empagliflozin

Empagliflozin is an antidiabetic medication used in addition to diet and exercise to improve glycemic control in adults and children 10 years and older with type II diabetes mellitus, and to reduce the risk of hospitalization and death in adults with heart failure or chronic kidney disease. Empagliflozin reduces blood glucose and blood sodium levels by inhibiting reabsorption of glucose and sodium in the kidneys, and increasing their excretion in the urine.

Empagliflozin belongs to a class of medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is a protein molecule that is responsible for glucose reabsorption from the glomerular filtrate in the kidneys. Empagliflozin inhibits SGLT2, thereby lowering the kidney's threshold for glucose, reducing reabsorption of glucose and promoting urinary excretion of glucose.

Empagliflozin also reduces sodium reabsorption in the kidney’s tubules and increases its excretion in urine. This reduces the pressure in the glomerulus, the filtering unit of the kidneys. Increasing sodium excretion in the urine also reduces preload and after-load on the heart and downregulates sympathetic nervous system activity, reducing heart failure risk in patients with cardiovascular disease.

Empagliflozin is approved by the FDA for the following:

• As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
• To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure.
• To reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.
• To reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.

Empagliflozin is not recommended for use in the following conditions:

• To improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
• To improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/minute/1.73 m2.
• Treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or treatment with more than 45 mg of prednisone or equivalent for kidney disease.

• Do not use empagliflozin in patients with a history of hypersensitivity to empagliflozin or any of its components.
  • Hypersensitivity reactions such as angioedema have been reported in patients treated with empagliflozin.
  • If the patient develops hypersensitivity reactions, discontinue empagliflozin immediately, treat appropriately and monitor until symptoms resolve.
• Do not use empagliflozin to treat patients with type I diabetes, it significantly increases the risk for diabetic ketoacidosis, a life-threatening complication.
  • Type II diabetic patients with pancreatic disorders are also at high risk for ketoacidosis due to treatment with SGLT2 inhibitors, including empagliflozin.
  • Diabetic or other ketoacidosis can result from reduced or missed insulin dose, acute febrile illness, surgery, volume depletion, reduced calorie intake, ketogenic diet or alcohol abuse.
  • Ketoacidosis causes dehydration and severe metabolic acidosis with symptoms that include nausea, vomiting, abdominal pain, shortness of breath, and general malaise.
  • Educate patients on symptoms of ketoacidosis and advise them to report such symptoms immediately.
  • Consider ketone monitoring in patients at risk for ketoacidosis.
  • Evaluate for ketoacidosis if the patient develops symptoms of metabolic acidosis. Discontinue empagliflozin and treat appropriately if ketoacidosis is confirmed. Monitor the patient until symptoms resolve before restarting empagliflozin.
  • Withhold empagliflozin temporarily in conditions that can predispose the patient to ketoacidosis and restart when the patient is stable and resumes oral intake.
• Empagliflozin reduces blood volume and can cause symptomatic hypotension and transient changes in creatinine. There are reports of acute kidney injury, including hospitalization and dialysis, in diabetic patients treated with SGLT2 inhibitors.
  • Patients with kidney impairment, patients on diuretics, elderly patients, and those with low systolic blood pressure are at a higher risk for volume depletion and hypotension.
  • Check blood volume status and correct, if necessary, monitor for signs and symptoms of hypotension, and renal function, and continue monitoring during therapy.
• Empagliflozin 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.
• Empagliflozin treatment can increase the risk for hypoglycemia in patients taking concomitant insulin or insulin secretagogue medications such as sulfonylureas. Adjust the dosage of insulin or insulin secretagogue appropriately. Inform patients of hypoglycemia risk and the signs and symptoms of hypoglycemia.
• Empagliflozin therapy is 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 symptoms immediately.
  • If necrotizing fasciitis is suspected, institute appropriate treatment immediately, discontinue empagliflozin, monitor glucose levels closely and provide alternate treatment for glycemic control.
• Empagliflozin increases the risk for genital fungal (mycotic) infections, particularly in patients with a history of recurrent mycotic infections. Monitor patients and treat them appropriately.
• Clinical studies suggest empagliflozin may increase the risk for lower limb amputations.
  • Risk factors include history of peripheral artery disease and/or diabetic foot infections, including bone infection (osteomyelitis).
  • Counsel patients on the importance of preventive foot care.
  • Monitor patients for signs and symptoms of infection, new pain or soreness, ulcers or sores in the lower limbs, advise patients to report such symptoms, and treat promptly.

