Empagliflozin-Metformin

Empagliflozin-Metformin is a prescription medication indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes mellitus (T2DM) when treatment with both empagliflozin and metformin is appropriate. 

• Empagliflozin, when used as a component of empagliflozin/metformin, is also indicated in T2DM to reduce the risk of
• Cardiovascular death in adults with established cardiovascular disease
• Cardiovascular death and hospitalization for heart failure in adults with heart failure
• 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

Empagliflozin-Metformin is available under the following different brand names: Synjardy, Synjardy XR

Adult dosage

Tablet, Immediate-Release

• 5mg/500mg
• 5mg/1000mg
• 12.5mg/500mg
• 12.5mg/1000mg

Tablet, Extended-Release

• 5mg/1000mg
• 10mg/1000mg
• 12.5mg/1000mg
• 25mg/1000mg

Type 2 Diabetes Mellitus

Adult dosage

• Not to exceed 25 mg/2000 mg per day

• Immediate-release tablet
  • Take twice daily with meals, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • Empagliflozin total daily dose: 10 mg
  • For additional glycemic control, empagliflozin may be increased to a maximum total daily dose of 25 mg in patients tolerating 10 mg/day, and metformin may be increased to a maximum total daily dose of 2,000 mg/day, with gradual escalation to reduce gastrointestinal adverse reactions with metformin
  • Switching to Synjardy
  • Patients on metformin: Switch to a tablet containing empagliflozin 5 mg with a similar total daily dose (three times daily) of metformin
  • Patients on empagliflozin: Switch to a tablet containing metformin 500 mg with a similar three times daily regimen to empagliflozin
  • Patients already treated with empagliflozin and metformin: Switch to a tablet containing the same total daily doses of each component
• Extended-release tablet
  • Recommended empagliflozin dose: 10 mg oral once daily
  • For additional glycemic control, empagliflozin may be increased to a maximum of 25 mg once daily in patients tolerating 10 mg once daily
  • Metformin may be increased to a maximum once 2,000 mg once daily, with gradual escalation to reduce gastrointestinal adverse reactions
  • Switching to Synjardy XR
  • Patients on metformin: Switch to XR tablet containing a similar three times daily of metformin and a total daily dose of empagliflozin 10 mg
  • Patients on empagliflozin: Switch to XR tablet containing the same three times daily of empagliflozin and three times daily of metformin extended-release 1000 mg
  • Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same three times daily of empagliflozin and a similar three times daily of metformin

Pediatric dosage

• Children younger than 10 years of age: Safety and efficacy not established
• Children aged 10 years and older: 
  • Individualize the starting dose based on the patient’s current drug regimen
  • Take orally twice daily with meals (ie, divide total daily dose into 2 doses/day); gradually escalate the dose to reduce gastrointestinal adverse effects associated with metformin
  • Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin 2,000 mg

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Empagliflozin-Metformin include:

• low blood sugar (hypoglycemia)
• urinary tract infection
• increased urination
• genital yeast infections
• headache
• diarrhea
• nausea
• vomiting
• runny nose
• sore throat
• gas
• abdominal discomfort
• indigestion
• weakness or lack of energy
• high cholesterol
• joint pain

Serious side effects of the Empagliflozin-Metformin include:

• hives
• difficulty breathing
• swelling of the face, lips, tongue, or throat
• burning or painful urination
• frequent or urgent urination
• pink or bloody urine
• little or no urination
• unusual vaginal discharge, burning, itching, or odor
• redness, itching, swelling of the penis
• unusual discharge from the penis
• pain, redness, or swelling in or around the genital or anal area
• fever
• feeling unwell
• sudden sweating
• shaking
• fast heartbeat
• hunger
• blurred vision
• dizziness
• tingling hands or feet
• thirst
• increased urination
• confusion
• drowsiness
• flushing
• rapid breathing
• fruity breath odor
• vomiting
• diarrhea
• extreme sweating
• dry mouth
• thirst
• light-headedness
• fainting

