Glyburide / metformin Side Effects

Not all side effects for glyburide / metformin may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to glyburide / metformin: oral tablet

In addition to its needed effects, some unwanted effects may be caused by glyburide / metformin. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking glyburide / metformin:

More common
  • Anxious feeling
  • behavior change similar to being drunk
  • blurred vision
  • cold sweats
  • confusion
  • convulsions (seizures)
  • cool pale skin
  • cough
  • difficulty in concentrating
  • drowsiness
  • excessive hunger
  • fast heartbeat
  • fever
  • headache (continuing)
  • nausea
  • nervousness
  • nightmares
  • restless sleep
  • shakiness
  • slurred speech
  • sneezing
  • sore throat
  • unconsciousness
  • unusual tiredness or weakness
Rare
  • Abdominal or stomach discomfort
  • decreased appetite
  • diarrhea
  • fast shallow breathing
  • general feeling of discomfort
  • muscle pain or cramping
  • unusual sleepiness

Some of the side effects that can occur with glyburide / metformin may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Dizziness
  • headache
  • vomiting

For Healthcare Professionals

Applies to glyburide / metformin: oral tablet

Metabolic

Metabolic side effects of metformin have included lactic acidosis, which is a potentially fatal metabolic complication of biguanide therapy. The incidence of lactic acidosis has been about 0.03 cases per 1,000 patient years with approximately 0.015 fatal cases per 1,000 patient-years. The risk of lactic acidosis is particularly high in patients with underlying renal insufficiency. Cases of lactic acidosis occurring in patients with normal renal function have been rarely reported. Concomitant cardiovascular or liver disease, sepsis, and hypoxia may also increase the risk of lactic acidosis.

Hypoglycemia, an extension of glyburide's pharmacologic effects, has occurred in 1.6% to 3.1% of patients. Hypoglycemia may be severe and protracted. Strenuous exercise, decreased caloric intake, general debilitation, adrenal insufficiency, pituitary insufficiency, and ethanol use may increase the risk of hypoglycemia. Fatalities are reported. In addition, hyponatremia and disulfiram-like reactions are reported.[Ref]

Lactic acidosis is a medical emergency requiring immediate evaluation and treatment. The case fatality rate may be as high as 50%. Patients taking metformin who present with even vague medical illnesses such as myalgia, malaise, somnolence, abdominal discomfort, and so forth, should be evaluated for a metabolic etiology like lactic acidosis.

Signs and symptoms of severe acidosis may include vomiting, abdominal pain, nausea, dyspnea, hypothermia, hypotension, and bradycardia.

Laboratory evaluation of metformin induced lactic acidosis generally includes determination of the following: blood glucose concentration, lactic acid concentration, serum electrolytes, blood pH, metformin concentration, and exclusion of ketoacidosis.

If lactic acidosis is present, immediate institution of general supportive care is indicated. Prompt hemodialysis is also generally recommended in order to correct the acidosis and remove metformin. Hemodialysis often results in rapid improvement. Some investigators have suggested that dialysis with a bicarbonate buffered dialysate may be particularly effective.

Hypoglycemia, an extension of glyburide's pharmacologic effects, may be severe, protracted, refractory to glucose infusion, and, in some cases, may require diazoxide. It most commonly presents as coma or disturbed consciousness. Other signs of hypoglycemia include tachycardia, tremor, chest pain, weakness, and increased sweating. In one review of 57 spontaneously reported cases, the mean dose of glyburide associated with hypoglycemia was 10 mg per day although there were cases with doses as low as 2.5 mg per day. The median age in these cases was 75 years. Ten patients died. In another review of 13 cases, in which renal failure, advanced age, and congestive heart failure were deemed to be predisposing factors, hypoglycemia persisted for more than 60 hours in two patients.

Patients with renal dysfunction, liver disease, adrenal or pituitary insufficiency, or congestive heart failure may be at increased risk for hypoglycemia as are those who are elderly, debilitated, or malnourished. In addition, acute illness, lack of adherence to diet, ethanol ingestion, or strenuous exercise may precipitate hypoglycemia.[Ref]

Gastrointestinal

Gastrointestinal side effects of metformin have included nausea, anorexia, metallic taste, diarrhea, dyspepsia, flatulence, and abdominal pain. One study has reported a 20% incidence of diarrhea.[Ref]

Hematologic

Hematologic side effects of glyburide have included rare reports of leukopenia, thrombocytopenia, eosinophilia, and hemolytic anemia.

