Empagliflozin + Metformin Hydrochloride interactions

Food & lifestyle

• alcohol

  Major

  Others

  Alcohol can potentiate the effect of metformin on lactate metabolism and increase the risk of lactic acidosis. In addition, alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Although hypoglycemia rarely occurs during treatment with metformin alone, the risk may increase with acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

  What to do: Metformin should be taken with meals, and excessive alcohol intake should be avoided during treatment. Diabetes patients in general should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Alcohol should not be consumed on an empty stomach or following exercise, as it may increase the risk of hypoglycemia. Patients should contact their physician immediately if they experience potential signs and symptoms of lactic acidosis such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific abdominal distress (especially after stabilization of metformin therapy, when gastrointestinal symptoms are uncommon). With more marked acidosis, there may also be associated hypothermia, hypotension, and resistant bradyarrhythmias. Metformin should be withdrawn promptly if lactic acidosis is suspected. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful in establishing a diagnosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

  2 sources

  1. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb (2001):
  2. "Position Statement: evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes related complications. American Diabetes Association." Diabetes Care 25(Suppl 1) (2002): S50-S60

• alcohol

  Moderate

  Others

  Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

  What to do: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

  10 sources

  1. Jerntorp P, Almer LO "Chlorpropamide-alcohol flushing in relation to macroangiopathy and peripheral neuropathy in non-insulin dependent diabetes." Acta Med Scand 656 (1981): 33-6
  2. Jerntorp P, Almer LO, Holin H, et al. "Plasma chlorpropamide: a critical factor in chlorpropamide-alcohol flush." Eur J Clin Pharmacol 24 (1983): 237-42
  3. Barnett AH, Spiliopoulos AJ, Pyke DA, et al. "Metabolic studies in chlorpropamide-alcohol flush positive and negative type 2 (non-insulin dependent) diabetic patients with and without retinopathy." Diabetologia 24 (1983): 213-5
  4. Hartling SG, Faber OK, Wegmann ML, Wahlin-Boll E, Melander A "Interaction of ethanol and glipizide in humans." Diabetes Care 10 (1987): 683-6
  5. "Product Information. Diabinese (chlorpropamide)." Pfizer U.S. Pharmaceuticals (2002):
  6. "Product Information. Glucotrol (glipizide)." Pfizer U.S. Pharmaceuticals (2002):
  7. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.
  8. Skillman TG, Feldman JM "The pharmacology of sulfonylureas." Am J Med 70 (1981): 361-72

  Show all 10 sourcesShow fewer sources

  9. "Position Statement: evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes related complications. American Diabetes Association." Diabetes Care 25(Suppl 1) (2002): S50-S60
  10. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

Conditions

Conditions in which Empagliflozin + Metformin Hydrochloride needs care, as documented in this source.

• Acidosis, Lactic

  Major

  The use of metformin is contraindicated in patients with renal dysfunction (serum creatinine >= 1.5 mg/dL in males and 1.4 mg/dL in females, or above the upper limit of normal for age); congestive heart failure requiring pharmacologic treatment (especially unstable or acute CHF where there is risk of hypoperfusion and hypoxemia); and any condition associated with hypoxemia (e.g., severe anemia, myocardial infarction, asphyxia, shock), dehydration (e.g., severe diarrhea or vomiting), or sepsis. Patients with these conditions may be at increased risk for the development of lactic acidosis, which is a rare but serious metabolic complication associated with metformin accumulation in plasma usually at levels exceeding 5 mcg/mL. Metformin should also not be administered to patients with acute or chronic metabolic acidosis. In addition, metformin should generally be avoided in alcoholics and patients with clinical or laboratory evidence of hepatic disease, since alcohol potentiates the effects of metformin on lactate metabolism and impaired hepatic function may significantly limit the ability to clear lactate. All patients treated with metformin should have renal function monitored regularly (at least annually or more frequently if necessary) and be advised of the significance of nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and gastrointestinal disturbances that arise after stabilization of metformin dosage. More marked acidosis may be associated with hypothermia, hypotension, and resistant bradyarrhythmias. Immediate medical attention is necessary if these symptoms occur, and metformin therapy withheld until the situation can be clarified. If lactic acidosis is diagnosed, prompt supportive measures and hemodialysis are recommended.

  21 sources

  1. Chalopin JM, Tanter Y, Besancenot JF, Cabanne JF, Rifle G "Treatment of metformin-associated lactic acidosis with closed recirculation bicarbonate-buffered hemodialysis." Arch Intern Med 144 (1984): 203-5
  2. Biron P "Metformin monitoring." Can Med Assoc J 123 (1980): 11-2
  3. Ryder RE "Lactic acidotic coma with multiple medication including metformin in a patient with normal renal function." Br J Clin Pract 38 (1984): 229-30,232
  4. Luft D, Schmulling RM, Eggstein M "Lactic acidosis in biguanide-treated diabetics: a review of 330 cases." Diabetologia 14 (1978): 75-87
  5. Assan R, Heuclin C, Ganeval D, Bismuth C, George J, Girard JR "Metformin-induced lactic acidosis in the presence of acute renal failure." Diabetologia 13 (1977): 211-7
  6. Wiholm BE, Myrhed M "Metformin-associated lactic acidosis in Sweden 1977-1991." Eur J Clin Pharmacol 44 (1993): 589-91
  7. Lalau JD, Andrejak M, Moriniere P, Coevoet B, Debussche X, Westeel PF, Fournier A, Quichaud J "Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination." Int J Clin Pharmacol Ther Toxicol 27 (1989): 285-8
  8. Lalau JD, Westeel PF, Debussche X, Dkissi H, Tolani M, Coevoet B, Temperville B, Fournier A, Quichaud J "Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin." Intensive Care Med 13 (1987): 383-7

