Market Overview

FDA Approves Once-Daily QTERN® (Dapagliflozin and Saxagliptin) Tablets for Adults with Type-2 Diabetes

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AstraZeneca
(NYSE:AZN) today announced that the US Food and Drug Administration
(FDA) has approved once-daily QTERN® (10mg dapagliflozin and
5mg saxagliptin) for the treatment of type-2 diabetes. The new medicine
is indicated as an adjunct to diet and exercise to improve glycemic
(blood sugar level) control in adults with type-2 diabetes who have
inadequate control with dapagliflozin (10mg) or who are already treated
with dapagliflozin and saxagliptin.

Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic
Diseases, Global Medicines Development at AstraZeneca, said: "Type-2
diabetes is a complex disease that is at epidemic proportions, affecting
more than 29 million people in the US alone. The approval of QTERN is
good news for patients who may benefit from improved glycemic control by
adding a DPP-4 inhibitor to a SGLT-2 inhibitor in a convenient
once-daily tablet."

SGLT-2 inhibitors help patients achieve improved glycemic control by
reducing the reabsorption of glucose from the blood and enabling its
removal via the urine. SGLT-2 inhibitors, including FARXIGA®
(dapagliflozin), have demonstrated reductions in HbA1c and have also
been shown to reduce weight and blood pressure. DPP-4
inhibitors reduce blood glucose as measured by HbA1c. FARXIGA
is not indicated for weight loss or the treatment of hypertension.

QTERN is not indicated for the treatment of type 1 diabetes mellitus or
diabetic ketoacidosis. QTERN is contraindicated in patients with prior
serious hypersensitivity reaction to QTERN or its components, patients
with moderate to severe renal impairment, end stage renal disease, or on
dialysis. The most common adverse reactions experienced were upper
respiratory tract infection, urinary tract infection, and dyslipidemia.

INDICATION AND LIMITATIONS OF USE for QTERN®
(dapagliflozin and saxagliptin)

QTERN is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who have
inadequate control with dapagliflozin or who are already treated with
dapagliflozin and saxagliptin.

QTERN is not indicated for the treatment of type 1 diabetes mellitus or
diabetic ketoacidosis. QTERN should only be used in patients who
tolerate 10 mg dapagliflozin.

IMPORTANT SAFETY INFORMATION for QTERN®
(dapagliflozin and saxagliptin)

Contraindications

  • Prior serious hypersensitivity reaction to QTERN or its components
  • Moderate to severe renal impairment (eGFR <45 mL/min/1.73 m2),
    end-stage renal disease, or patients on dialysis

Warning and Precautions

  • Pancreatitis: There have been postmarketing reports of acute
    pancreatitis in patients taking saxagliptin, and in the SAVOR
    cardiovascular outcomes trial. Observe for pancreatitis. If
    pancreatitis is suspected, discontinue QTERN
  • Heart Failure: In the SAVOR cardiovascular outcomes trial, more
    patients treated with saxagliptin were hospitalized for heart failure
    compared to placebo. Patients with a prior history of heart failure or
    renal impairment had a higher risk for hospitalization for heart
    failure. Consider the risks and benefits of QTERN in patients who have
    known risk factors for heart failure. Monitor for signs and symptoms.
    If heart failure develops, consider discontinuation of QTERN
  • Hypotension: Dapagliflozin causes intravascular volume
    contraction, and symptomatic hypotension can occur. Assess and correct
    volume status before initiating QTERN in patients with impaired renal
    function, elderly patients, or patients on loop diuretics. Do not
    initiate QTERN in patients with an eGFR <60 mL/min/1.73 m2.
    Monitor for hypotension
  • Ketoacidosis has been reported in patients with type 1 and type
    2 diabetes receiving dapagliflozin. Some cases were fatal. Assess
    patients who present with signs and symptoms of metabolic acidosis for
    ketoacidosis, regardless of blood glucose level. If suspected,
    discontinue QTERN, evaluate and treat promptly. Before initiating
    QTERN, consider risk factors for ketoacidosis. Patients on QTERN may
    require monitoring and temporary discontinuation in situations known
    to predispose to ketoacidosis
  • Acute Kidney Injury and Impairment in Renal Function: Dapagliflozin
    causes intravascular volume contraction and renal impairment, with
    reports of acute kidney injury requiring hospitalization and dialysis.
    Consider temporarily discontinuing in settings of reduced oral intake
    or fluid losses. If acute kidney injury occurs, discontinue and
    promptly treat