Malabsorption of vitamin B12, due to intrinsic factor deficiency and possibly other mechanisms, has been reported in as many as 30% of patients treated with metformin. Megaloblastic anemia has occurred. Discontinuation of metformin or supplementation with vitamin B12 may be necessary.[Ref]

Hepatic

Hepatic side effects of glyburide have included elevations in serum transaminase, alkaline phosphatase, and bilirubin, although jaundice has been only rarely reported. Elevations in liver function tests are usually mild and often return to normal despite continued therapy. Rare cases of acute hepatic hypersensitivity characterized by pruritus, icterus, and cholestatic jaundice have also been reported. In addition, at least two cases of granulomatous hepatitis have been associated with glyburide use.

Postmarketing reports have included rare reports of cholestatic jaundice and hepatitis, some of which have progressed to liver failure. Glyburide-metformin should be discontinued if this occurs.[Ref]

A 52 year old female with a history of type II diabetes mellitus and hypertension developed lethargy, fatigue, and diarrhea after taking metformin for more than 2 weeks. After continuing metformin for a total of four weeks, her sclera became icteric and she was hospitalized. Aside from a soft systolic ejection fracture and a moderate degree of bilateral lower extremity edema, her physical examination was unremarkable. Laboratory data showed grossly elevated total bilirubin, AST, ALT, and alkaline phosphatase. Several days after her initial presentation all of her medications were discontinued. Her signs and symptoms significantly improved over the following several days, and she was discharged within two weeks of her hospitalization. The patient's presentation was considered consistent with drug-induced toxicity attributed to metformin.[Ref]

Other

A single case of leukocytoclastic vasculitis with pneumonitis has been reported in association with metformin therapy.[Ref]

Renal

Renal side effects of glyburide have included include polyuria and nocturia.[Ref]

Dermatologic

Dermatologic side effects have included pruritus, erythema, urticaria, morbilliform and maculopapular eruptions, and vesiculobullous rash in 1.5% of patients who received glyburide occurred in clinical trials In addition, pemphigus vulgaris, porphyria cutanea tarda, Stevens-Johnson syndrome, and photosensitivity have been reported.[Ref]

Hypersensitivity

Hypersensitivity side effects of glyburide have typically included dermatological effects but have also included acute hepatic hypersensitivity, cholestatic jaundice, necrotizing angiitis, hemolytic anemia, angioedema, arthralgia, myalgia, and vasculitis.[Ref]

Ocular

Ocular side effects of glyburide have included changes in accommodation and blurred vision.[Ref]

References

1. Feldman JM "Glyburide: a second-generation sulfonylurea hypoglycemic agent. History, chemistry, metabolism, pharmacokinetics, clinical use and adverse effects." Pharmacotherapy 5 (1985): 43-62

2. 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

3. Wiholm BE, Myrhed M "Metformin-associated lactic acidosis in Sweden 1977-1991." Eur J Clin Pharmacol 44 (1993): 589-91

4. "Glibenclamide: a review." Drugs 1 (1971): 116-40

5. De Fronzo RA, Goodman AM "Efficacy of metformin in non-insulin dependent diabetes mellitus." N Engl J Med 334 (1996): 269-70

6. Stang M, Wysowski DK, ButlerJones D "Incidence of lactic acidosis in metformin users." Diabetes Care 22 (1999): 925-7

7. Biron P "Metformin monitoring." Can Med Assoc J 123 (1980): 11-2

8. Lustik SJ, Vogt A, Chhibber AK "Postoperative lactic acidosis in patients receiving metformin." Anesthesiology 89 (1998): 266-7

9. 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

10. Sonnenblick M, Shilo S "Glibenclamide induced prolonged hypoglycaemia." Age Ageing 15 (1986): 185-9

11. Nightingale SL "Metformin approved for non-insulin-dependent diabetes." JAMA 273 (1995): 613

12. Prendergast BD "Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents." Clin Pharm 3 (1984): 473-85

13. 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

14. 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

15. Klonoff DC, Barrett BJ, Nolte MS, Cohen RM, Wyderski R "Hypoglycemia following inadvertent and factitious sulfonylurea overdosages." Diabetes Care 18 (1995): 563-7

16. 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

17. 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

18. 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

19. Luft D, Schmulling RM, Eggstein M "Lactic acidosis in biguanide-treated diabetics: a review of 330 cases." Diabetologia 14 (1978): 75-87

20. Lalau JD, Mourlhon C, Bergeret A, Lacroix C "Consequences of metformin intoxication." Diabetes Care 21 (1998): 2036-7

21. Asplund K, Wiholm BE, Lithner F "Glibenclamide-associated hypoglycaemia: a report on 57 cases." Diabetologia 24 (1983): 412-7

22. "Product Information. Micronase (glyburide)." Pharmacia and Upjohn, Kalamazoo, MI.

