dapagliflozin/saxagliptin

Dapagliflozin/saxagliptin is a combination medication used to improve glycemic control in adults with diabetes mellitus type 2, in addition to diet and exercise. Dapagliflozin reduces blood glucose levels by inhibiting the reabsorption of glucose in the kidneys. Saxagliptin alters the activity of insulin and glucagon, two pancreatic hormones that regulate blood glucose levels. The combination drug is not recommended for type 1 diabetes mellitus, because it can increase the risk of ketoacidosis, a serious complication of diabetes.

Insulin stimulates the uptake of glucose from the blood by the organs, while glucagon increases blood sugar levels and prevents it from dropping too low. Diabetes mellitus is a chronic metabolic disorder caused by inadequate production or improper functioning of insulin which impairs the body’s ability to convert glucose into the form of energy that cells use. With the result, blood glucose levels remain excessively high which can damage all organ systems. Diabetes mellitus type 2 generally develops in adults, usually due to lifestyle factors.

The combination drug dapagliflozin/saxagliptin helps reduce blood glucose levels in the following ways:

• Dapagliflozin: Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor drug. SGLT2 is a protein molecule that is responsible for majority of glucose reabsorption in the kidneys. Dapagliflozin inhibits SGLT2, reduces reabsorption of glucose and promotes its excretion in the urine.
• Saxagliptin: The intestines release incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), after a meal. Incretin hormones stimulate insulin release from the pancreas, reduce glucagon secretion and glucose production in the liver. Dipeptidyl peptidase-4 (DPP-4) enzyme, present in many tissues, inactivates the incretin hormones within minutes. Saxagliptin inhibits DPP-4 enzyme and slows down the inactivation of the incretin hormones.

• Do not use dapagliflozin/saxagliptin in patients with a history of hypersensitivity to dapagliflozin, saxagliptin or any component of the formulation.
• Do not use dapagliflozin/saxagliptin to treat patients with moderate-to-severe impairment of kidney function, end-stage renal disease (ESRD) or patients on dialysis.
• There are reports of acute pancreatitis in patients treated with saxagliptin. Monitor patients for signs and symptoms of pancreatitis, and if pancreatitis is suspected, discontinue dapagliflozin/saxagliptin immediately and treat appropriately.
• Clinical trials in patients with established atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD showed that saxagliptin may increase the risk for hospitalization for heart failure, and the risk is higher in patients with a history of heart failure or renal impairment.
  • Consider risks and benefits of treatment in patients at higher risk for heart failure.
  • Monitor patients for signs and symptoms of heart failure during treatment.
  • Educate patients on symptoms of heart failure and advise them to report such symptoms immediately.
  • Evaluate patients who develop heart failure symptoms, treat appropriately and consider discontinuing dapagliflozin/saxagliptin.
• Treatment with SGLT2 inhibitors, including dapagliflozin, has been reported to lead to ketoacidosis, a life-threatening and sometimes, fatal complication of diabetes that requires immediate hospitalization.
  • Consider patient’s risk for developing ketoacidosis before initiation dapagliflozin/saxagliptin.
  • Monitor patients for symptoms of ketoacidosis and consider discontinuing in patients with clinical conditions that predispose to ketoacidosis and restarting after the conditions resolve.
  • In patients undergoing elective surgery, consider temporary discontinuation of dapagliflozin/saxagliptin for at least 3 days before surgery.
  • Educate patients on symptoms of ketoacidosis and advise them to report such symptoms immediately.
• Dapagliflozin can deplete blood volume leading to hypotension and kidney injury.
  • Elderly patients, patients taking loop diuretics, and patients with impaired kidney function are at a higher risk.
  • Assess patient’s blood volume status and kidney function before starting dapagliflozin/saxagliptin therapy.
  • Monitor for signs and symptoms of hypotension and impairment of renal function during treatment.
• Dapagliflozin increases the risk for serious urinary tract infections including urosepsis and pyelonephritis. Monitor patients for signs and symptoms of urinary tract infections and treat promptly.
• Dapagliflozin/saxagliptin can cause hypoglycemia and the risk is higher when used in combination with insulin or insulin secretagogue medications such as sulfonylureas. Adjust the dosage of insulin or insulin secretagogue appropriately.
• There have been reports of a rare but life-threatening bacterial genital infection, necrotizing fasciitis of the perineum (Fournier’s gangrene), associated with dapagliflozin, that have required surgical intervention.
  • Educate patients of symptoms of necrotizing fasciitis and advise them to report symptoms immediately.
  • If necrotizing fasciitis is suspected, institute appropriate treatment immediately, discontinue dapagliflozin/saxagliptin, monitor glucose levels closely and provide alternate treatment for glycemic control.
• There have been serious hypersensitivity reactions in some patients, including angioedema, anaphylaxis and exfoliative skin conditions, generally within the first 3 months of treatment initiation with saxagliptin.
  • Use dapagliflozin/saxagliptin with caution in patients with a history of angioedema to any other dipeptidyl peptidase-4 (DPP-4) inhibitor.
  • Advise patient to report hypersensitivity reactions immediately, provide appropriate treatment and monitor until symptoms resolve.
  • Provide alternate treatment for diabetes if no other cause for the hypersensitivity reactions is found.
• Dapagliflozin increases the risk for genital fungal infections, particularly in patients with a history. Monitor patient and treat appropriately.
• DPP-4 inhibitors, including saxagliptin can cause severe and disabling arthralgia, that may occur immediately after initiation of therapy or even after years. Consider saxagliptin as a possible cause if patient develops arthralgia, and discontinue if appropriate.
• A rare skin disorder, bullous pemphigoid, has been reported in some patients taking DPP-4 inhibitors. Advise patients to report development of blisters and erosions. If bullous pemphigoid is suspected, discontinue dapagliflozin/saxagliptin and refer to a dermatologist for appropriate treatment.

