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Dapagliflozin

Generic name: dapagliflozin systemic

Brand names: Farxiga

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Farxiga: 5 mg, 10 mg

Pharmacology

Mechanism of Action

By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, dapagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule, which may decrease cardiac preload/afterload and downregulate sympathetic activity.

Pharmacokinetics/Pharmacodynamics

Metabolism

Primarily mediated by UGT1A9 to an inactive metabolite (dapagliflozin 3-O-glucuronide); CYP-mediated metabolism (minor)

Excretion

Urine (75%; < 2% as parent drug); feces (21%; ~15% as parent drug)

Time to Peak

2 hours

Half-Life Elimination

~12.9 hours

Protein Binding

~91%

Use in Specific Populations

Special Populations: Renal Function Impairment

Patients with mild, moderate, or severe impairment had higher systemic exposure compared to patients with normal renal function.

Special Populations: Hepatic Function Impairment

In patients with severe impairment (Child-Pugh class C), mean Cmax and AUC were increased up to 40% and 67%, respectively.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; risk reduction of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.

Use: Off Label

Heart failure with reduced ejection fractiona

Data from a large, double-blind, randomized, placebo-controlled trial support the use of dapagliflozin in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes mellitus, to reduce the risk of worsening heart failure and cardiovascular death. Dapagliflozin should not be used for patients with type 1 diabetes mellitus. Patients should have symptomatic HFrEF and elevated N-terminal pro-B-type natriuretic peptide to be considered candidates. Patients should be optimized on other oral HFrEF therapies as tolerated (eg, beta-blocker, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker or angiotensin II receptor blocker-neprilysin inhibitor, and a mineralocorticoid receptor antagonist [if indicated]) and should also have standard device therapy (eg, an implantable cardioverter-defibrillator, cardiac resynchronization therapy, or both) if indicated McMurray 2019.

Contraindications

History of serious hypersensitivity to dapagliflozin or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis

Canadian labeling: Additional contraindications (not in US labeling): eGFR <45 mL/minute/1.73 m2

Dosage and Administration

Dosing: Adult

Note: Hypovolemia, if present, should be corrected prior to initiating therapy.

Diabetes mellitus, type 2: Note: May be used as an adjunctive agent or alternative monotherapy for patients who fail initial therapy with lifestyle intervention and metformin or cannot take metformin. Dapagliflozin may be preferred as an additional antidiabetic agent or alternative first-line agent in patients with heart failure or chronic kidney disease given the demonstrated cardiovascular and renal benefits (ADA 2019; DeSantis 2019; McMurray 2019; Wiviott 2019; Zelniker 2019).

For improvement in glycemic control: Oral: Initial: 5 mg once daily; may increase to 10 mg once daily, if needed to achieve glycemic goals.

For risk reduction of hospitalization for heart failure in patients with type 2 diabetes: Oral: 10 mg once daily. Note: Reduction of hospitalization for heart failure has been demonstrated in patients with established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors as well as in patients with established heart failure with reduced ejection fraction (McMurray 2019; Wiviott 2019).

Use in patients with diabetic nephropathy (off-label use): Although the manufacturer recommends against routine use in patients with eGFR <45 mL/minute/1.73 m2, in the setting of prevalent kidney disease, sodium-glucose cotransporter 2 (SGLT2) inhibitors have established renal and cardiovascular benefits when eGFR is ≥30 mL/minute/1.73 m2. For patients with diabetic nephropathy, eGFR ≥30 mL/minute/1.73 m2 and urine albumin excretion >300 mg/day, an SGLT2 inhibitor should be considered (Bakris 2019; Neuen 2019; Zelniker 2019). Because SGLT2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Wexler 2019).

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylurea): Reduced dose of insulin and/or insulin secretagogues may be needed.

Heart failure with reduced ejection fraction (adjunctive agent) (off-label use): Note: May be used as an adjunctive agent in persistently symptomatic patients with elevated N-terminal pro-B-type natriuretic peptide despite optimized oral pharmacologic therapies (eg, beta-blocker, angiotensin-converting enzyme inhibitor [or alternative], and a mineralocorticoid receptor antagonist [if indicated]) and device therapy, if indicated (eg, an implantable cardioverter-defibrillator, cardiac resynchronization therapy, or both). Benefits were consistently demonstrated in patients with or without type 2 diabetes (McMurray 2019).

Oral: 10 mg once daily. May consider temporary discontinuation or dose reduction to 5 mg once daily if acute renal dysfunction, volume depletion, or hypotension is a concern (McMurray 2019).

