`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`
`AstraZeneca United States
`AstraZeneca completes acquisition of
`diabetes alliance assets in the U.S. from
`BristolMyers Squibb
`
`Monday, 3 February 2014
`
`AstraZeneca (NYSE: AZN) today announced that on February 1, 2014, it completed its
`acquisition of the entirety of BristolMyers Squibb’s interests in the companies’ diabetes
`alliance. The acquisition gives AstraZeneca ownership of the intellectual property and
`global rights for the development, manufacture and commercialization of the diabetes
`business, which in the U.S. includes ONGLYZA® (saxagliptin), KOMBIGLYZE™ XR
`(saxagliptin and metformin HCl extended release), FARXIGA™ (dapagliflozin), BYETTA®
`(exenatide), BYDUREON® (exenatide extendedrelease for injectable suspension),
`Symlin® (pramlintide acetate) and the investigational agent metreleptin.
`
`On completion of the acquisition, AstraZeneca paid BristolMyers Squibb $2.7 billion for
`initial consideration. AstraZeneca has also agreed to pay up to $1.4 billion in regulatory,
`launch and sales payments, and various salesrelated royalty payments up until 2025,
`$600 million of which relates to the approval of FARXIGA in the U.S. In addition,
`AstraZeneca may make payments up to $225 million when certain assets are subsequently
`transferred.
`
`The transaction reinforces AstraZeneca’s longterm commitment to patients with diabetes,
`a core strategic area and an important platform for returning AstraZeneca to growth.
`
`“AstraZeneca is firmly committed to working closely with healthcare providers and the
`diabetes community to address the diverse medical needs of the 25.8 million patients
`living with diabetes in the U.S.,” said Paul Hudson, President, AstraZeneca US and
`Executive Vice President, North America. “Under one leadership, this acquisition will enable
`AstraZeneca to maximize the potential and expedite progress of our innovative portfolio of
`noninsulin antidiabetic medicines.”
`
`INDICATION and IMPORTANT SAFETY INFORMATION for ONGLYZA® (saxagliptin)
`tablets
`
`Indication and Limitations of Use for ONGLYZA:
`
`ONGLYZA (saxagliptin) 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.
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`1/16
`
`AstraZeneca Exhibit 2122
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 16
`
`
`
`2/7/2016
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`Important Safety Information for ONGLYZA (saxagliptin):
`
`Contraindications
`
`History of a serious hypersensitivity reaction to ONGLYZA (saxagliptin) (eg,
`anaphylaxis, angioedema, or exfoliative skin conditions)
`
`Warnings and Precautions
`
`Pancreatitis: There have been postmarketing reports of acute pancreatitis in
`patients taking ONGLYZA (saxagliptin). 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 DPP4 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
`(saxagliptin) 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 addon 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 addon to glyburide
`trial (2.4%, 0.8% and 0.7%, respectively), with ONGLYZA 5 mg compared to placebo
`in the addon 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 addon to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`2/16
`
`Page 2 of 16
`
`
`
`2/7/2016
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`Drug Interactions
`
`Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the
`dose of ONGLYZA (saxagliptin) 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 (saxagliptin) is 2.5 mg
`once daily for patients with moderate or severe renal impairment, or with endstage
`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 wellcontrolled 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 (saxagliptin) 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 (saxagliptin) 2.5 mg and
`5 mg tablets and click here for Medication Guide.
`
`INDICATION and IMPORTANT SAFETY INFORMATION for KOMBIGLYZE™ XR
`(saxagliptin and metformin HCl extendedrelease) tablets
`
`Indication and Limitations of Use for KOMBIGLYZE XR:
`
`KOMBIGLYZE XR (saxagliptin and metformin HCl extendedrelease) 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
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`3/16
`
`Page 3 of 16
`
`
`
`2/7/2016
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`somnolence, and nonspecific abdominal distress.
`
`Laboratory abnormalities include low pH, increased anion gap, and elevated blood
`lactate.