23. Deutsch JC, Santhoshkumar CR, Kolhouse JF "Efficacy of metformin in non-insulin-dependent diabetes mellitus." N Engl J Med 334 (1996): 269

24. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.

25. Kolterman OG "Glyburide in non-insulin-dependent diabetes: an update." Clin Ther 14 (1992): 196-213

26. 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

27. Pearlman BL, Fenves AZ, Emmett M "Metformin-associated lactic acidosis." Am J Med 101 (1996): 109-10

28. Tanja JJ, Langlass TM "Metformin: a biguanide." Diabetes Educ 21 (1995): 509

29. "Product Information. Glucovance (glyburide-metformin)" Bristol-Myers Squibb, Princeton, NJ.

30. "Metformin for non-insulin-dependent diabetes mellitus." Med Lett Drugs Ther 37 (1995): 41-4

31. Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS "Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy." Diabetologia 24 (1983): 16-8

32. Scarpello JHB, Hodgson E, Howlett HCS "Effect of metformin on bile salt circulation and intestinal motility in Type 2 diabetes mellitus." Diabetic Med 15 (1998): 651-6

33. Menzies DG, Campbell IW, McBain A, Brown IR "Metformin efficacy and tolerance in obese non-insulin dependent diabetics: a comparison of two dosage schedules." Curr Med Res Opin 11 (1989): 273-8

34. Dandona P, Fonseca V, Mier A, Beckett AG "Diarrhea and metformin in a diabetic clinic." Diabetes Care 6 (1983): 472-4

35. Tomkin GH "Metformin and B 12 malabsorption." Ann Intern Med 76 (1972): 668

36. 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

37. Deutsch JC, Santhosh-Kumar CR, Kolhouse JF "Efficacy of metformin in non-insulin-dependent diabetes mellitus." N Engl J Med 334 (1996): 269

38. Nataas OB, Nesthus I "Immune haemolytic anaemia induced by glibenclamide in selective IgA deficiency." Br Med J (Clin Res Ed) 295 (1987): 366-7

39. Israeli A, Matzner Y, Or R, Raz I "Glibenclamide causing thrombocytopenia and bleeding tendency: case reports and a review of the literature." Klin Wochenschr 66 (1988): 223-4

40. Stowers JM, Smith OA "Vitamin B 12 and metformin." Br Med J 3 (1971): 246-7

41. 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

42. Meadow P, Tullio CJ "Glyburide-induced hepatitis ." Clin Pharm 8 (1989): 470

43. Del-Val A, Garrigues V, Ponce J, Benages R "Glibenclamide-induced cholestasis ." J Hepatol 13 (1991): 375

44. Goodman RC, Dean PJ, Radparvar A, Kitabchi AE "Glyburide-induced hepatitis." Ann Intern Med 106 (1987): 837-9

45. Wongpaitoon V, Mills PR, Russell RI, Patrick RS "Intrahepatic cholestasis and cutaneous bullae associated with glibenclamide therapy." Postgrad Med J 57 (1981): 244-6

46. Saw D, Pitman E, Maung M, Savasatit P, Wasserman D, Yeung CK "Granulomatous hepatitis associated with glyburide." Dig Dis Sci 41 (1996): 322-5

47. Clarke BF, Campbell IW, Ewing DJ, Beveridge GW, MacDonald MK "Generalized hypersensitivity reaction and visceral arteritis with fatal outcome during glibenclamide therapy." Diabetes 23 (1974): 739-42

48. Babich MM, Pike I, Shiffman ML "Metformin-induced acute hepatitis." Am J Med 104 (1998): 490-2

49. Klapholz L, Leitersdorf E, Weinrauch L "Leucocytoclastic vasculitis and pneumonitis induced by metformin." Br Med J (Clin Res Ed) 293 (1986): 483

50. Rado JP, Borbely L "Enchancement of polyuria by glibenclamide in diabetes insipidus." Lancet 2 (1971): 216

51. Shaw KM, Bloom A, Bulpitt CJ "Glibenclamide and nocturia ." Br Med J 1 (1977): 1415

52. Landor M, Rosenstreich DL "Vesiculobullous rash in a patient with systemic lupus erythematosus." Ann Allergy 70 (1993): 196-203

53. Paterson AJ, Lamey PJ, Lewis MA, Nolan A, Rademaker M "Pemphigus vulgaris precipitated by glibenclamide therapy." J Oral Pathol Med 22 (1993): 92-5

54. Teller J, Rasin M, Abraham FA "Accommodation insufficiency induced by glybenclamide." Ann Ophthalmol 21 (1989): 275-6

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.

Hide
(web2)