Common side effects of empagliflozin include:

• Urinary tract infection
• Increased urination
• Genital fungal (mycotic) infections
• Upper respiratory tract infection
• Imbalance of blood fats (dyslipidemia)
• Joint pain (arthralgia)
• Nausea
• Thirst
• Blood volume depletion with symptoms including:
  • Low blood pressure (hypotension)
  • Dehydration
  • Drop in blood pressure with postural change (orthostatic hypotension)
  • Fainting (syncope)
• Low blood glucose levels (hypoglycemia)
• Lower limb amputations
• Increase in serum creatinine
• Decrease in eGFR
• Increase in LDL cholesterol
• Increase in hematocrit
• Ketoacidosis
• Kidney infections including:
  • Urosepsis
  • Pyelonephritis
• Acute kidney injury
• Necrotizing fasciitis of the perineum (Fournier’s gangrene)
• Constipation
• Hypersensitivity reactions including:
  • Rash
  • Hives (urticaria)
  • Swelling beneath the skin and in the mucous tissue (angioedema)

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
• 25 mg

Adult:

Type 2 Diabetes Mellitus

• Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM)
• Also indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease
• 10 mg orally once daily
• May increase to 25 mg/day if needed and tolerated

Heart Failure

• Indicated to reduce risk of cardiovascular death plus hospitalization in adults with heart failure (HF)
• 10 mg orally once daily

Chronic Kidney Disease

• Indicated to reduce risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney (CKD) disease at risk of progression
• 10 mg orally once daily

Dosage Modifications

• Hepatic impairment: No dosage adjustment required

Surgery

• Withhold for at least 3 days, if possible, before major surgery or procedures associated with prolonged fasting
• Resume once patient is clinically stable and has resumed oral intake

Renal Impairment

• Type 2 diabetes mellitus
  • Estimated glomerular filtration rate (eGFR) 30-90 mL/minute/1.73 m2: No dosage adjustment required
  • eGFR below 30 mL/minute/1.73 m2 without cardiovascular (CV) risk factors: Not recommended
  • Glucose lowering benefit of 25 mg/day decreased in patients with worsening renal function
  • Risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function
• T2DM and CV disease, HF, or CKD
  • T2DM with CV disease GFR 30 mL/minute/1.73 m2 or higher: No dosage adjustment required
  • HF or CKD with eGFR 20 mL/minute/1.73 m2 or above: No dosage adjustment required
  • eGFR below 20 mL/minute/1.73 m2 or on dialysis: Not studied

Geriatric:

• No dosage change is recommended based on age; see Adult Dosing
• Risk of volume depletion-related adverse reactions increased in patients who were 75 years or older to 2.1%, 2.3%, and 4.4% for placebo, 10 mg, and 25 mg, respectively
• Risk of urinary tract infections increased in patients who were 75 years or older to 10.5%, 15.7%, and 15.1% for placebo, 10 mg, and 25 mg, respectively

Pediatric:

Type 2 Diabetes Mellitus

• Indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years or older with type 2 diabetes mellitus
• Children below 10 years
  • Safety and efficacy not established
• Children 10 years and above
  • 10 mg orally once every morning
  • May increase to 25 mg/day if needed and tolerated

Dosing Considerations

Limitations of use

• Not indicated for treatment of type 1 diabetes or diabetic ketoacidosis
• Not recommended for use to improve glycemic control in adults and pediatric patients with type 2 diabetes mellitus with an eGFR below 30 mL/minute/1.73 m2

Before initiating therapy

• Assess renal function beforehand and periodically thereafter
• Correct condition in patients with volume depletion

Overdose

There is insufficient information on empagliflozin overdose. Overdose may be treated with symptomatic and supportive care, including gastric lavage to eliminate undigested drug in the gastrointestinal tract. Removal of empagliflozin through hemodialysis has not been studied.

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.

• Empagliflozin has no listed severe or serious interactions with other drugs.
• Empagliflozin has moderate interactions with at least 42 different drugs.
• Mild interactions of empagliflozin include:
  • patiromer

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.

• Limited available data on the use of empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.
• Based on animal studies that show adverse kidney effects from empagliflozin, use of empagliflozin is not recommended during the second and third trimesters of pregnancy.
• 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).
• There is limited information on the presence of empagliflozin in breastmilk, its effects on milk production or the breastfed infant. Empagliflozin is present in animal milk and likely present in human milk as well.
• Human kidney matures in the uterus and in the first 2 years of life and exposure to empagliflozin can adversely affect the developing kidneys. Empagliflozin is not recommended in nursing mothers because of the potential for serious adverse reactions in the breastfed infant, including postnatal kidney development.

• Take empagliflozin exactly as prescribed.
• You will need regular tests while on treatment with empagliflozin. Do not miss your appointments.
• Discontinue empagliflozin and seek medical care immediately, if you experience symptoms of ketoacidosis, a life-threatening condition. Symptoms include nausea, vomiting, abdominal pain, tiredness, and difficulty breathing.
• Report to your physician if you experience any of the following while on treatment with empagliflozin:
• Drink adequate fluids and avoid alcohol while taking empagliflozin. Seek medical care if you feel dehydrated or have symptoms of hypotension such as dizziness or fainting.
• Notify your physician if you experience:
  • Hypersensitivity reactions such as swelling beneath the skin or mucous tissue (angioedema)
  • 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
• Follow proper foot care measures as advised by your physician, to prevent diabetic foot sores and ulcers. Report to your physician immediately if you have new pain or tenderness, ulcers, sores or infection in your leg or foot.
• Store empagliflozin safely out of reach of children.
• In case of overdose, seek medical care or contact Poison Control.