    Dapagliflozin increases serum creatinine and
    decreases eGFR. Elderly patients and patients with impaired renal
    function may be more susceptible to these changes. Before initiating
    QTERN, evaluate renal function and monitor periodically. Discontinue
    QTERN in patients if eGFR falls persistently below 60 mL/min/1.73 m2
  • Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the
    risk for urinary tract infections (UTIs) and serious UTIs have been
    reported with dapagliflozin. Evaluate for signs and symptoms of UTIs
    and treat promptly
  • Hypoglycemia: QTERN can increase the risk of hypoglycemia when
    coadministered with insulin and insulin secretagogues. Consider
    lowering the dose of these agents when coadministered with QTERN
  • Hypersensitivity Reactions: Serious reactions have been
    reported 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 QTERN. Use
    caution in patients with a history of angioedema to another DPP-4
    inhibitor
  • Genital Mycotic Infections: Dapagliflozin increases the risk of
    genital mycotic infections, particularly in patients with prior
    genital mycotic infections. Monitor and treat appropriately
  • Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur
    with dapagliflozin. Monitor LDL-C and treat per standard of care
  • Bladder cancer: An imbalance in bladder cancers was observed in
    clinical trials. There were too few cases to determine whether the
    emergence of these events is related to dapagliflozin, and
    insufficient data to determine whether dapagliflozin has an effect on
    pre-existing bladder tumors. QTERN should not be used in patients with
    active bladder cancer. Use with caution in patients with a history of
    bladder cancer
  • Severe and Disabling Arthralgia has been reported in patients
    taking DPP-4 inhibitors. The time to onset of symptoms following
    initiation of drug therapy varied from one day to years. Patients
    experienced relief of symptoms upon discontinuation. A subset of
    patients experienced a recurrence of symptoms when restarting the same
    drug or a different DPP-4 inhibitor. Consider discontinuing drug if
    appropriate
  • Bullous Pemphigoid: There have been postmarketing reports of
    bullous pemphigoid requiring hospitalization in patients taking DPP-4
    inhibitors. Tell patients to report development of blisters or
    erosions. If suspected, discontinue QTERN
  • Macrovascular Outcomes: There have been no clinical studies
    establishing conclusive evidence of macrovascular risk reduction with
    QTERN

Adverse Reactions

Most common adverse reactions reported in ≥5% of patients treated with
10 mg dapagliflozin and 5 mg saxagliptin were upper respiratory tract
infection (13.6%), urinary tract infection (5.7%), and dyslipidemia
(5.1%).

Drug Interactions

Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with
QTERN significantly increases saxagliptin concentrations. Do not
coadminister QTERN.

Use in Specific Populations

  • Pregnancy: Advise females of the potential risk to a fetus
    especially during the second and third trimesters
  • Lactation: Advise females of the potential risk to a fetus
    especially during the second and third trimesters

Please click here
for US Full Prescribing Information and Medication Guide for QTERN.

INDICATION AND LIMITATIONS OF USE for FARXIGA®
(dapagliflozin)

FARXIGA 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®
(dapagliflozin)

Contraindications

  • History of a serious hypersensitivity reaction to FARXIGA
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2), end
    stage renal disease, or patients on dialysis

