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Drug Interactions between levofloxacin and lixisenatide

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

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Moderate

levoFLOXacin lixisenatide

Applies to: levofloxacin and lixisenatide

MONITOR: Quinolone antibiotics may interfere with the therapeutic effects of insulin and other antidiabetic agents. The use of quinolones has been associated with disturbances in blood glucose homeostasis possibly stemming from effects on pancreatic beta cell ATP-sensitive potassium channels that regulate insulin secretion. Both hyperglycemia and hypoglycemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., sulfonylurea) or insulin. Although hyperglycemia is significantly more common and infection itself may be an underlying risk factor, hypoglycemia may cause greater morbidity and mortality. An internal safety review conducted by the U.S. Food and Drug Administration (FDA) identified at least 67 reports of severe hypoglycemia associated with quinolone use resulting in coma, death, or permanent and disabling injuries, primarily in elderly and diabetic patients with renal impairment and/or complicated infections. This is in addition to the numerous cases that have been reported for gatifloxacin, which led to its withdrawal from the U.S. market in 2008. Of the five quinolones that the FDA reviewed, levofloxacin had the most cases (44), followed by ciprofloxacin (12), moxifloxacin (9), ofloxacin (2), and gemifloxacin (0). Other quinolones such as nalidixic acid and norfloxacin, as well as some others that have never been marketed or are no longer marketed such as clinafloxacin and temafloxacin, have also been associated with dysglycemia, thus it is generally believed to be a class effect, albeit with varying risks amongst the individual agents. Available data also seem to indicate different time frames for the development of hypo- and hyperglycemia, with the former generally occurring within 1 to 3 days following quinolone initiation and the latter within 4 to 10 days later.

MANAGEMENT: Blood glucose should be closely monitored whenever quinolones are prescribed to diabetic patients, especially if they are elderly, have renal impairment, or are severely ill. Patients should be apprised of the increased risk of dysglycemia and be particularly alert to potential signs and symptoms of hypoglycemia 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 quinolone, and contact their physician. Alternative antibiotics may need to be considered.