Rare side effects of the Empagliflozin-Metformin include:

• None 

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

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Empagliflozin-Metformin has severe interactions with no other drugs.
• Empagliflozin-Metformin has serious interactions with the following drugs:
  • contrast media (iodinated)
  • ethanol
  • ioversol
  • methylene blue
  • pacritinib
  • ranolazine
  • risdiplam
  • selegiline
  • selegiline transdermal
  • tafenoquine
  • tedizolid
  • tranylcypromine
  • trilaciclib
• Empagliflozin-Metformin has moderate interactions with at least 202 other drugs.
• Empagliflozin-Metformin has minor interactions with at least 63 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Severe renal disease (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease, or dialysis
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis (treat ketoacidosis with insulin)
• History of serious hypersensitivity reaction to empagliflozin or metformin

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Empagliflozin-Metformin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Empagliflozin-Metformin?”

Cautions

Metformin-associated lactic acidosis

• Lactic acidosis reported during postmarketing surveillance
• If lactic acidosis is suspected, immediately discontinue the metformin product and institute general supportive measures promptly in a hospital setting
• Prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions)
• Hemodialysis has often resulted in the reversal of symptoms and recovery
• Risk factors for metformin-associated lactic acidosis include
• Renal impairment: Before initiating, obtain eGFR; do not initiate if eGFR is less than 45 mL/min/1.73 m2; contraindicated with eGFR less than 30 mL/min/1.73 m2
• Drug interactions: Review coadministered drugs to avoid increased risk of lactic acidosis (e.g., alcohol, OCT2/MATE inhibitors, carbonic anhydrase inhibitors)
• Aged 65 years and older: Owing to increased likelihood of hepatic, renal, or cardiac impairment
• Radiologic studies with contrast: Re-evaluate eGFR 48 hr after procedure
• Surgery/procedures: Restricted food and fluid intake may increase the risk of volume depletion, hypotension, and renal impairment
• Hypoxic states: Acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia) may increase risk; shock, acute MI, and sepsis may cause prerenal azotemia
• Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism
• Hepatic impairment: May impair lactate clearance and result in higher lactate blood levels

Ketoacidosis

• Empagliflozin significantly increases the risk of diabetic ketoacidosis in patients with type 1 diabetes mellitus (T1DM)
• In placebo-controlled trials of patients with T1DM, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo, and fatal ketoacidosis has occurred with empagliflozin
• SGLT2 inhibitors are not indicated for glycemic control in patients with T1DM
• Type 2 diabetes mellitus and pancreatic disorders (eg, history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis
• There have been postmarketing reports of fatal events of ketoacidosis in patients with T2DM using SGLT2 inhibitors
• Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse
• Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath
• Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL)
• Ketoacidosis and glucosuria may persist longer than typically expected
• Urinary glucose excretion persists for 3 days after discontinuing SGLT2 inhibitors; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting >6 days and some up to 2 weeks after discontinuation
• Consider ketone monitoring in patients at risk for ketoacidosis if indicated
• Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis
• Discontinue the drug if ketoacidosis is suspected and promptly evaluate and treat ketoacidosis, if confirmed
• Monitor patients for resolution of ketoacidosis before restarting
• Withhold, if possible, in temporary clinical situations that may predispose patients to ketoacidosis
• Resume when the patient is clinically stable and has resumed oral intake
• Inform patients of the signs and symptoms of ketoacidosis and instruct them to discontinue the drug and seek medical attention immediately if signs and symptoms occur

Volume depletion

• Empagliflozin can cause intravascular volume depletion, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine
• There are reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with T2DM receiving SGLT2 inhibitors
• Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension
• Before initiating treatment in patients with any of the above characteristics, assess volume status and renal function
• Correct volume depletion before initiating
• Monitor for signs and symptoms of volume depletion and renal function after initiating
• Urosepsis and pyelonephritis
• Serious urinary tract infections (UTI), including urosepsis and pyelonephritis requiring hospitalization, were reported in patients receiving empagliflozin
• Treatment with empagliflozin increases the risk of UTI
• Evaluate for signs and symptoms of UTI and treat promptly