Common side effects of dapagliflozin/saxagliptin include:

• Upper respiratory tract infection
• Urinary tract infection
• Imbalance of blood fat levels (dyslipidemia)
• Increase in low-density lipoprotein (LDL) cholesterol
• Diarrhea
• Headache
• Back pain
• Joint pain (arthralgia)
• Genital fungal (mycotic) infections
• Low blood glucose levels (hypoglycemia)
• Depletion of blood volume and associated events including:
  • Dehydration
  • Low blood volume (hypovolemia)
  • Low blood pressure (hypotension)
• Impairment of kidney function
• Increase in serum creatinine
• Reduced urine output
• Acute kidney failure
• Increase in serum inorganic phosphorous
• Increase in hematocrit
• Increase in serum creatine kinase
• Decrease in serum bicarbonate
• Decrease in lymphocyte count

Less common side effects of dapagliflozin/saxagliptin include:

Dapagliflozin

• Rash
• Ketoacidosis, a serious complication of diabetes
• Acute kidney injury
• Serious urinary tract infections such as:
  • Urosepsis
  • Pyelonephritis
• Life threatening bacterial genital infection (necrotizing fasciitis of the perineum known as Fournier’s gangrene)

Saxagliptin

• Hypersensitivity reactions including:
  • Exfoliative skin reactions
  • Swelling beneath the skin and mucous membranes (angioedema)
  • Severe allergic reaction (anaphylaxis)
• Inflammation of the pancreas (pancreatitis)
• Severe and disabling arthralgia
• Bullous pemphigoid, a rare skin disorder with fluid-filled blisters
• Breakdown of muscle cells (rhabdomyolysis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 10 mg/5 mg

Adult:

Type 2 Diabetes Mellitus

• 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
• 1 tablet (i.e., 10 mg/5 mg) orally once daily in the morning with or without food

Dosage Modifications

Renal impairment

• Estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m²: Do not initiate
• Discontinue if eGFR persistently falls to below 60 mL/min/1.73 m²
• eGFR below 45 mL/min/1.73 m²: Contraindicated

Hepatic impairment

• May be administered with hepatic impairment
• Severe hepatic impairment: Individually assess benefit-risk

Coadministration with strong CYP3A4/5 inhibitors

• Do not co-administer with strong CYP3A4/5 inhibitors
• Examples include ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin

Dosing Considerations

• In patients with volume depletion, correct this condition prior to initiating drug
• Assess renal function before initiating and periodically thereafter

Limitations of use

• Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis
• Should only be used in patients who tolerate dapagliflozin 10 mg

Pediatric:

• Safety and efficacy not established

Overdose

Dapagliflozin/saxagliptin overdose can lower blood glucose levels excessively and lead to hypoglycemia. Overdose may be treated with symptomatic and supportive care. Saxagliptin can be removed from the blood by hemodialysis, however, there are no studies on the removal of dapagliflozin by hemodialysis.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Dapagliflozin/saxagliptin has no known severe interactions with other drugs.
• Serious interactions of dapagliflozin/saxagliptin include:
  • apalutamide
  • ceritinib
  • chloramphenicol
  • cobicistat
  • erdafitinib
  • ethanol
  • fexinidazole
  • idelalisib
  • ivosidenib
  • lasmiditan
  • lonafarnib
  • sotorasib
  • tepotinib
  • tucatinib
  • voxelotor
• Dapagliflozin/saxagliptin has moderate interactions with at least 116 different drugs.
• Dapagliflozin/saxagliptin has mild interactions with at least 88 different drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies of dapagliflozin/saxagliptin use in pregnant women, however, animal reproductive studies show dapagliflozin can affect the fetal kidneys if used during second and third trimesters of pregnancy.
• Dapagliflozin/saxagliptin is not recommended for use in pregnant women in the second and third trimesters.
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications, and fetal risks for birth defects and abnormally large growth (macrosomia).
• There is no information on the presence of dapagliflozin or saxagliptin in breastmilk, or its effects on milk production and the breastfed infant. Dapagliflozin and saxagliptin are present in rat’s milk.
• Dapagliflozin/saxagliptin is not recommended for use in nursing mothers because of the potential for serious adverse reactions in the breastfed infant, including injury to the developing kidneys.

• Take dapagliflozin/saxagliptin exactly as instructed. Swallow tablets whole, do not chew or crush.
• You may need regular checkups, follow up with your physician and do not miss your appointments. You will test positive for glucose in urine because of the way dapagliflozin/saxagliptin works.
• Discontinue dapagliflozin/saxagliptin and contact your physician immediately if you develop:
  • Symptoms of pancreatitis, which include severe abdominal pain and vomiting
  • Symptoms of diabetic ketoacidosis, including nausea, vomiting, abdominal pain, tiredness and labored breathing, even if your blood sugar is not elevated.
  • Severe allergic reactions such as rash, hives, peeling or flaking skin, swelling of skin, swelling of face, tongue, lips and throat, and swallowing and/or breathing difficulties.
• Report to your physician immediately if you develop:
  • Symptoms of heart failure such as rapid weight gain, swelling of feet and increasing shortness of breath
  • Low blood pressure symptoms; drink adequate fluids because dehydration increases the risk for reduced blood volume and associated hypotension
  • Symptoms of urinary tract infection
  • Pain, swelling, redness or tenderness of genitals or in the area between the genitals and rectum, along with malaise and/or fever above 100.4 F
  • Symptoms of genital fungal infection
  • Severe joint pain
  • Blisters or erosions in the skin
• Store dapagliflozin/saxagliptin safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.