dapagliflozin/metformin

Dapagliflozin/metformin is a combination medication used in the treatment of diabetes mellitus type II in adults, in addition to diet and exercise. Dapagliflozin reduces blood glucose levels by inhibiting the reabsorption of glucose in the kidneys. Metformin improves glucose tolerance and lowers both basal levels of blood glucose as well as the post-meal glucose surge. The two drugs together are more effective in improving glycemic control and reducing the risk of cardiovascular death in diabetic adults with established cardiovascular disease or risk factors.

Dapagliflozin and metformin work in the following ways:

• Dapagliflozin: Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor drug. SGLT2 is a protein molecule that is responsible for the majority of glucose reabsorption in the kidneys. Dapagliflozin inhibits SGLT2, reduces reabsorption of glucose and promotes its excretion in the urine.
• Metformin: Metformin belongs to a class of medications known as biguanides. Metformin improves the body's response to natural insulin and increases peripheral glucose intake and utilization. Metformin also reduces glucose absorption from the intestines and decreases glucose production by the liver.

The FDA-approved uses of dapagliflozin/metformin include:

• Improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM) when treatment with both dapagliflozin and metformin is appropriate.
• Reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.
• Reduce the risk of cardiovascular death and hospitalization for heart failure in adults with T2DM and heart failure (NYHA class II-IV) with reduced ejection fraction.

Dapagliflozin/metformin is not indicated for use in the treatment of patients with diabetes mellitus type I because it can increase the risk of ketoacidosis, a serious complication of diabetes. The use of dapagliflozin/metformin is limited to adults with diabetes mellitus type 2 because of the metformin component of the formulation.

• Do not use dapagliflozin/metformin in patients with a history of severe hypersensitivity reactions such as angioedema or anaphylactic reactions to dapagliflozin, metformin or any other component of the medication.
• Do not use dapagliflozin/metformin in patients with severely impaired kidney function, end-stage renal disease (ESRD) or those receiving dialysis.
• Do not use dapagliflozin/metformin to treat patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis is a medical emergency that must be treated with insulin.
• Metformin use is associated with lactic acidosis, including fatal cases.
  • Symptoms may be nonspecific and include muscle pain, malaise, abdominal pain, respiratory distress and drowsiness. Severe acidosis can cause abnormally low body temperature, heart rate and blood pressure.
  • If a patient develops metformin-associated lactic acidosis, discontinue the medication immediately, institute supportive measures and perform hemodialysis to correct acidosis and eliminate metformin.
  • Educate patients on the symptoms of lactic acidosis and advise them to report symptoms immediately.
  • Take appropriate measures to reduce the risk of metformin-associated lactic acidosis in patients with potential risk for acidosis, which may include close monitoring, temporary or permanent discontinuation of metformin based on the severity of the risk. Risk factors include:
    • Impaired kidney function
    • Concomitant use of drugs that can increase lactic acidosis risk
    • Advanced age of 65 years or older
    • Radiological studies with contrast agent
    • Surgery and other procedures
    • Low oxygen levels (hypoxic state)
    • Impaired liver function
    • Excessive alcohol intake
• 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 the patient's blood volume status and kidney function before starting dapagliflozin/metformin therapy.
  • Monitor for signs and symptoms of hypotension and impairment of renal function during treatment.
• 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 the patient's blood volume status and kidney function before starting dapagliflozin/metformin therapy.
  • Monitor for signs and symptoms of hypotension and impairment of renal function during treatment.
• 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 the patient's risk for developing ketoacidosis before initiation of dapagliflozin/metformin.
  • Monitor patients for symptoms of ketoacidosis and consider discontinuing in patients with clinical conditions that predispose to ketoacidosis and restarting after the conditions resolve.
  • If a patient develops signs and symptoms of ketoacidosis, discontinue dapagliflozin/metformin, evaluate the patient and institute appropriate treatment for ketoacidosis promptly.
  • In patients undergoing elective surgery, consider temporary discontinuation of dapagliflozin/metformin for at least 3 days before surgery.
  • Educate patients on symptoms of ketoacidosis and advise them to report such symptoms immediately.
• 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/metformin 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.
• Dapagliflozin has been reported to be associated with a rare but life-threatening bacterial genital infection, necrotizing fasciitis of the perineum (Fournier’s gangrene), that has required surgical intervention.
  • Educate patients on symptoms of necrotizing fasciitis and advise them to report such symptoms immediately.
  • If necrotizing fasciitis is suspected, institute appropriate treatment immediately, discontinue dapagliflozin/metformin, monitor glucose levels closely and provide alternate treatment for glycemic control.
• Dapagliflozin increases the risk for genital fungal infections, particularly in patients with a history of genital mycotic infections. Monitor the patient and treat appropriately.
• Metformin treatment may decrease vitamin B12 levels, and the risk is higher in patients with inadequate vitamin B12 or calcium intake/absorption. Monitor the patient’s vitamin B12 levels and manage appropriately.