`
`If acidosis is suspected, KOMBIGLYZE XR (saxagliptin and metformin HCI
`extendedrelease) 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 (saxagliptin and
`metformin HCI extendedrelease) 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 patientyears). 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 (saxagliptin and metformin HCI
`extendedrelease) 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 (saxagliptin and metformin HCI extendedrelease).
`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.
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`4/16
`
`Page 4 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`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 glucoselowering 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
`(saxagliptin and metformin HCI extendedrelease), 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 DPP4 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 antidiabetic 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 treatmentnaive patients treated with
`coadministered saxagliptin and metformin immediaterelease (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%).
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`5/16
`
`Page 5 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`Confirmed hypoglycemia was reported more commonly in patients treated with
`saxagliptin 5 mg compared to placebo in the addon 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 addon 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 (saxagliptin and metformin HCI extendedrelease) 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 wellcontrolled studies
`in pregnant women. KOMBIGLYZE XR (saxagliptin and metformin HCI extended
`release) 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 (saxagliptin and
`metformin HCI extendedrelease) (5/500*5/1000*2.5/1000 mg tablets), including Boxed
`WARNING about lactic acidosis, and click here for Medication Guide.
`
`INDICATION AND LIMITATION OF USE FOR FARXIGA™ (dapagliflozin)
`
`FARXIGA (dapagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus.
`
`FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the
`treatment of diabetic ketoacidosis.
`
`IMPORTANT SAFETY INFORMATION FOR FARXIGA
`
`Contraindications
`
`History of a serious hypersensitivity reaction to FARXIGA (dapagliflozin)
`Severe renal impairment, end stage renal disease, or patients on dialysis
`
`Warnings and Precautions
`
`Hypotension: FARXIGA (dapagliflozin) causes intravascular volume contraction.
`Symptomatic hypotension can occur after initiating FARXIGA, particularly in patients
`with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, or
`patients on loop diuretics. Before initiating FARXIGA in patients with one or more of
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`6/16
`
`Page 6 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`these characteristics, assess and correct volume status. After initiating therapy,
`monitor for signs and symptoms of hypotension.
`Impairment in Renal Function: FARXIGA (dapagliflozin) increases serum
`creatinine and decreases eGFR. Elderly patients and patients with impaired renal
`function may be more susceptible to these changes. Adverse reactions related to
`renal function can occur after initiating FARXIGA. Before initiating FARXIGA, evaluate
`renal function and monitor periodically thereafter. Discontinue FARXIGA when eGFR is
`persistently <60 mL/min/1.73 m2.
`Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues: Insulin and insulin secretagogues are known to cause
`hypoglycemia. FARXIGA can increase the risk of hypoglycemia when combined with
`these agents. Consider a lower dose of insulin or the insulin secretagogue to reduce
`the risk of hypoglycemia when used in combination with FARXIGA.
`Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic
`infections. Patients with a history of genital mycotic infections were more likely to
`develop genital mycotic infections. Monitor and treat appropriately.
`Increases in LowDensity Lipoprotein Cholesterol (LDLC): Increases in LDLC
`occur with FARXIGA. After initiating FARXIGA, monitor LDLC and treat per standard
`of care.
`Bladder cancer: Across 22 clinical studies, newly diagnosed cases of bladder cancer
`were reported in 0.17% of FARXIGAtreated patients and 0.03% of
`placebo/comparatortreated patients. After excluding patients in whom exposure to
`study drug was <1 year at the time of diagnosis of bladder cancer, there were 4
`cases with FARXIGA and no cases with placebo/comparator. Bladder cancer risk
`factors and hematuria (a potential indicator of preexisting tumors) were balanced
`between treatment arms at baseline. There were too few cases to determine whether
`the emergence of these events is related to FARXIGA.
`
`There are insufficient data to determine whether FARXIGA has an effect on pre
`existing bladder tumors. FARXIGA should not be used in patients with active bladder
`cancer. Use with caution in patients with a prior history of bladder cancer.
`Macrovascular Outcomes: There have been no clinical studies establishing
`conclusive evidence of macrovascular risk reduction with FARXIGA or any other
`antidiabetic drug.