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer in the morning with or without food.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Test Interactions

Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.

Adverse Reactions

Incidences may include dapagliflozin used as add-on therapy.

1% to 10%:

Endocrine & metabolic: Dyslipidemia (3%), hypovolemia (1% to 3%)

Gastrointestinal: Nausea (3%)

Genitourinary: Urinary tract infection (6%), increased urine output (3% to 4%), dysuria (2%)

Hematologic & oncologic: Increased hematocrit (1%)

Infection: Genitourinary fungal infection (3% to 8%), influenza (3%)

Neuromuscular & skeletal: Back pain (4%), limb pain (2%)

Respiratory: Nasopharyngitis (7%)

Frequency not defined:

Hypersensitivity: Angioedema, hypersensitivity reaction

Neuromuscular & skeletal: Bone fracture

Renal: Decreased estimated GFR (eGFR), increased serum creatinine

<1%, postmarketing, and/or case reports: Acute renal failure, allergic skin reaction (severe), anaphylaxis, increased LDL cholesterol, ketoacidosis, necrotizing fasciitis (perineum), pyelonephritis, renal insufficiency, severe dermatological reaction, skin rash, urinary tract infection with sepsis

Warnings/Precautions

Concerns related to adverse effects:

  • Bone fractures: An increased incidence of bone fractures occurred in patients with moderate renal impairment (eGFR 30 to 60 mL/minute/1.73 m2) in 1 randomized controlled trial (Kohan 2014); however, a second randomized controlled trial did not confirm a similar increased risk in patients with eGFR 45 to 60 mL/minute/1.73 m2 (Fioretto 2018). In the overall population, dapagliflozin does not appear to increase risk of fractures, though longer term data may be necessary to clarify risk (Jabbour 2018; Ruanpeng 2017; Tang 2016).
  • Genital mycotic infections: May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
  • Hypersensitivity reactions: Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe. Discontinue dapagliflozin if hypersensitivity occurs and treat as appropriate.
  • Hypotension: May cause symptomatic hypotension due to intravascular volume depletion, especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor blockers), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
  • Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL) (Bobart 2016; FDA 2015; Handelsman 2016). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or discontinuation of insulin, caloric restriction, alcohol abuse, extensive exercise, myocardial infarction, stroke, severe infection, surgery, any other extreme stress event) (Handelsman 2016). The American Association of Clinical Endocrinologists and American College of Endocrinology recommend considering withholding of SGLT2 inhibitors for at least 24 hours prior to events that may precipitate diabetic ketoacidosis (Handelsman 2016), while others have suggested withholding for 3 to 5 days (Bobart 2016). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
  • Lipid abnormality: May cause LDL-cholesterol (C) elevation; monitor LDL-C and treat as needed.
  • Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving dapagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
  • Renal effects: Acute kidney injury has been reported. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. Assess renal function prior to initiation and periodically during treatment.
  • Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.

Disease-related concerns:

  • Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.

  • Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. The US manufacturer recommends against use in patients with eGFR <45 mL/minute/1.73 m2 and contraindicates use in severe renal impairment (eGFR <30 mL/minute/1.73 m2), end-stage renal disease, and in dialysis patients. However, use of SGLT2 inhibitors in select patients (heart failure, diabetic nephropathy) with eGFR ≥30 mL/minute/1.73 m2 may be considered (McMurray 2019; Neuen 2019; Zelniker 2019).

Concurrent drug therapy issues:

  • Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

  • Elderly: Elderly patients may be predisposed to symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, and dehydration) and renal impairment or failure.

Other warnings/precautions:

  • Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
  • Hospitalized patients: Use of SGLT2 inhibitors are not routinely recommended for hospitalized patients (ADA 2019).

Monitoring Parameters

Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2019); renal function (baseline and periodically during treatment); low-density lipoprotein cholesterol; monitor for genital mycotic infections and urinary tract infection; hypersensitivity reactions; volume status (eg, weight, blood pressure, hematocrit, electrolytes); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016])

Pregnancy

Pregnancy Considerations

Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of canagliflozin during the second and third trimesters of pregnancy

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than dapagliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Patient Education

What is this drug used for?

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).
  • It is used in certain people to lower the risk of having to go to the hospital for heart failure.

Frequently reported side effects of this drug

  • Nose irritation
  • Throat irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
  • Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
  • Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy
  • Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
  • Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
  • Pain, swelling, or signs of infection in the genitals or rectum
  • Vaginal yeast infection
  • Penile yeast infection
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated January 28, 2020.