Common side effects of dapagliflozin/metformin include:

• Female genital fungal (mycotic) infections
• Male genital mycotic infections
• Urinary tract infections
• Increased urination
• Discomfort with urination
• Nose and throat inflammation (nasopharyngitis)
• Throat inflammation (pharyngitis)
• Cough
• Diarrhea
• Nausea
• Constipation
• Headache
• Influenza
• Back pain
• Pain in extremity
• Dizziness
• Imbalance of blood fats (dyslipidemia)
• Lactic acidosis
• Diabetic ketoacidosis
• Volume depletion
• Low blood glucose levels (hypoglycemia)
• Hypersensitivity reactions including:
  • Hives (urticaria)
  • Swelling beneath the skin and in mucous tissue (angioedema)
  • Severe allergic reactions (anaphylaxis)
• Increase in serum creatinine
• Decrease in eGFR
• Increase in hematocrit
• Increase in LDL cholesterol
• Decrease in vitamin B12 level
• Rash
• 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)
• Liver injury

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, extended-release

• 2.5 mg/1000 mg
• 5 mg/500 mg
• 5 mg/1000 mg
• 10 mg/500 mg
• 10 mg/1000 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) when treatment with both dapagliflozin and metformin is appropriate
• Individualize starting dose based on current regimen
• Not already taking dapagliflozin: Initiate dapagliflozin at 5 mg orally once daily
• Adjust dose based on effectiveness and tolerability; not to exceed 10 mg dapagliflozin and 2,000 mg metformin

Heart Failure and/or Chronic Kidney Disease

Dapagliflozin indicated to reduce risk of

• Hospitalization risk for heart failure (HF) in adults with T2DM and established cardiovascular disease (CVD) or multiple CV risk factors
• CV death and hospitalization for HF in adults with T2DM who have HF (NYHA class II-IV) with reduced ejection fraction
• Sustained eGFR rate decline, end-stage renal disease (ESRD), CV death, and hospitalization for HF in adults with chronic kidney disease at risk of progression

Dose

• Individualize starting dose based on current regimen
• For indications related to heart failure and/or chronic kidney disease, recommended dapagliflozin is 10 mg orally once daily
• Adjust dose based on effectiveness and tolerability; not to exceed 10 mg dapagliflozin and 2,000 mg metformin

Dosage Modifications

Renal impairment

• Obtain estimated glomerular filtration rate (eGFR) before starting metformin
• eGFR 45 mL/minute/1.73 m² or higher: No dosage adjustment required
• eGFR 30-45 mL/minute/1.73 m²: Not recommended
• eGFR below 30 mL/minute/1.73 m²: Contraindicated
• Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)

Discontinuation for iodinated contrast imaging procedures

• Discontinue dapagliflozin/metformin at time of, or prior to, an iodinated contrast imaging procedure in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast
• Re-evaluate eGFR 48 hours after imaging procedure; restart if renal function is stable

