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Farxiga

Generic Name: Dapagliflozin Propanediol
Class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical Name: (1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol,
Molecular Formula: C21H25ClO6
CAS Number: 461432-26-8

Warning(s)

Special Alerts:

[Posted 06/14/2016]

AUDIENCE: Endocrinology, Internal Medicine, Nephrology, Pharmacy

ISSUE: FDA has strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports, we have revised the warnings in the drug labels to include information about acute kidney injury and added recommendations to minimize this risk.

BACKGROUND: Canagliflozin and dapagliflozin are prescription medicines used with diet and exercise to help lower blood sugar in adults with type 2 diabetes. They belong to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin and dapagliflozin lower blood sugar by causing the kidneys to remove sugar from the body through the urine.

From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases* of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use (see Drug Safety Communication, available at: , for the Data Summary). This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware.

RECOMMENDATION:Health care professionals should consider factors that may predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin. These include decreased blood volume; chronic kidney insufficiency; congestive heart failure; and taking other medications such as diuretics, blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Assess kidney function prior to starting canagliflozin or dapagliflozin and monitor periodically thereafter. If acute kidney injury occurs, promptly discontinue the drug and treat the kidney impairment.

Patients should seek medical attention immediately if they experience signs and symptoms of acute kidney injury. This is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body. Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet. Patients should not stop taking their medicine without first talking to their health care professionals. Doing so can lead to uncontrolled blood sugar levels that can be harmful. Read the patient Medication Guide, available at: , you receive with your canagliflozin or dapagliflozin prescriptions. It explains the benefits and risks associated with the medicine.

[Posted 12/04/2015]

AUDIENCE: Pharmacy, Emergency Medicine

ISSUE: An FDA safety review has resulted in adding warnings to the labels of a specific class of type 2 diabetes medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors about the risks of too much acid in the blood and of serious urinary tract infections. Both conditions can result in hospitalization.

FDA issued a Drug Safety Communication in May 2015 warning about the risk of ketoacidosis with SGLT2 inhibitors and alerting that the Agency would continue to evaluate this safety issue. A review of the FDA Adverse Event Reporting System (FAERS) database from March 2013 to May 2015 identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.

FDA also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as urinary tract infections with the SGLT2 inhibitors reported to FAERS from March 2013 through October 2014. All 19 patients were hospitalized, and a few required admission to an intensive care unit or dialysis in order to treat kidney failure.

As a result, FDA added new Warnings and Precautions to the labels of all SGLT2 inhibitors to describe these two safety issues, and to provide prescribing and monitoring recommendations. FDA is also requiring manufacturers of SGLT2 inhibitors to conduct a required postmarketing study. This required enhanced pharmacovigilance study requests that manufacturers perform analyses of spontaneous postmarketing reports of ketoacidosis in patients treated with SGLT2 inhibitors, including specialized follow-up to collect additional information, for a period of 5 years.

BACKGROUND: SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.

RECOMMENDATION: Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have any symptoms of ketoacidosis.

Health care professionals should assess for ketoacidosis and urinary tract infections in patients taking SGLT2 inhibitors who present with suggestive symptoms. Ketoacidosis associated with the use of SGLT2 inhibitors can occur even if the blood sugar level is not very high. If ketoacidosis is suspected, the SGLT2 inhibitor should be discontinued and treatment instituted promptly.

For further information visit the FDA website at: and .