Warnings and Precautions

  • Hypotension: FARXIGA causes intravascular volume contraction,
    and symptomatic hypotension can occur. Assess and correct volume
    status before initiating FARXIGA in patients with impaired renal
    function, elderly patients, or patients on loop diuretics. Monitor for
    hypotension
  • Ketoacidosis has been reported in patients with type 1 and type
    2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients
    who present with signs and symptoms of metabolic acidosis for
    ketoacidosis, regardless of blood glucose level. If suspected,
    discontinue FARXIGA, evaluate and treat promptly. Before initiating
    FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA
    may require monitoring and temporary discontinuation in situations
    known to predispose to ketoacidosis
  • Acute Kidney Injury and Impairment in Renal Function: FARXIGA
    causes intravascular volume contraction and renal impairment, with
    reports of acute kidney injury requiring hospitalization and dialysis.
    Consider temporarily discontinuing in settings of reduced oral intake
    or fluid losses. If acute kidney injury occurs, discontinue and
    promptly treat. FARXIGA increases serum creatinine and decreases eGFR.
    Elderly patients and patients with impaired renal function may be more
    susceptible to these changes. Before initiating FARXIGA, evaluate
    renal function and monitor periodically. FARXIGA is not recommended in
    patients with an eGFR persistently between 30 and <60 mL/min/1.73 m2
  • Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the
    risk for urinary tract infections [UTIs] and serious UTIs have been
    reported with FARXIGA. Evaluate for signs and symptoms of UTIs and
    treat promptly
  • Hypoglycemia: FARXIGA can increase the risk of hypoglycemia
    when coadministered with insulin and insulin secretagogues. Consider
    lowering the dose of these agents when coadministered with FARXIGA
  • Genital Mycotic Infections: FARXIGA increases the risk of
    genital mycotic infections, particularly in patients with prior
    genital mycotic infections. Monitor and treat appropriately
  • Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur
    with FARXIGA. Monitor LDL-C and treat per standard of care
  • Bladder cancer: An imbalance in bladder cancers was observed in
    clinical trials. There were too few cases to determine whether the
    emergence of these events is related to FARXIGA, and 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 history of bladder cancer
  • Macrovascular Outcomes: There have been no clinical studies
    establishing conclusive evidence of macrovascular risk reduction with
    FARXIGA

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse
reactions (≥5%) associated with FARXIGA 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 well-controlled
    studies of FARXIGA in pregnant women. Consider appropriate alternative
    therapies, especially during the second and third trimesters. Use
    during pregnancy only if the potential benefit justifies the potential
    risk to the fetus
  • Nursing Mothers: Discontinue FARXIGA or discontinue nursing

Please click here
for US Full Prescribing Information and
Medication
Guide
for FARXIGA.

NOTES TO EDITORS

About QTERN

QTERN combines two anti-hyperglycemic agents with complementary
mechanisms of action in a once-daily tablet: Dapagliflozin, a
sodium-glucose cotransporter 2 (SGLT-2) inhibitor; and saxagliptin, a
dipeptidyl peptidase-4 (DPP-4) inhibitor. The FDA approved QTERN based
on data from a 24-week, Phase III, multi-center, randomized,
double-blind, placebo-controlled trial (n=315) designed to evaluate the
efficacy and safety of saxagliptin added to dapagliflozin in adult
patients with type-2 diabetes who experienced inadequate glycemic
control (HbA1c ≥7% to ≤10.5%) with metformin (≥1,500 mg per day). The
safety of combined use of dapagliflozin and saxagliptin has been
evaluated in a pooled safety analysis (N=1,169; 492 treated with QTERN)
of three Phase III placebo-controlled clinical trials for up to 52 weeks.

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science with the goal of
developing life-changing medicines that aim to reduce the global burden
and complications of diabetes. As a core therapy area for the company,
we are focusing our research and development efforts on diverse
populations and patients with significant co-morbidities, such as
cardiovascular disease, obesity, non-alcoholic steatohepatitis (NASH),
and chronic kidney disease.

Our commitment to diabetes is exemplified by the depth and breadth of
our global clinical research program. This commitment is advancing
understanding of the treatment effects of our diabetes medicines in
broad patient populations, as well as exploring combination product
approaches to help more patients achieve treatment success earlier in
their disease progression. Our ambition is to reduce the long-term
impact of diabetes.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in three
main therapy areas - Oncology, Cardiovascular & Metabolic Diseases and
Respiratory. The Company also is selectively active in the areas of
autoimmunity, neuroscience and infection. AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit www.astrazeneca-us.com
and follow us on Twitter @AstraZenecaUS.

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