Dosing Considerations

Assess patient's current therapy

• Individualize starting dose based on current therapy
• If taking an evening dose of metformin XR, skip last dose before starting dapagliflozin/metformin
• Adjust dose based on effectiveness and tolerability; not to exceed daily dose of dapagliflozin 10 mg and metformin 2000 mg

Before initiating

• Assess renal function before initiating and periodically thereafter
• Assess volume status and, if necessary, correct volume depletion before initiating

Limitations of use

• Not for type 1 diabetes mellitus or diabetic ketoacidosis
• Because of the metformin component, use limited to adults with type 2 diabetes mellitus for all indications

Pediatric:

• Safety and efficacy not established

Overdose

Metformin overdose can cause lactic acid buildup (lactic acidosis) with symptoms including muscle pain, malaise, abdominal pain, respiratory distress and drowsiness. Hemodialysis may be useful in removing metformin, but removal of dapagliflozin through hemodialysis has not been studied. Dapagliflozin/metformin overdose may be treated with symptomatic and supportive care.

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/metformin has no listed severe interactions with other drugs.
• Serious interactions of dapagliflozin/metformin include:
  • contrast media (iodinated)
  • ethanol
  • ioversol
  • methylene blue
  • pacritinib
  • ranolazine
  • risdiplam
  • selegiline
  • selegiline transdermal
  • tafenoquine
  • tedizolid
  • tranylcypromine
  • trilaciclib
• Dapagliflozin/metformin has moderate interactions with at least 190 different drugs.
• Dapagliflozin/metformin has mild interactions with at least 63 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.

• The limited available data on the use of dapagliflozin/metformin or dapagliflozin are not sufficient to identify a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use in pregnant women have not revealed a clear drug-associated risk for major birth defects or miscarriage.
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications, and fetal risks of birth defects and abnormally large growth (macrosomia) and associated conditions.
• Based on animal reproductive data that show adverse kidney developmental effects from use of dapagliflozin, dapagliflozin/metformin is not recommended for use during the second and third trimesters of pregnancy.
• Treatment with metformin may result in unintended pregnancy because of metformin’s effects on ovulation.
• There is no information on the presence of dapagliflozin/metformin or dapagliflozin in breastmilk, or the effects on milk production or the breastfed infant. Limited studies show metformin is present in breastmilk, but there is no information on its effects on milk production or the breastfed infant. Dapagliflozin is present in animal milk.
• Human kidney matures in the uterus and in the first 2 years of life, and exposure to dapagliflozin can adversely affect the kidneys. Use of dapagliflozin/metformin is not recommended in nursing mothers because of the potential for serious adverse reactions, including kidney adverse effects, in the breastfed infant.

• Take dapagliflozin/metformin exactly as prescribed.
• You will need regular tests while on treatment with dapagliflozin/metformin. Follow up with your physician and keep up with your appointments.
• Inform your physicians that you are taking dapagliflozin/metformin, prior to surgical and radiological procedures. You may need to temporarily discontinue the drug.
• Avoid excessive alcohol intake while on treatment with dapagliflozin/metformin.
• Drink adequate fluids while on dapagliflozin/metformin therapy and report any kidney-related symptoms and urinary infections to your physician immediately.
• Report to your treating physician immediately if you experience:
  • Symptoms of lactic acidosis such as unexplained hyperventilation, feeling unwell, muscular pains and unusual drowsiness
  • Symptoms of low blood pressure
  • Hypersensitivity reactions such as hives, angioedema or anaphylaxis
  • Signs and symptoms of hypoglycemia
  • 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
• Discontinue dapagliflozin/metformin immediately and seek medical care, if you experience symptoms of ketoacidosis, a life-threatening condition, with symptoms that include nausea, vomiting, abdominal pain, tiredness, and labored breathing, 
• Store dapagliflozin/metformin safely out of reach of children.
• In case of overdose, seek medical care or call Poison Control.