Introduction

Antidiabetic agent; sodium-glucose cotransporter 2 (SGLT2) inhibitor.1

Uses for Farxiga

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 2 3 15 32 34

Used in combination with other antidiabetic agents (e.g., metformin and/or a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione], a dipeptidyl peptidase-4 [DPP-4] inhibitor) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1 4 5 6 7 8 9 10 12 13 16

Not indicated for type 1 diabetes mellitus or treatment of diabetic ketoacidosis.1

Farxiga Dosage and Administration

Administration

Oral Administration

Administer once daily in the morning, with or without food.1

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule.1 Do not double dose to replace a missed dose.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.1

Adults

Diabetes Mellitus
Oral

Initially, 5 mg once daily.1

If well tolerated, increase dosage to 10 mg once daily in patients who require additional glycemic control.1

Special Populations

Hepatic Impairment

Mild, moderate or severe hepatic impairment: No dosage adjustment necessary.1

Renal Impairment

Mild renal impairment (estimated GFR ≥60 mL/minute per 1.73 m2): No dosage adjustment necessary.1

Moderate renal impairment: Do not initiate if GFR <60 mL/minute per 1.73 m2.1 (See Renal Impairment under Cautions.) If GFR persistently <60 mL/minute per 1.73 m2, discontinue drug.1

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2): Contraindicated.1

Geriatric Patients

No dosage adjustment necessary based solely on age.1

Gender

Dosage adjustment based on gender not necessary.1

Race

Dosage adjustment based on race not necessary.1

Body Weight

Dosage adjustment based on body weight not necessary.1

Cautions for Farxiga

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • History of serious hypersensitivity reaction to dapagliflozin.1

  • Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2), end-stage renal disease, or on dialysis.1

Warnings/Precautions

Ketoacidosis

Ketoacidosis (e.g., diabetic ketoacidosis, ketoacidosis, ketosis) requiring hospitalization reported with SGLT2 inhibitors; may occur without markedly elevated blood glucose concentrations (e.g., <200 mg/dL).39 40 41 42

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed.39 40 (See Advice to Patients.)

Some clinicians suggest monitoring of urine and/or plasma ketone levels if patients feel unwell, regardless of ambient glucose concentrations.40 42

Hypotension

May cause intravascular volume contraction.1 Symptomatic hypotension can occur, particularly in patients with impaired renal function (estimated GFR <60 mL/minute per 1.73 m2), geriatric patients, or patients receiving loop diuretics.1 (See Specific Drugs under Interactions.) Assess and correct intravascular volume status prior to initiating dapagliflozin in such patients.1

Monitor patients for signs and symptoms of hypotension after initiating therapy.1

Renal Effects

May increase Scr concentration and decrease estimated GFR; geriatric patients and patients with impaired renal function may be more susceptible to these changes.1 Adverse reactions related to renal function can occur following initiation.1

Evaluate renal function prior to initiation of dapagliflozin and monitor periodically thereafter.1

Concomitant Therapy with Hypoglycemic Agents

When adding dapagliflozin to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1 (See Specific Drugs under Interactions)

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection).1 11 37 Patients with a history of genital mycotic infections were more likely to develop such infections.1 37

Monitor patients for genital mycotic infections and institute appropriate treatment if these infections occur.1

Risk of Bone Fracture

Increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, observed in patients receiving another SGLT2 inhibitor (canagliflozin).43 Bone fractures observed more frequently than with placebo in patients with moderate renal impairment (estimated GFR 30 to <60 mL/minute per 1.73 m2) receiving dapagliflozin, usually within 52 weeks of initiating therapy.1 FDA continuing to evaluate bone fracture risk with SGLT2 inhibitors.43

Effects on Lipoproteins

Increases in LDL-cholesterol can occur.1 Monitor serum LDL-cholesterol concentrations and treat such lipid elevations according to the standard of care.1

Bladder Cancer

Newly diagnosed cases of bladder cancer reported in clinical studies.1 10 Too few cases to determine whether the emergence of these events is related to dapagliflozin; insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumors. 1

Do not use dapagliflozin in patients with active bladder cancer.1 Consider benefits of glycemic control versus unknown risks for cancer recurrence.1

Macrovascular Outcomes

Evidence of macrovascular risk reduction with dapagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity), some serious, reported.1 If a hypersensitivity reaction occurs, discontinue dapagliflozin, institute appropriate treatment, and monitor patients until signs and symptoms resolve.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

Efficacy similar in patients <65 years of age and those ≥65 years of age after controlling for renal function (estimated GFR).1 Such patients more likely to experience adverse effects related to volume depletion and renal impairment or failure.1