`
`Adverse Reactions
`
`In a pool of 12 placebocontrolled studies, the most common adverse reactions
`(≥5%) treated with FARXIGA (dapagliflozin) 5 mg, 10 mg, and placebo respectively
`were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis
`(6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).
`
`Use in Specific Populations
`
`Pregnant Women: There are no adequate and wellcontrolled studies of FARXIGA
`(dapagliflozin) in pregnant women. Consider appropriate alternative therapies,
`especially during the second and third trimesters.
`Nursing Mothers: It is not known whether FARXIGA is excreted in human milk.
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`7/16
`
`Page 7 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`Because of the potential for serious adverse reactions in nursing infants from
`FARXIGA, discontinue nursing or discontinue FARXIGA.
`Geriatric Use: A higher proportion of patients ≥65 years treated with FARXIGA had
`adverse reactions related to volume depletion and renal impairment or failure
`compared to patients treated with placebo. No FARXIGA dose change is
`recommended based on age.
`
`Please click here for US Full Prescribing Information and click here for Medication Guide for
`FARXIGA (dapagliflozin) 5 mg and 10 mg tablets.
`
`INDICATION and IMPORTANT SAFETY INFORMATION for BYETTA® (exenatide)
`Injection
`
`Indication and Important Limitations of Use for BYETTA:
`
`BYETTA (exenatide) 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 nonfatal
`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 (exenatide) 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 (exenatide) has been
`associated with acute pancreatitis, including fatal and nonfatal 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 glucoseindependent 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
`endstage renal disease. Use with caution in patients with renal transplantation or
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`8/16
`
`Page 8 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`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 hightiter 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 (exenatide) or any other antidiabetic drug.
`
`Most Common Adverse Reactions (≥5%)
`
`24week monotherapy trial vs placebo (PBO): nausea (8% vs 0%).
`Three 30week combination trials of BYETTA (exenatide) 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%).
`16week 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%).
`30week 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 PBOtreated patients. Three 30week 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. 30week 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 (exenatide) slows gastric emptying and can reduce the
`extent and rate of absorption of orally administered drugs. Use with caution with
`
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`9/16
`
`Page 9 of 16
`
`
`
`2/7/2016
`
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`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 (exenatide).
`
`Use in Specific Populations
`
`Pregnant and Nursing Women: Based on animal data, BYETTA (exenatide) 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
`18006339081. 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 BYDUREON® (exenatide
`extendedrelease for injectable suspension)
`
`Indication and Important Limitations of Use for BYDUREON:
`
`BYDUREON (exenatide extendedrelease for injectable suspension) 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 Ccell tumor findings to
`humans, prescribe only to patients for whom potential benefits are considered to
`outweigh potential risk.
`Not recommended as firstline 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 nonfatal
`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 (exenatide extendedrelease for injectable suspension);
`consider other antidiabetic therapies for these patients.
`
`Important Safety Information for BYDUREON:
`
`BOXED WARNING: RISK OF THYROID CCELL TUMORS
`
`Exenatide extendedrelease causes an increased incidence in thyroid Ccell
`tumors at clinically relevant exposures in rats compared to controls. It is
`http://www.astrazenecaus.com/media/pressreleases/Article/20140203astrazenecacompletesacquisitionofdiabetesalliance
`
`10/16
`
`Page 10 of 16
`
`
`
`2/7/2016
`AstraZeneca AstraZeneca completes acquisition of diabetes alliance assets in the U.S. from BristolMyers Squibb
`unknown whether BYDUREON (exenatide extendedrelease for injectable
`suspension) causes thyroid Ccell 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 nonfatal hemorrhagic or
`necrotizing pancreatitis. After initiation of BYDUREON (exenatide extended
`release for injectable suspension), 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 (exenatide extendedrelease for
`injectable suspension) with other glucoseindependent insulin secretagogues (eg,
`meglitinides) could increase the risk of hypoglycemia.
`Renal Impairment: Should not be used in patients w