 4%), dizziness (9% vs 6%), headache (9% vs 6%), dyspepsia (6% vs 3%).

• 16-week trial of BYETTA added to thiazolidinedione (TZD) ± MET vs PBO: nausea (40% vs 15%), vomiting (13% vs 1%), dyspepsia (7% vs 1%), diarrhea (6% vs 3%).

• 30-week trial of BYETTA added to insulin glargine ± MET and/or TZD vs PBO: nausea (41% vs 8%), vomiting (18% vs 4%), diarrhea (18% vs 8%), headache (14% vs 4%), constipation (10% vs 2%), dyspepsia (7% vs 2%), asthenia (5% vs 1%).

• Hypoglycemia: BYETTA as monotherapy vs PBO, 3.8% (10 mcg) and 5.2% (5 mcg) vs 1.3%; BYETTA vs PBO, with metformin (MET): 5.3% (10 mcg) and 4.5% (5 mcg) vs 5.3%; with SU, 35.7% (10 mcg) and 14.4% (5 mcg) vs 3.3%; with MET + SU, 27.8% (10 mcg) and 19.2% (5 mcg) vs 12.6%; with TZD, 10.7% (10 mcg) vs 7.1%; with insulin glargine, 24.8% (10 mcg) vs 29.5%.

• Withdrawals: monotherapy trial: 2 of 155 BYETTA patients withdrew due to headache and nausea vs 0 PBO-treated patients. Three 30-week combination trials of BYETTA added to MET and/or SU vs PBO: nausea (3% vs <1%), vomiting (1% vs 0). 16-week trial of BYETTA added to TZD ± MET vs PBO: nausea (9%) and vomiting (5%), with <1% PBO patients withdrawing due to nausea. 30-week trial of BYETTA added to insulin glargine ± MET and/or TZD vs PBO: nausea (5.1% vs 0), vomiting (2.9% vs 0).

Drug Interactions

• Oral Medications: BYETTA slows gastric emptying and can reduce the extent and rate of absorption of orally administered drugs. Use with caution with medications that have a narrow therapeutic index or require rapid gastrointestinal absorption. Oral medications dependent on threshold concentrations for efficacy, such as contraceptives or antibiotics, should be taken at least 1 hour before BYETTA.

• Warfarin: Postmarketing reports of increased international normalized ratio (INR) sometimes associated with bleeding with concomitant use of warfarin. Monitor INR frequently until stable upon initiation or alteration of BYETTA.

Use in Specific Populations

• Pregnant and Nursing Women: Based on animal data, BYETTA may cause fetal harm and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081. When administered to a nursing woman, a decision should be made whether to discontinue nursing or discontinue BYETTA.

• Pediatric Patients: Use in pediatric patients is not recommended as safety and effectiveness have not been established.

Please click here for the US full Prescribing Information for BYETTA^® (exenatide) injection 5 mcg and 10 mcg, and click here for the Medication Guide.

INDICATION and IMPORTANT SAFETY INFORMATION for ONGLYZA^®(saxagliptin)

Indication and Limitations of Use for ONGLYZA:

ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

ONGLYZA has not been studied in patients with a history of pancreatitis.

Important Safety Information for ONGLYZA:

Contraindications

• History of a serious hypersensitivity reaction to ONGLYZA (eg, anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

• Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After initiating ONGLYZA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using ONGLYZA.

• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA.

• Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with ONGLYZA.

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

Most Common Adverse Reactions

• Most common adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with control were upper respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).

• When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for ONGLYZA 2.5 mg, 5 mg, and placebo was 3.1%, 8.1% and 4.3%, respectively.

• Confirmed hypoglycemia was reported more commonly in patients treated with ONGLYZA 2.5 mg and ONGLYZA 5 mg compared to placebo in the add-on to glyburide trial (2.4%, 0.8% and 0.7%, respectively), with ONGLYZA 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively), with ONGLYZA 2.5 mg compared to placebo in the renal impairment trial (4.7% and 3.5%, respectively), and with ONGLYZA 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the dose of ONGLYZA should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Use in Specific Populations

• Patients with Renal Impairment: The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter.

• Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. ONGLYZA, like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered to a nursing woman.

• Pediatric Patients: Safety and effectiveness of ONGLYZA in pediatric patients have not been established.

Please click here for US Full Prescribing Information for Onglyza (5 mg tablets), and click here for Medication Guide.

INDICATION and IMPORTANT SAFETY INFORMATION for KOMBIGLYZE™XR (saxagliptin and metformin HCl extended-release) tablets

Indication and Limitations of Use for KOMBIGLYZE XR:

KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.

KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

KOMBIGLYZE XR has not been studied in patients with a history of pancreatitis.

