FDA Drug
`risk
`failure
`and alogliptin
`
` to
`
`
`Safety
`
`
` Communication:
`
`labelstype
`
`
`2
`
`
`FDA
`
`
`of
`
`diabetes
`
`is
`This
`with
`
`an
`diabetes
`2014.
`
`update
`
`
`
`
`
`risk drug
`
`
`
`to
`
`
`saxagliptin
`
`
`
`the
`
`
`
`
`
`
`
`Safety Announceme nt
`
`
`
`|4-5-2016]
`
`A
`
`
`
`U.S.
`
`
`
`blindness,
`
`2 diabetes
`nerve
`
`Medicines).
`
`
`
`can
`
`ing
`
`lead
`and
`
`
`
`to
`
`
`
`serious
`
`Patients
`
`taking
`
`these
`
`
`
`medicines
`
`
`
`JTX-146 Page 1 of 4
`
`146
`
`MYLAN - EXHIBIT 1032
`Mylan et al. v. AstraZeneca
`IPR2015-01340
`
`

`
`List ofsaxagliptin- and alogliptin-containing Medicines
`
`Brand name
`Onglyza
`Kombiglyze XR
`Nesha
`Kazano
`Oseni
`
`Active ingredient(s)
`saxagliptin
`saxagliptin and metformin extended release
`alogliptin
`alogliptin and mefformin
`alogliptin and pioglitazone
`
`We evaluated two large clinical trials conducted in paticms with heart disease. These
`clinical trials were also discussed atthe FDA Endocrinobgic and Metabolic Drugs
`Advisor. Committee meeting in April 2015. Each trial showed that more patients who
`received saxag~tin- or alogliptin-containing medicines were hospitalized for heart
`failure compared to patients who received an inactive treatment called a placebo (see
`Data Summary). In the saxagliptin trial, 3.5% of patients who received the drug were
`hosp~lized for heart failure versus 2.8% of patients who received a phcebo. This is the
`same as35 out of every 1,000 patients compared to28 out of every 1,000 patients. Risk
`factors included a history of heart failure or kidney impairment. In the abgliptin trial,
`3.9% ofalogllptin-treated patients were hospitalized for heart failure versus 3.3% in the
`placebo group. This is the same as 39 out of every 1,000 patients compared to 33 out of
`every 1,000 patients.
`
`As a result, we have added new Warnings and Precautions tothe labels of medicines that
`contain saxagliptin or ak)gl~tin to inform of the potential increased risk of heart failure.
`
`We urge health care professionals and patients to report side effects involving saxagliptin,
`alogllptin, or other medicines to the FDA MedWatch program, using the information in
`the ’~;ontact FDA" box atthe bottom of/he page.
`
`List ofsaxagliptin- and alogliptin-containing Medicines
`
`Brand name
`Onglyza
`Kombiglyze XR
`Nesina
`Kazano
`Oseni
`
`Active ingredient(s)
`saxag~tin
`saxagliptin and metformin extended release
`aloglipt in
`alogliptin and metformin
`alog~tin and pioglitazone
`
`Facts about saxagliptin and alogliptin
`
`¯ Saxagliptin and alogfiptin are part of the class of prescription medicines called
`dipeptidyl peptidase-4 (DPP-4) inhl"oitors, which are used with diet and exercise
`to control high blood sugar in adults with type 2 diabetes.
`¯ These medicines lower blood sugar by helping the body increase the level of the
`hormone insulin afiermeals. Insulin helps move sugar from the blood into the
`
`JTX-146 Page 2 of 4
`
`

