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Drug Interactions between Diabinese and gemfibrozil

This report displays the potential drug interactions for the following 2 drugs:

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Major

chlorproPAMIDE gemfibrozil

Applies to: Diabinese (chlorpropamide) and gemfibrozil

MONITOR CLOSELY: Coadministration with potent or moderate inhibitors of CYP450 2C9 may significantly increase the plasma concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme. Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg), tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination with fluconazole, a moderate CYP450 2C9 inhibitor. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the single-dose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30% (chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose levels were not statistically significant in these studies, although approximately 48% of patients treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0 to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included. Based on available data, fluconazole use does not appear to be associated with a significant risk of severe hypoglycemia at dosages <200 mg/day in sulfonylurea-treated patients. However, higher dosages may cause greater inhibition of sulfonylurea clearance and increased hypoglycemic effects, particularly in the elderly and patients with renal or hepatic impairment. There have been case reports of profound hypoglycemia, including coma and death, during treatment of sulfonylureas with fluconazole, oral miconazole, as well as voriconazole. Concomitant use of sulfonylureas with fluconazole has also been associated with increased risk of serum transaminase elevations.

MANAGEMENT: Caution is advised when sulfonylureas are used concomitantly with potent or moderate CYP450 2C9 inhibitors. Blood glucose should be closely monitored, and the sulfonylurea dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate appropriate remedial therapy immediately, discontinue the CYP450 2C9 inhibitor if possible, and contact their physician.

References

  1. Lazar JD, Wilner KD (1990) "Drug interactions with fluconazole." Rev Infect Dis, 12 Suppl 3, s327-33
  2. Rowe BR, Thorpe J, Barnett A (1992) "Safety of fluconazole in women taking oral hypoglycaemic agents." Lancet, 339, p. 255-6
  3. Pond SM, Birkett DJ, Wade DN (1977) "Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole." Clin Pharmacol Ther, 22, p. 573-9
  4. (2002) "Product Information. Glucotrol (glipizide)." Pfizer U.S. Pharmaceuticals
  5. (2002) "Product Information. Micronase (glyburide)." Pharmacia and Upjohn
  6. "Product Information. Monistat 7 (miconazole topical)." Ortho McNeil Pharmaceutical
  7. (2001) "Product Information. Diflucan (fluconazole)." Roerig Division
  8. (2001) "Product Information. Amaryl (glimepiride)." Hoechst Marion Roussel
  9. Miners JO, Birkett DJ (1998) "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism." Br J Clin Pharmacol, 45, p. 525-38
  10. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) "Effects of the antifungal agents on oxidative drug metabolism: clinical relevance." Clin Pharmacokinet, 38, p. 111-80
  11. Komatsu K, Ito K, Nakajima Y, Kanamitsu S, Imaoka S, Funae Y, Green CE, Tyson CA, Shimada N, Sugiyama Y (2000) "Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments." Drug Metab Disposition, 28, p. 475-81
  12. Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivisto KT (2001) "Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride." Clin Pharmacol Ther, 69, p. 194-200
  13. Abad S, Moachon L, Blanche P, Bavoux F, Sicard D, Salmon-Ceron D (2001) "Possible interaction between glicazide, fluconazole and sulfamethoxazole resulting in severe hypoglycaemia." Br J Clin Pharmacol, 52, p. 456-7
  14. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  15. Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivisto KT (2002) "Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes." Clin Pharmacol Ther, 72, p. 326-32
  16. Shon JH, Yoon YR, Kim MJ, et al. (2005) "Chlorpropamide 2-hydroxylation is catalysed by CYP2C9 and CYP2C19 in vitro: chlorpropamide disposition is influenced by CYP2C9, but not by CYP2C19 genetic polymorphism." Br J Clin Pharmacol, 59, p. 552-63
  17. Holstein A, Plaschke A, Ptak M, et al. (2005) "Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents." Br J Clin Pharmacol, 60, p. 103-6
  18. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  19. Jeong S, Nguyen PD, Desta Z (2009) "Comprehensive in vitro inhibition analysis of eight cytochrome P450 (CYP) enzymes by voriconazole: major effect on CYPs 2B6, 2C9, 2C19 and 3A." Antimicrob Agents Chemother, 53, p. 541-51
  20. Ragia G, Petridis I, Tavridou A, Christakidis D, Manolopoulos VG (2009) "Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas." Pharmacogenomics, 10, p. 1781-7
  21. Shobha JC, Muppidi MR (2010) "Interaction between voriconazole and glimepiride." J Postgrad Med, 56, p. 44-5
  22. Back DJ, Tjia JF, Karbwang J, Colbert J (1988) "In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolones." Br J Clin Pharmacol, 26, p. 23-9
  23. Schelleman H, Bilker WB, Brensinger CM, Wan F, Hennessy S (2010) "Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide." Clin Pharmacol Ther, 88, p. 214-22
  24. Tirkkonen T, Heikkila P, Huupponen R, Laine K (2010) "Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide." J Intern Med, 268, p. 359-66
  25. Niwa T, Shiraga T, Takagi A (2005) "Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, CYP3A4 activities in human liver microsomes." Biol Pharm Bull, 28, p. 1805-8
View all 25 references

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Drug and food interactions

Moderate

chlorproPAMIDE food

Applies to: Diabinese (chlorpropamide)

GENERALLY AVOID: 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. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: 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.

References

  1. Jerntorp P, Almer LO (1981) "Chlorpropamide-alcohol flushing in relation to macroangiopathy and peripheral neuropathy in non-insulin dependent diabetes." Acta Med Scand, 656, p. 33-6
  2. Jerntorp P, Almer LO, Holin H, et al. (1983) "Plasma chlorpropamide: a critical factor in chlorpropamide-alcohol flush." Eur J Clin Pharmacol, 24, p. 237-42
  3. Barnett AH, Spiliopoulos AJ, Pyke DA, et al. (1983) "Metabolic studies in chlorpropamide-alcohol flush positive and negative type 2 (non-insulin dependent) diabetic patients with and without retinopathy." Diabetologia, 24, p. 213-5
  4. Hartling SG, Faber OK, Wegmann ML, Wahlin-Boll E, Melander A (1987) "Interaction of ethanol and glipizide in humans." Diabetes Care, 10, p. 683-6
  5. (2002) "Product Information. Diabinese (chlorpropamide)." Pfizer U.S. Pharmaceuticals
  6. (2002) "Product Information. Glucotrol (glipizide)." Pfizer U.S. Pharmaceuticals
  7. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.
  8. Skillman TG, Feldman JM (1981) "The pharmacology of sulfonylureas." Am J Med, 70, p. 361-72
  9. (2002) "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), S50-S60
  10. Cerner Multum, Inc. "UK Summary of Product Characteristics."
View all 10 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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