  Show all 21 sourcesShow fewer sources

  9. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb (2001):
  10. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group "Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus." N Engl J Med 333 (1995): 541-9
  11. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE "Metabolic effects of metformin in non-insulin-dependent diabetes mellitus." N Engl J Med 333 (1995): 550-4
  12. Sambol NC, Chiang J, Lin ET, Goodman AM, Liu CY, Benet LZ, Cogan MG "Kidney function and age are both predictors of pharmacokinetics of metformin." J Clin Pharmacol 35 (1995): 1094-102
  13. Gueriguian J, Green L, Misbin RI, Stadel B, Fleming GA "Efficacy of metformin in non-insulin dependent diabetes mellitus." N Engl J Med 334 (1996): 269
  14. De Fronzo RA, Goodman AM "Efficacy of metformin in non-insulin dependent diabetes mellitus." N Engl J Med 334 (1996): 269-70
  15. Deutsch JC, Santhoshkumar CR, Kolhouse JF "Efficacy of metformin in non-insulin-dependent diabetes mellitus." N Engl J Med 334 (1996): 269
  16. Bailey CJ, Path MR, Turner RC "Metformin." N Engl J Med 334 (1996): 574-9
  17. Pearlman BL, Fenves AZ, Emmett M "Metformin-associated lactic acidosis." Am J Med 101 (1996): 109-10
  18. Lustik SJ, Vogt A, Chhibber AK "Postoperative lactic acidosis in patients receiving metformin." Anesthesiology 89 (1998): 266-7
  19. Lalau JD, Mourlhon C, Bergeret A, Lacroix C "Consequences of metformin intoxication." Diabetes Care 21 (1998): 2036-7
  20. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA "Lactic acidosis in patients with diabetes treated with metformin." N Engl J Med 338 (1998): 265-6
  21. Stang M, Wysowski DK, ButlerJones D "Incidence of lactic acidosis in metformin users." Diabetes Care 22 (1999): 925-7

• Cardiovascular Diseases

  Major

  The use of oral hypoglycemic agents may be associated with an increased risk of cardiovascular mortality compared to treatment with diet alone or diet with insulin. This warning is based on the University Group Diabetes Program (UGDP) study, a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. Patients treated with diet plus a fixed dosage of either tolbutamide (a sulfonylurea) or phenformin (a biguanide) for 5 to 8 years had a cardiovascular mortality rate approximately 2.5 times that of patients treated with diet alone, resulting in discontinuation of both these treatments in the study. Despite controversy regarding interpretation of these results, clinicians and patients should be aware of the potential risk when making treatment decisions for diabetes, particularly in the presence of underlying cardiovascular disease. Data are not available for other sulfonylureas or biguanides, nor for hypoglycemic agents belonging to other classes. However, given the similarities in chemical structure and/or mode of action, the same caution should be applied.

  9 sources

  1. "Product Information. Diabinese (chlorpropamide)." Pfizer U.S. Pharmaceuticals (2002):
  2. "Product Information. Glucotrol (glipizide)." Pfizer U.S. Pharmaceuticals (2002):
  3. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.
  4. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb (2001):
  5. "Product Information. Amaryl (glimepiride)." Hoechst Marion Roussel (2001):
  6. "Product Information. Prandin (repaglinide)." Novo Nordisk Pharmaceuticals Inc (2001):
  7. "Product Information. Tolinase (tolazamide)." Pharmacia and Upjohn (2001):
  8. "Product Information. Orinase (tolbutamide)." Pharmacia and Upjohn (2001):

  Show all 9 sourcesShow fewer sources

  9. "Product Information. Dymelor (acetohexamide)." Lilly, Eli and Company (2001):

• Kidney Diseases

  Major

  The glucose lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors is decreased in patients with worsening renal function. Additionally, patients with renal impairment function (eGFR less than 60 mL/min/1.73 m2) the elderly, and patients on loop diuretics may be more likely to experience adverse reactions related to volume depletion such as hypotension and acute kidney injury during therapy. Renal function should be evaluated prior to treatment initiation and monitored regularly in at-risk patients. Assess volume status and correct volume depletion before initiating therapy. The use of SGLT-2 inhibitors in patients undergoing dialysis is contraindicated. In both patients with and without type 2 diabetes, beneficial effects in chronic kidney disease and heart failure have been observed with SGLT2 inhibitor therapy. The manufacturer's product labeling should be consulted for indication specific renal dosing for SGLT2 inhibitors.

