dapagliflozin/saxagliptin (Rx)

>10%

Upper respiratory tract infection (13.6%)

1-10%

Urinary tract infection (5.7%)

Dyslipidemia (5.1%)

Headache (4.3%)

Diarrhea (3.7%)

Back pain (3.3%)

Genital infection (3%)

Arthralgia (2.4%)

Renal impairment (2%)

Increased serum inorganic phosphorus (1.7%)

Hypoglycemia (1.6%)

Increased hematocrit (1.3%)

Elevated creatine kinase (1%)

<1%

Volume depletion (hypotension, dehydration, hypovolemia)

Acute pancreatitis

Decreased lymphocyte count

Newly diagnosed bladder cancer

Postmarketing Reports

Saxagliptin

• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Pancreatitis
• Severe and disabling arthralgia
• Bullous pemphigoid
• Rhabdomyolysis

Dapagliflozin

• Ketoacidosis
• Acute kidney injury and impaired renal function
• Urosepsis and pyelonephritis
• Rash

Contraindications

History of hypersensitivity to dapagliflozin or saxagliptin, including anaphylaxis, angioedema, or exfoliative skin conditions

Moderate-to-severe renal impairment (eGFR <45 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Cautions

Acute pancreatitis reported; after initiating drug, monitor for signs and symptoms of pancreatitis; if suspected, promptly discontinue dapagliflozin/saxagliptin and initiate appropriate management

Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

May increase risk for developing heart failure (HF) or exacerbation of existing HR; observe patients for signs and symptoms of HF

Dapagliflozin causes intravascular volume contraction; symptomatic hypotension and acute kidney injury can occur, particularly with impaired renal function, elderly patients, chronic renal insufficiency, congestive HF, or coadministration of certain drugs (eg, diuretics, ACE inhibitors, ARBs, NSAIDs); before initiating, volume status should be assessed and corrected; do not initiate if eGFR is <60 mL/min/1.73 m²

Evaluate renal function prior to initiation of therapy and monitor periodically thereafter; contraindicated in patients with an eGFR <45 mL/min/1.73 m²

Hypoglycemia risk increased with insulin and insulin secretagogues; adjust dose

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate for signs and symptoms of UTIs and treat promptly, if indicated

Dose-related increases in LDL-C reported with dapagliflozin

Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10 (0.17%)/6045 patients treated with dapagliflozin and 1 (0.03%)/3512 patient treated with placebo/comparator; bladder cancer risk factors and hematuria (a potential indicator of preexisting tumors) were balanced between treatment arms at baseline and there were too few cases to determine whether the emergence of these events is related to dapagliflozin

Do not administer to patients with active bladder cancer and should be administered with caution in patients with a prior history of bladder cancer

No conclusive evidence of macrovascular risk reduction with dapagliflozin or any other antidiabetic agent

GLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic control

Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate

Serious hypersensitivity reactions with saxagliptin reported (typically within the first 3 months of therapy)

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use; patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor

Ketoacidosis

• Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
• Consider temporarily discontinuing therapy for at least 3 days for patients who undergo scheduled surgery
• Consider monitoring for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery); ensure risk factors for ketoacidosis are resolved prior to restarting therapy
• Educate patients on signs and symptoms of ketoacidosis and instruct patients to discontinue therapy and seek medical attention immediately if signs and symptoms occur

Pregnancy

Not recommended during the second and third trimesters

Adverse renal affects shown in animal studies

Animal studies

• Adverse renal pelvic and tubular dilatations, that were not fully reversible, were observed in juvenile rats when dapagliflozin was administered at an exposure 15-times the exposure at the 10-mg clinical dose during a period of renal development corresponding to the late second and third trimesters of human pregnancy
• Saxagliptin did not show adverse effects during organogenesis, corresponding to the first trimester of human pregnancy

Lactation

Unknown if distributed in human breast milk

Saxagliptin and dapagliflozin are present in the milk of lactating rats; since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney

Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of dapagliflozin/saxagliptin is not recommended while breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Dapagliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; SGLT-2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

Saxagliptin: Dipeptidyl peptidase IV (DPP-4) inhibition that results in increased incretin hormones and enhanced glycemic control; incretin hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner, but are inactivated by the DDP-4 enzyme within minutes

Absorption

Bioavailability

• Dapagliflozin: 78%; high-fat meal decreases absolute bioavailability by 50%

Peak plasma time

• Dapagliflozin: 2 hr (fasting); 3 hr (high-fat meal)
• Saxagliptin: 2 hr; 4 hr (active metabolite)

Peak plasma concentration

• Saxagliptin: 24 ng/mL
• Saxagliptin active metabolite: 47 ng/mL

AUC

• Saxagliptin: 78 ng·h/mL
• Saxagliptin active metabolite: 214 ng·h/mL

Distribution

Protein bound

• Dapagliflozin: 91%
• Saxagliptin and active metabolite: Negligible

Metabolism

Dapagliflozin

• Primarily mediated by UGT1A9
• CYP-mediated metabolism is a minor clearance pathway in humans
• Extensively metabolized, primarily to dapagliflozin 3-O-glucuronide (inactive)

Saxagliptin

• Primarily mediated by CYP3A4/5
• The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is 50% as potent as saxagliptin
• Strong CYP3A4/5 inhibitors and inducers alter the pharmacokinetics of saxagliptin and its active metabolite

Elimination

Half-life

• Dapagliflozin: 12.9 hr
• Saxagliptin: 2.5 hr; 3.1 hr (active metabolite)

Renal clearance

• Saxagliptin: 230 mL/min

Excretion

• Dapagliflozin

  • Renal: 75% (<2% as parent drug)
  • Feces: 21% (15% as parent drug)

• Saxagliptin

  • Renal: 24%; 36% (active metabolite); 75% (total radioactivity)
  • Feces: 22%

Oral Administration

Take once daily in the morning

May take with or without food

Do not split or cut tablets

Storage

Store at controlled room temperature; 20-25°C (68-77°F)

Excursion permitted to 15-30°C (59-86°F)