Hepatic Impairment

No dosage adjustment necessary for patients with mild, moderate, or severe hepatic impairment.1 Assess benefits versus risks in patients with severe hepatic impairment; safety and efficacy not established in such patients.1 22

Renal Impairment

Patients with moderate renal impairment (estimated GFR 30 to <60 mL/minute per 1.73 m2) receiving dapagliflozin had no overall improvement in glycemic control and had higher rates of renal-related adverse reactions and more bone fractures than placebo recipients; do not initiate in such patients.1 35

Not expected to be effective in patients with severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2) or end-stage renal disease; contraindicated in such patients.1

Impact of hemodialysis on dapagliflozin exposure is not known; contraindicated in patients on dialysis.1

Assess renal function prior to initiation of therapy and periodically thereafter.1

Common Adverse Effects

Female genital mycotic infection,1 2 3 4 6 7 8 nasopharyngitis,1 2 3 5 6 7 8 urinary tract infection,1 2 3 4 5 6 8 33 back pain,1 5 8 increased urination,1 male genital mycotic infection,1 2 3 4 7 nausea,1 4 dyslipidemia,1 4 8 constipation,1 discomfort with urination,1 pain in extremity.1 8

Interactions for Farxiga

Metabolism principally mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.1 20

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not inhibit CYP-450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 in vitro.1 19 Did not induce CYP isoenzymes 1A2, 2B6, or 3A4 in vitro.1 19

Drugs Affected by Organic Anion Transporter

Dapagliflozin 3-O-glucuronide, inactive metabolite of dapagliflozin, is a substrate of organic anion transport (OAT) 3.1 Dapagliflozin and dapagliflozin 3-O-glucuronide did not meaningfully inhibit OAT1 or OAT3 active transporters; pharmacokinetic interactions unlikely with OAT1 or OAT3 substrates.1

Drugs Affected by Organic Cation Transporter

Did not meaningfully inhibit organic cation transporter (OCT) 2; pharmacokinetic interactions unlikely with substrates of OCT2.1

Drugs Affected by P-glycoprotein Transport

Weak P-glycoprotein substrate; did not meaningfully inhibit P-glycoprotein.1 19 20 Unlikely to affect pharmacokinetics of concurrently administered P-glycoprotein substrates.1

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Antidiabetic agents

Risk of hypoglycemia increased when used concomitantly with insulin secretagogue (e.g,, sulfonylurea) or insulin1

Reduced dosage of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia1

Bumetanide

Increased bumetanide AUC and peak plasma concentration1 (see also Diuretics entry in this table)

No dosage adjustment necessary1

Digoxin

No clinically meaningful effect on digoxin AUC or peak plasma concentration1 20 26

No adjustment of digoxin dosage necessary1

Diuretics

Possible increased incidence of symptomatic hypotension1

Assess and correct intravascular volume prior to dapagliflozin initiation; monitor for signs and symptoms of hypotension after initiating therapy1

Glimepiride

Increased glimepiride AUC1 20

No dosage adjustment necessary1 25

Hydrochlorothiazide

No clinically important effect on pharmacokinetics of either drug1 20 (see also Diuretics entry in this table)

No dosage adjustment necessary1

Mefenamic acid

Increased dapagliflozin peak plasma concentration and AUC1 20 24

No adjustment of dapagliflozin dosage necessary.24

Metformin

No clinically meaningful effect on pharmacokinetics of either drug 1 20 25

No dosage adjustment necessary1 25

Pioglitazone

Decreased pioglitazone peak plasma concentration1 20

No dosage adjustment necessary1 25

Rifampin

Decreased dapagliflozin peak plasma concentration and AUC 1 20 24

No adjustment of dapagliflozin dosage necessary1 24

Simvastatin

Increased simvastatin AUC1 26

No dosage adjustment necessary1

Sitagliptin

No clinically meaningful effect on pharmacokinetics of either drug (single-dose administration)1