  4 sources

  1. "Product Information. Invokana (canagliflozin)." Janssen Pharmaceuticals (2013):
  2. "Product Information. Farxiga (dapagliflozin)." Bristol-Myers Squibb (2014):
  3. "Product Information. Jardiance (empagliflozin)." Boehringer Ingelheim (2014):
  4. "Product Information. Steglatro (ertugliflozin)." Merck & Co., Inc (2017):

• Hypoglycemia

  Moderate

  Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

  18 sources

  1. "Product Information. Diabinese (chlorpropamide)." Pfizer U.S. Pharmaceuticals (2002):
  2. "Product Information. Glucotrol (glipizide)." Pfizer U.S. Pharmaceuticals (2002):
  3. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.
  4. "Product Information. Micronase (glyburide)." Pharmacia and Upjohn (2002):
  5. "Multum Information Services, Inc. Expert Review Panel"
  6. "Product Information. Humulin BR (insulin)." Lilly, Eli and Company, Indianapolis, IN.
  7. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb (2001):
  8. "Product Information. Amaryl (glimepiride)." Hoechst Marion Roussel (2001):

  Show all 18 sourcesShow fewer sources

  9. "Product Information. Prandin (repaglinide)." Novo Nordisk Pharmaceuticals Inc (2001):
  10. Braunwald E, Hauser SL, Kasper DL, Fauci AS, Isselbacher KJ, Longo DL, Martin JB, eds., Wilson JD "Harrison's Principles of Internal Medicine." New York, NY: McGraw-Hill Health Professionals Division (1998):
  11. "Product Information. Tolinase (tolazamide)." Pharmacia and Upjohn (2001):
  12. "Product Information. Dymelor (acetohexamide)." Lilly, Eli and Company (2001):
  13. "Product Information. Lantus (insulin glargine)." Aventis Pharmaceuticals (2001):
  14. "Product Information. NovoLOG (insulin aspart)." Novo Nordisk Pharmaceuticals Inc (2022):
  15. "Product Information. Starlix (nateglinide)." Novartis Pharmaceuticals (2001):
  16. "Product Information. Apidra (insulin glulisine)." Aventis Pharmaceuticals (2004):
  17. "Product Information. Levemir (insulin detemir)." Novo Nordisk Pharmaceuticals Inc (2005):
  18. "Product Information. Tresiba FlexTouch (insulin degludec)." Novo Nordisk Pharmaceuticals Inc (2015):

• Hypotension

  Moderate

  Sodium-glucose cotransporter 2 (SGLT-2) inhibitors cause intravascular volume contraction which may lead to symptomatic hypotension after treatment initiation especially in the elderly, in patients with impaired renal function, patients with low systolic blood pressure, or those using diuretics . Volume status should be assessed and corrected before starting treatment and patients should be monitored during therapy.

  4 sources

  1. "Product Information. Invokana (canagliflozin)." Janssen Pharmaceuticals (2013):
  2. "Product Information. Farxiga (dapagliflozin)." Bristol-Myers Squibb (2014):
  3. "Product Information. Jardiance (empagliflozin)." Boehringer Ingelheim (2014):
  4. "Product Information. Steglatro (ertugliflozin)." Merck & Co., Inc (2017):

• Infections

  Moderate

  An increase in the risk of genital mycotic infections has been reported with the use of a sodium-glucose cotransporter 2 (SGLT-2) inhibitors. Care should be exercised when using this agent in patients who have a history of genital mycotic infections or who are uncircumcised as these patients are more likely to develop genital mycotic infections. Monitor and treat appropriately.

  1 source

  1. "Product Information. Steglatro (ertugliflozin)." Merck & Co., Inc (2017):

• Vitamin B 12 Deficiency

  Moderate

  Metformin may interfere with vitamin B12 (cyanocobalamin) absorption from the B12-intrinsic factor complex. A decrease to subnormal levels of previously normal serum B12 levels has been reported in approximately 7% of patients treated with metformin during controlled clinical trials. Although the decrease is generally well-tolerated and rarely associated with clinical manifestations such as megaloblastic anemia, caution may be warranted when metformin therapy is administered in patients with preexisting B12 deficiency. Vitamin B12 supplementation as well as annual measurements of hematologic parameters may be appropriate.

  6 sources

  1. Tomkin GH "Metformin and B 12 malabsorption." Ann Intern Med 76 (1972): 668
  2. Callaghan TS, Hadden DR, Tomkin GH "Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment." Br Med J 280 (1980): 1214-5
  3. Stowers JM, Smith OA "Vitamin B 12 and metformin." Br Med J 3 (1971): 246-7
  4. Tomkin GH, Hadden DR, Weaver JA, Montgomery DA "Vitamin-B12 status of patients on long-term metformin therapy." Br Med J 2 (1971): 685-7
  5. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb (2001):
  6. Deutsch JC, Santhosh-Kumar CR, Kolhouse JF "Efficacy of metformin in non-insulin-dependent diabetes mellitus." N Engl J Med 334 (1996): 269