`
`tissues, so the body can use the sugar as a source of energy and keep bleod sugar
`levels stable.
`In addition to heart failure, other possinle side effects of saxagliptin and abgliptin
`include inflammation of the pancreas (pancreatitis), severe joint pain (arthralgia),
`allergic reactions, and low blood sugar (hypoglycemia) when combined with
`other prescription medicines used to treat diabetes.
`In 2015, approximately 386,000 patients received a dispensed prescription for
`saxagliptin-containing products (saxagliptin and saxag~tin-mefformin), and
`56,000 patients received a dispensed prescription for alogliptin-containing
`products (aiogliptin, alogliptin-pioglitazone, and alogliptin-metformin) from the
`U.S. outpatient retail pharmacy setting. ~
`
`Additional Information for Patients
`
`¯ FDA has added warnings about the risk of hospitalization for heart failure to the
`labels ofsaxagliptin- and alogliptin-containing type 2 diabetes medicines (see List
`ofsaxagliptin oralogliptin-containing Medicines). Heart failure occurs whenthe
`heart cannot pump enough blood to meet the body’s needs.
`¯ Before taking saxagliptin or alogliptin, tell your health care professional if(cid:128)you
`have a history ofbeart failure or lddney impairment, as an increased risk of
`hospitalization for heart failure was found in clinical trials that included patients
`with these medical issues.
`¯ Do not stop taking your saxagliptin or alogliptin medicine without first talking to
`your health care professional.
`¯ Contact your health care professional right away if you develop signs and
`symptoms of heart failure when taking saxagliptin or alogliptin, such as:
`¯ Unusual shortness of breath during daily activities
`¯ Trouble breathing when lying down
`¯ Tiredness, weakness, or fatigue
`¯ Weight gain with swelling in the ankles, feet, legs, or stomach
`¯ Read the patient Medication Guide you receive with your prescriptions. It
`exphins the benefits and risks associated with the use of the medicine.
`¯ Ta~ to your health care professional if you have any questions or concerns about
`saxagliptin or alogliptin.
`¯ Report side effects from saxagliptin, alogliptin, or other medicines to the FDA
`MedWatch program, using the information in the "Contact FDA" box atthe
`bottom of this page.
`
`Additional Information for Health Care Professionals
`
`¯ FDA has added warnings about the risk of hospitalization for heart failure to the
`labels ofsaxagliptin and alogliptin-containing type 2 diabetes medicines (see List
`ofsaxagliptin and alogliptin-containing Medicines).
`¯ Risk factors of hospitalization for heart failure include a history of heart failure or
`renal impakment, and this safety risk was found in clinical trials among patients
`with these medical issues.
`
`JTX-146 Page 3 of 4
`
`

`
`¯
`
`¯ Consider the risk and benefits ofsaxagliptin or alogliptin prior to initiating
`treatment in patients at a higher risk for heart failure.
`¯ Observe patients receiving saxagliptin or alogliptin for signs and symptoms of
`heart failure.
`lf heart failure develops, consider discontinuing the drug and monitor diabetes
`control. If blood sugar level is not welt-controlled with apatlent’s current
`treatment, other diabetes medicines may be required.
`¯ Encourage patients to read the Medication Guide they receive with their
`prescriptions.
`¯ Report adverse events involving saxagliptin, alogliptin, or other medicines to the
`FDA MedWatch program, using the information in the ’~2ontact FDA" box atthe
`bottom of this page.
`
`Data Summary
`
`The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes
`Mellltus (SAVOR) trial was a large, prospective, multleenter, randomized, double-blind,
`placebo-controlled trial conducted in 16,492 patiems with type 2 diabetes mellttus having
`established cardiovascular disease or at high risk of cardiovascular disease. Patients were
`foliowed for a median duration of 2 years and up to a total of approximately 2.8 years.
`More patients randomized to the saxagliptin group (289/8280, 3.5%) were hospitalized
`for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In atime
`to first event analysis, the risk of hospitalization for beart failure was significamly higher
`in the saxagliptin treatment group (estimated hazard ratio: 1.27; 95% confidence interval:
`1.07, 1.51). ldemified risk factors in patients hospitalized for heart failure included a
`history of heart failure or renal impairmem.
`
`The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in
`Patients with Type 2 Diabetes Mellttus and Acute Coronary Syndrome (EXAMINE) trial
`was a multieenter, randomized, double-blind, placebo-controlled trial. It enrolled 5,380
`patients with type 2 diabetes and established cardiovascular disease who had a recent
`acute coronary syndrome event (i.e., acute myocardial infarction or unstable angina
`requiring hospitalization). Patients were followed for 1.5 years on average and up to a
`total of 3.4 years. More patients randomized to the alogliptin group (106/2701, 3.9%)
`experienced at least one hospitalization for heart failure compared to patients randomized
`to placebo (89/2679, 3.3%).
`
`The results of the SAVOR and EXAM1NE ttials were discussed at FDA’s
`Endocrinologic and Metabolic Dru~s Advisor’/Committee meeting held on April 14,
`2015.
`
`Reference
`
`l. IMS Health, Total Patient Tracker. Year 2015. Extracted January 2016.
`
`JTX-146 Page 4 of 4