No dosage adjustment necessary1 25

Urine glucose tests (e.g., 1,5-anhydroglucitol assay)

SGLT2 inhibitors increase urinary glucose excretion and will result in false-positive urine glucose tests1

Use alternative methods to monitor glycemic control1

Valsartan

Decreased peak plasma concentrations of valsartan and dapagliflozin and increased valsartan AUC1 20 26

No dosage adjustment necessary1

Voglibose (not commercially available in the US)

No clinically meaningful effect on dapagliflozin1

Warfarin

No clinically meaningful effect on warfarin pharmacokinetics or pharmacodynamics1 20 26

No warfarin dosage adjustment necessary1 20

Farxiga Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability: 78%.1 27 Peak plasma concentration usually attained within 2 hours after oral dosing in fasted state.1 18 19 20 23 30

Food

Administration with a high-fat meal decreased peak plasma concentration by up to 50% and prolonged time to peak plasma concentration by approximately 1 hour, but did not alter AUC.1 20 21 These changes are not considered clinically meaningful; administer dapagliflozin with or without food.1 20 21

Special Populations

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No clinically important differences in peak plasma concentration or AUC.1

Severe hepatic impairment (Child-Pugh class C): AUC and peak plasma concentration increased by 67 and 40%, respectively, compared with individuals with normal hepatic function following a single 10-mg dose of dapagliflozin.1 22

Mild renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased by 45% compared with individuals with normal renal function.1

Moderate renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased 2.04-fold compared with individuals with normal renal function.1

Severe renal impairment: Geometric mean systemic exposure of dapagliflozin at steady state increased 3.03-fold compared with individuals with normal renal function.1

Distribution

Extent

Extensively distributed.20

Plasma Protein Binding

Approximately 91%.1 19

Special Populations

Renal or hepatic impairment does not meaningfully alter plasma protein binding.1

Elimination

Metabolism

Metabolized principally by UGT1A9 to inactive metabolites.1

Elimination Route

75 and 21% of total radioactivity excreted in urine and feces, respectively, with <21 19 and approximately 15% in urine and feces, respectively, as parent drug.1 20

Half-life

Approximately 12.9 hours following a single oral dose of 10 mg.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits SGLT2, a transporter expressed in proximal renal tubules and responsible for majority of reabsorption of filtered glucose from the tubular lumen.1 20

  • Reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion.1 17 30 31

  • Increases glucose excretion independent of insulin secretion.36

  • Improves muscle insulin sensitivity;28 29 however, glucosuria induction appears to increase endogenous glucose production.28

  • Endogenous glucose production increases, accompanied by an increase in fasting plasma glucagon concentration.28

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1 38

  • Importance of informing patients of the potential risks and benefits of dapagliflozin and of alternative therapies.1 38 Importance of not using dapagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 38

  • Importance of informing patients and their caregivers of the signs and symptoms of metabolic acidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status change) and instructing patients to seek medical attention immediately should they experience any such signs or symptoms.39 42 Patients should not discontinue dapagliflozin without consulting the prescribing clinician.39

  • Importance of informing patients that symptomatic hypotension may occur with dapagliflozin and to report such symptoms to their clinicians.1 38 Inform patients that dapagliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1 38

  • Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).1 38 Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g., rash or redness of the glans or foreskin of the penis).1 38 Advise patients of treatment options and when to seek medical advice.1 38

  • Importance of informing patients that urinary tract infections may occur.1 38 Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician if such signs and symptoms occur.1

  • Importance of informing patients that due to the mechanism of action of dapagliflozin, patients taking the drug will test positive for glucose in their urine.1 Importance of not using urine glucose tests to monitor glycemic status while taking dapagliflozin.1

  • Risk of serious hypersensitivity reactions, such as urticaria and angioedema.1 38 If signs or symptoms of such a reaction occur, importance of discontinuing dapagliflozin and promptly informing clinician.1 38

    Importance of informing patients to promptly report any signs of macroscopic hematuria or other symptoms potentially indicative of bladder cancer.1 38

  • Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A1c; HbA1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1 38

  • Importance of promptly seeking medical advice during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.1 38

  • Importance of taking dapagliflozin exactly as directed by clinician.1 38 (See Administration under Dosage and Administration.)