Important Safety Information for KOMBIGLYZE XR:

BOXED WARNING: LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.

The onset of lactic acidosis 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, KOMBIGLYZE XR should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions]

Contraindications

• Renal impairment (eg, serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance)

• Hypersensitivity to metformin hydrochloride

• Acute or chronic metabolic acidosis, including diabetic ketoacidosis

• History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

• The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years). When it occurs, it is fatal in approximately 50% of cases. Reported cases of lactic acidosis have occurred primarily in diabetic patients with significant renal insufficiency.

• Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis.

• Lactic acidosis risk increases with the degree of renal dysfunction and patient age. The risk may be significantly decreased by use of minimum effective dose of metformin and regular monitoring of renal function. Careful renal monitoring is particularly important in the elderly. KOMBIGLYZE XR should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

• Withhold KOMBIGLYZE XR in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

• There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiating KOMBIGLYZE XR, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using KOMBIGLYZE XR.

• Before initiation of KOMBIGLYZE XR, and at least annually thereafter, renal function should be assessed and verified as normal.

• KOMBIGLYZE XR is not recommended in patients with hepatic impairment.

• Metformin may lower vitamin B12 levels. Measure hematological parameters annually.

• Warn patients against excessive alcohol intake.

• KOMBIGLYZE XR should be suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until patient's oral intake has resumed and renal function is normal.

• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin

  • Saxagliptin: When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with KOMBIGLYZE XR.

  • Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, during concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

• Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. KOMBIGLYZE XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours after the procedure and reinstituted only after renal function is normal.

• There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with KOMBIGLYZE XR.

• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other anti-diabetic drug.

Adverse Reactions

• Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).

• Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (7.7% vs 7.6%), urinary tract infection (6.8% vs 6.1%), and headache (6.5% vs 5.9%).

• Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin immediate-release (IR) and more commonly than in patients treated with metformin IR alone were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).

• Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with metformin, the incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo. Confirmed hypoglycemia was reported more commonly with saxagliptin 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, limit KOMBIGLYZE XR to 2.5 mg/1000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Use in Specific Populations

• Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. KOMBIGLYZE XR should be used during pregnancy only if clearly needed. It is not known whether saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when KOMBIGLYZE XR is administered to a nursing woman.

• Pediatric Patients: Safety and effectiveness of KOMBIGLYZE XR in pediatric patients have not been established.

Please click here for US Full Prescribing Information for KOMBIGLYZE XR (5/500*5/1000*2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis, and click here for Medication Guide.

INDICATIONS and IMPORTANT SAFETY INFORMATION for Symlin^®(pramlintide acetate) Injection

Indications:

Symlin^® (pramlintide acetate) is indicated as adjunct treatment in adults with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy (with or without a concurrent sulfonylurea agent and/or metformin in type 2 diabetes).

Important Safety Information:

BOXED WARNING: SEVERE HYPOGLYCEMIA

SYMLIN is used with insulin and has been associated with an increased risk of insulin induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk.

Contraindications

• Known hypersensitivity to SYMLIN or any of its components, including metacresol

• Confirmed diagnosis of gastroparesis

• Hypoglycemia unawareness

Warnings

Proper patient selection is critical to safe and effective use of SYMLIN: Review HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight before initiation of therapy. Only consider SYMLIN for patients with insulin-using type 2 or type 1 diabetes who fulfill the following criteria:

• have failed to achieve adequate glycemic control despite individualized insulin management

• are receiving ongoing care under the guidance of a healthcare professional skilled in insulin-use and supported by a diabetes educator

Do NOT consider SYMLIN for patients meeting any of the following criteria:

• poor compliance with current insulin regimen

• poor compliance with prescribed self-blood glucose monitoring

• HbA1c >9%

• recurrent severe hypoglycemia requiring assistance during the past 6 months

• presence of hypoglycemia unawareness

• confirmed diagnosis of gastroparesis

• require the use of drugs that stimulate gastrointestinal motility

• pediatric patients

Hypoglycemia: SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be co-administered with insulin therapy and in this setting SYMLIN increases the risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. Severe hypoglycemia associated with SYMLIN occurs within the first 3 hours following a SYMLIN injection. Serious injuries may occur if severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for insulin-induced severe hypoglycemia. These precautions include frequent pre- and post-meal glucose monitoring combined with an initial 50% reduction in pre-meal doses of short-acting insulin. The addition of any antihyperglycemic agent such as SYMLIN to an existing regimen of one or more antihyperglycemic agents (e.g., insulin, sulfonylurea), or other agents that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments; closely monitor blood glucose.

Precautions

Never mix Symlin and insulin: Administer as separate injections. Mixing can alter the pha