References

  1. (2002) "Product Information. Cipro (ciprofloxacin)." Bayer
  2. (2001) "Product Information. Noroxin (norfloxacin)." Merck & Co., Inc
  3. (2001) "Product Information. Floxin (ofloxacin)." Ortho McNeil Pharmaceutical
  4. (2001) "Product Information. Levaquin (levofloxacin)." Ortho McNeil Pharmaceutical
  5. (2001) "Product Information. Raxar (grepafloxacin)." Glaxo Wellcome
  6. (2001) "Product Information. Trovan (trovafloxacin)." Pfizer U.S. Pharmaceuticals
  7. Edwards DJ, Bowles SK, Svensson CK, Rybak MJ (1988) "Inhibition of drug metabolism by quinolone antibiotics." Clin Pharmacokinet, 15, p. 194-204
  8. (2001) "Product Information. Tequin (gatifloxacin)." Bristol-Myers Squibb
  9. Gajjar DA, LaCreta FP, Kollia GD, et al. (2000) "Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise." Pharmacotherapy, 20 (6 Pt 2), s76-86
  10. Roberge RJ, Kaplan R, Frank R, Fore C (2000) "Glyburide-ciprofloxacin interaction with resistant hypoglycemia." Ann Emerg Med, 36, p. 160-3
  11. Rubinstein E (2001) "History of quinolones and their side effects." Chemotherapy, 47 Suppl 3, p. 3-8
  12. Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH (2002) "Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents." Am J Med, 113, p. 232-4
  13. Baker SE, Hangii MC (2002) "Possible gatifloxacin-induced hypoglycemia." Ann Pharmacother, 36, p. 1722-6
  14. (2003) "Product Information. Factive (gemifloxacin)." *GeneSoft Inc
  15. (2003) "Hypoglycemia and hyperglycemia with fluoroquinolones." Med Lett Drugs Ther, 45, p. 64
  16. Donaldson AR, Vandiver JR, Finch CK (2004) "Possible gatifloxacin-induced hyperglycemia." Ann Pharmacother, 38, p. 602-5
  17. LeBlanc M, Belanger C, Cossette P (2004) "Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy." Pharmacotherapy, 24, p. 926-31
  18. Biggs WS (2004) "Hypoglycemia and hyperglycemia associated with gatifloxacin use in elderly patients." J Am Board Fam Pract, 16, p. 455-7
  19. Gavin JR 3rd, Kubin R, Choudhri S, et al. (2004) "Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing studies." Drug Saf, 27, p. 671-86
  20. Saraya A, Yokokura M, Gonoi T, Seino S (2004) "Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K(+) channels." Eur J Pharmacol, 497, p. 111-7
  21. Lin G, Hays DP, Spillane L (2004) "Refractory hypoglycemia from ciprofloxacin and glyburide interaction." J Toxicol Clin Toxicol, 42, p. 295-7
  22. Friedrich LV, Dougherty R (2004) "Fatal hypoglycemia associated with levofloxacin." Pharmacotherapy, 24, p. 1807-12
  23. Khovidhunkit W, Sunthornyothin S (2004) "Hypoglycemia, hyperglycemia, and gatifloxacin." Ann Intern Med, 141, p. 969
  24. Happe MR, Mulhall BP, Maydonovitch CL, Holtzmuller KC (2004) "Gatifloxacin-induced hyperglycemia." Ann Intern Med, 141, p. 968-9
  25. Greenberg AL, Decerbo M, Fan J (2005) "Gatifloxacin therapy associated with hypoglycemia." Clin Infect Dis, 40, p. 1210-1
  26. Blommel AL, Lutes RA (2005) "Severe hyperglycemia during renally adjusted gatifloxacin therapy." Ann Pharmacother, 39, p. 1349-52
  27. Brogan SE, Cahalan MK (2005) "Gatifloxacin as a possible cause of serious postoperative hypoglycemia." Anesth Analg, 101, p. 635-6
  28. Graumlich JF, Habis S, Avelino RR, et al. (2005) "Hypoglycemia in inpatients after gatifloxacin or levofloxacin therapy: nested case-control study." Pharmacotherapy, 25, p. 1296-302
  29. Frothingham R (2005) "Glucose homeostasis abnormalities associated with use of gatifloxacin." Clin Infect Dis, 41, p. 1269-76
  30. Bhasin R, Arce FC, Pasmantier R (2005) "Hypoglycemia associated with the use of gatifloxacin." Am J Med Sci, 330, p. 250-3
  31. McMorran M, Morrison H, Letourneau G (2006) Gatifloxacin (Tequin): hypoglycemia and hyperglycemia. http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v13n3_e.html#1
  32. Park-Wyllie LY, Juurlink DN, Kopp A, et al. (2006) "Outpatient gatifloxacin therapy and dysglycemia in older adults." N Engl J Med, 354, p. 1352-61
  33. Wang S, Rizvi AA (2006) "Levofloxacin-induced hypoglycemia in a nondiabetic patient." Am J Med Sci, 331, p. 334-5
  34. Kanbay M, Aydogan T, Bozalan R, et al. (2006) "A rare but serious side effect of levofloxacin: hypoglycemia in a geriatric patient." Diabetes Care, 29, p. 1716-7
  35. Zvonar R (2006) "Gatifloxacin-induced dysglycemia." Am J Health Syst Pharm, 63, p. 2087-2092
  36. Zhanel GG, Fontaine S, Adam H, et al. (2006) "A Review of New Fluoroquinolones : Focus on their Use in Respiratory Tract Infections." Treat Respir Med, 5, p. 437-465
  37. Yip C, Lee AJ (2006) "Gatifloxacin-induced hyperglycemia: a case report and summary of the current literature." Clin Ther, 28, p. 1857-66
  38. Tomita T, Onishi M, Sato E, Kimura Y, Kihira K (2007) "Gatifloxacin induces augmented insulin release and intracellular insulin." Biol Pharm Bull, 30, p. 644-7
  39. Kelesidis T, Canseco E (2010) "Quinolone-induced hypoglycemia: a life-threatening but potentially reversible side effect." Am J Med, 123, e5-6
  40. (2017) "Product Information. Baxdela (delafloxacin)." Melinta Therapeutics, Inc.
  41. (2021) "Product Information. Ciprofloxacin Hydrochloride (ciprofloxacin)." Aurobindo Pharma USA Inc
  42. FDA. Food and Drug Admnistration (2023) FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-reinforces-safety-information-about
View all 42 references

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Drug and food interactions

Moderate

levoFLOXacin food

Applies to: levofloxacin

ADJUST DOSING INTERVAL: Food may reduce the oral absorption and bioavailability of levofloxacin. According to the drug product labeling, administration of levofloxacin 500 mg with food prolonged the time to peak concentration by 1 hour and decreased the Cmax decreased by 25% following administration of the oral solution and by 14% following administration of the oral tablet.