  • Importance of women informing their clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 38

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 38

  • Importance of informing patients of other important precautionary information.1 38 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dapagliflozin Propanediol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg (of dapagliflozin)

Farxiga

Bristol-Myers Squibb

10 mg (of dapagliflozin)

Farxiga

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Bristol-Myers Squibb Company. Farxiga (dapagliflozin) tablets prescribing information. Princeton, NJ; 2015 Mar.

2. Ferrannini E1, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010 Oct; 33:2217-24. [PubMed 20566676]

3. Bailey CJ, Iqbal N, T'joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012 Oct; 14:951-9. [PubMed 22776824]

4. . Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012 May; 66:446-56. [PubMed 22413962]

5. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26; 375:2223-33. [PubMed 20609968]

6. Nauck MA, Del Prato S, Meier JJ et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011 Sep; 34:2015-22. [PubMed 21816980]

7. Strojek K, Yoon KH, Hruba V. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011 Oct; 13:928-38. [PubMed 21672123]

8. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012 Jul; 35:1473-8. [PubMed 22446170]

9. Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin Is Effective as Add-on Therapy to Sitagliptin With or Without Metformin: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Diabetes Care.. 2014 Mar; 37:740-50. [PubMed 24144654]

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13. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2013 Aug 1; :.

14. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012 Mar; 97:1020-31. [PubMed 22238392]

15. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014 Jan 1; 36:84-10. [PubMed 24378206]

16. Wilding JP, Norwood P, T'joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care. 2009 Sep; 32:1656-62. [PubMed 19528367]

17. DeFronzo RA, Hompesch M, Kasichayanula S et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013 Oct; 36:3169-76. [PubMed 23735727]

18. Yang L, Li H, Li H et al. Pharmacokinetic and pharmacodynamic properties of single- and multiple-dose of dapagliflozin, a selective inhibitor of SGLT2, in healthy Chinese subjects. Clin Ther. 2013 Aug; 35:1211-1222. [PubMed 23910664]

19. Obermeier M, Yao M, Khanna A et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2010 Mar;; :. [PubMed 19996149]

20. Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014 Jan; 53:17-27. [PubMed 24105299]

21. Kasichayanula S, Liu X, Zhang W et al. Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab. 2011 Aug; 13:770-3. [PubMed 21435141]

22. Kasichayanula S, Liu X, Zhang W et al. Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study.. Clin Ther. 2011 Nov; 33:1798-808. [PubMed 22030444]

23. Kasichayanula S, Liu X, Pe Benito M et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013 Sep; 76:432-44. [PubMed 23210765]

24. Kasichayanula S, Liu X, Griffen SC, Lacreta FP, Boulton DW. Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin. Diabetes Obes Metab. 2013 Mar; 15:280-3. [PubMed 23061428]

25. Kasichayanula S, Liu X, Shyu WC et al. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab. 2011 Jan; 13:47-54. [PubMed 21114603]

26. Kasichayanula S, Chang M, Liu X et al. Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin. Adv Ther. 2012 Feb; 29:163-77. [PubMed 22271159]

27. Boulton DW, Kasichayanula S, Keung CF et al. Simultaneous oral therapeutic and intravenous 14C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin. Br J Clin Pharmacol. 2013 Mar; 75:763-8. [PubMed 22823746]

28. Merovci A, , Solis-Herrera C, Daniele G et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014 Feb 3; 124:509-14. [PubMed 24463448]

29. Mudaliar S, Henry RR, Boden G et al. Changes in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin. Diabetes Technol Ther. 2014 Mar; 16:137-44. [PubMed 24237386]

30. Komoroski B, Vachharajani N, Boulton D et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009 May; 85:520-6. [PubMed 19129748]

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