Hypoglycemia

• Insulin and insulin secretagogues are known to cause hypoglycemia. In adults, the risk of hypoglycemia may be increased if empagliflozin/metformin is coadministered with insulin secretagogues (eg, sulfonylurea) or insulin
• In pediatric patients, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use
• Risk of hypoglycemia may be lowered by reducing the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin
• Inform patients of hypoglycemic risk and educate them regarding the signs and symptoms of hypoglycemia

Necrotizing fasciitis (Fournier gangrene)

• Reports of necrotizing fasciitis of the perineum (Fournier gangrene) reported in patients with diabetes mellitus receiving SGLT2 inhibitors
• Necrotizing fasciitis is a rare, but serious and life-threatening infection requiring urgent surgical intervention
• Cases have been reported in both females and males
• Serious outcomes include hospitalization, multiple surgeries, and death
• Assess patients who present with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise
• If suspected, immediately treat with broad-spectrum antibiotics and, if necessary, surgical debridement
• Discontinue the drug and closely monitor blood glucose levels; provide appropriate alternate therapy for glycemic control

Genital mycotic infections

• SGLT2 inhibitors increase the risk of genital mycotic infections
• Patients with a history of chronic or recurrent genital mycotic infections are more likely to develop genital mycotic infections
• Monitor and treat as appropriate

Lower limb amputation

• In some clinical studies with SGLT2 inhibitors, an imbalance in the incidence of lower limb amputation has been observed
• Across 4 empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5 events per 1,000 patient-years in the placebo group and empagliflozin group, respectively
• In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was 2.9 and 4.3 events per 1,000 patient-years in the placebo and empagliflozin groups, respectively
• Toe and mid-foot amputation were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involved amputations above and below the knee
• Some patients had multiple amputations
• Peripheral artery disease and diabetic foot infection (including osteomyelitis), most often were precipitating medical events leading to amputation
• Risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation), or diabetes
• Counsel patients regarding the importance of routine preventative foot care
• Monitor patients for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving lower limbs, and institute appropriate treatment

Hypersensitivity reactions

• Serious hypersensitivity reactions (eg, angioedema) reported
• If a hypersensitivity reaction occurs, discontinue the drug
• Treat promptly per standard of care, and monitor until signs and symptoms resolve
• Contraindicated in patients with hypersensitivity to empagliflozin, metformin, or any excipients

Vitamin B12 deficiency

• In metformin clinical trials, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in ~7% of metformin-treated patients
• Such a decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia, but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation
• Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels
• Measure hematologic parameters on an annual basis and vitamin B12 at 2-3 year intervals, and manage any abnormalities

Drug interaction overview

• Empagliflozin
  • A serious life-threatening condition requiring urgent hospitalization was identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors
  • Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required
  • Urine glucose tests are not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors, increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
  • The 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
• Metformin
• Alcohol is known to potentiate metformin’s effect on lactate metabolism; warn patients against excessive alcohol intake while in therapy
• Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
• Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, dichlorphenamide) frequently causes a decrease in serum bicarbonate and induces non-anion gap, hyperchloremic metabolic acidosis; coadministration with carbonic anhydrase inhibitors may increase the risk of lactic acidosis
• Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control; these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid

Pregnancy and Lactation

• Not recommended during the second and third trimesters of pregnancy based on animal data
• Limited available data on use in pregnant women is not sufficient to determine a drug-associated risk for major birth defects and miscarriages
• Metformin may result in ovulation in some anovulatory women; discuss the potential for unintended pregnancy with premenopausal women
• Clinical considerations
  • Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications; poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity
• Lactation
  • There is no information regarding the presence of human milk, the effects on the breastfed infant, or milk production
  • Empagliflozin is 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 a risk of developing human kidney
  • Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that the use of drug combination is not recommended while breastfeeding