MANAGEMENT: To ensure maximal and consistent oral absorption, levofloxacin oral solution should be taken at least one hour before or two hours after meals. For administration of the oral solution with continuous enteral nutrition, some experts recommend that the tube feeding should be interrupted for one hour before and two hours after the dose of levofloxacin. The oral tablets may be taken without regard to food.

References

  1. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT (2009) "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm, 66, p. 1438-67

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Moderate

lixisenatide food

Applies to: lixisenatide

ADJUST DOSING INTERVAL: Lixisenatide slows gastric emptying, which may impact the absorption of concomitantly administered oral medications. The interaction has been studied with various medications, which demonstrated primarily an effect on the rate rather than the overall extent of absorption.

Acetaminophen: When acetaminophen 1000 mg was administered 1 hour and 4 hours after lixisenatide 10 mcg injection, acetaminophen peak plasma concentration (Cmax) was decreased by 29% and 31%, respectively; and median time to peak plasma concentration (Tmax) was delayed by 2 hours and 1.75 hours, respectively. The Cmax and Tmax of acetaminophen were not significantly altered when acetaminophen was given one hour before lixisenatide injection, and systemic exposure (AUC) was not affected whether administered before or after lixisenatide administration. Based on these results, no dose adjustment for acetaminophen is required; however, it may be advisable to take acetaminophen at least one hour before lixisenatide if a rapid onset of action is required.

Oral Contraceptives: When an oral contraceptive containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg was administered 1 hour and 4 hours after lixisenatide 10 mcg injection, ethinyl estradiol Cmax was decreased by 52% and 39%, respectively, while levonorgestrel Cmax was decreased by 46% and 20%, respectively. Median Tmax values were delayed by 1 to 3 hours, but overall exposure (AUC) and mean terminal half-life (T1/2) of ethinyl estradiol and levonorgestrel were not significantly altered. Administration of the oral contraceptive 1 hour before or 11 hours after lixisenatide had no effect on any of the measured pharmacokinetic parameters of either ethinyl estradiol or levonorgestrel. Based on these results, no dose adjustment for oral contraceptives is required; however, some authorities recommend that oral contraceptives be administered at least 1 hour before or 11 hours after lixisenatide.

Atorvastatin: When atorvastatin 40 mg and lixisenatide 20 mcg were coadministered in the morning for 6 days, atorvastatin Cmax was decreased by 31% and Tmax was delayed by 3.25 hours, but AUC was not affected. When atorvastatin was administered in the evening and lixisenatide in the morning, the AUC and Cmax of atorvastatin were increased by 27% and 66%, respectively, but there was no change in Tmax. Based on these results, no dose adjustment for atorvastatin is required; however, some authorities recommend that atorvastatin be administered at least 1 hour before lixisenatide.

Warfarin: When warfarin 25 mg was coadministered with repeated dosing of lixisenatide 20 mcg, warfarin Cmax was decreased by 19% and Tmax was delayed by 7 hours, but there were no effects on AUC or International Normalized Ratio (INR). Based on these results, no dose adjustment for warfarin is required; however, closer monitoring of INR may be appropriate following initiation or discontinuation of lixisenatide treatment.

Digoxin: When digoxin 0.25 mg and lixisenatide 20 mcg were coadministered at steady state, digoxin Cmax was decreased by 26% and Tmax was delayed by 1.5 hours, but AUC was not affected. Based on these results, no dose adjustment for digoxin is required.

Ramipril: When ramipril 5 mg and lixisenatide 20 mcg were coadministered for 6 days, ramipril Cmax was decreased by 63% and AUC was increased by 21%, while Cmax and AUC of the active metabolite (ramiprilat) were not affected. The Tmax values of ramipril and ramiprilat were delayed by approximately 2.5 hours. Based on these results, no dose adjustment for ramipril is required.

MANAGEMENT: Caution is advised during concomitant use of lixisenatide with oral medications that have a narrow therapeutic index or that require careful clinical monitoring. These medications should be administered on a consistent schedule relative to lixisenatide, and blood levels and/or pharmacologic effects should be closely monitored. In addition, if they are to be administered with food, patients should be advised to take them with a meal or snack when lixisenatide is not administered. Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before lixisenatide. Gastro-resistant formulations containing substances sensitive to stomach degradation should be administered 1 hour before or 4 hours after lixisenatide. Patients taking oral contraceptives should be advised to take them at least 1 hour before or 11 hours after lixisenatide.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."

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Therapeutic duplication warnings

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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.

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