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Drug Interactions between Onmel and Wigraine

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

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Interactions between your drugs

Major

itraconazole ergotamine

Applies to: Onmel (itraconazole) and Wigraine (caffeine / ergotamine)

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 including azole antifungal agents may significantly increase the plasma concentrations of ergot derivatives, which are primarily metabolized by the isoenzyme. The interaction has occurred in patients receiving ergotamine or dihydroergotamine with other potent CYP450 3A4 inhibitors such as macrolide antibiotics and protease inhibitors. Clinical ergotism has been reported, which can lead to gangrene and myocardial infarction in severe cases. Even small, single doses of ergotamine have resulted in clinically significant interactions, occasionally resulting in surgical amputation or death. Within the azole class, ketoconazole and itraconazole are considered the most potent inhibitors, while fluconazole is comparatively weak and generally causes clinically significant interactions with CYP450 3A4 substrates only at dosages of 200 mg/day or more.

MANAGEMENT: Given the potential for ergot toxicity characterized by peripheral vasospasm, ischemia, thrombosis, tachycardia and hypertension, concomitant use of ergot derivatives with itraconazole, ketoconazole, posaconazole, or voriconazole is considered contraindicated. Some authorities consider concomitant administration of ergot derivatives and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole. Use with other azole antifungal agents, including fluconazole at high multiple doses, should probably be avoided if possible.

References

  1. Leroy F, Asseman P, Pruvost P, Adnet P, Lacroix D, Thery C "Dihydroergotamine-erythromycin-induced ergotism." Ann Intern Med 109 (1988): 249
  2. Matthews NT, Havill JH "Ergotism with therapeutic doses of ergotamine tartrate." N Z Med J 89 (1979): 476-7
  3. Francis H, Tyndall A, Webb J "Severe vascular spasm due to erythromycin-ergotamine interaction." Clin Rheumatol 3 (1984): 243-6
  4. Hayton AC "Precipitation of acute ergotism by triacetyloleandomycin." N Z Med J 69 (1969): 42
  5. "Product Information. D.H.E. 45 (dihydroergotamine)." Sandoz Pharmaceuticals Corporation PROD (2002):
  6. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  7. Ghali R, De Lean J, Douville Y, Noel HP, Labbe R "Erythromycin-associated ergotamine intoxication: arteriographic and electrophysiologic analysis of a rare cause of severe ischemia of the lower extremities and associated ischemic neuropathy." Ann Vasc Surg 7 (1993): 291-6
  8. Horowitz RS, Dart RC, Gomez HF "Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction." Arch Intern Med 156 (1996): 456-8
  9. "Product Information. Migranal (dihydroergotamine nasal)." Novartis Pharmaceuticals PROD (2001):
  10. Rosenthal E, Sala F, Chichmanian RM, Batt M, Cassuto JP "Ergotism related to concurrent administration of ergotamine tartrate and indinavir." JAMA 281 (1999): 987
  11. Liaudet L, Buclin T, Jaccard C, Eckert P "Severe ergotism associated with interaction between ritonavir and ergotamine." Br Med J 318 (1999): 771
  12. Caballero-Granado FJ, Viciana P, Cordero E, Gomez-Vera MJ, del Nozal M, Lopez-Cortes LF "Ergotism related to concurrent administration of ergotamine tartrate and ritonavir in an AIDS patient." Antimicrob Agents Chemother 41 (1997): 1207
  13. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  14. Bird PA, Sturgess AD "Clinical ergotism with severe bilateral upper limb ischaemia precipitated by an erythromycin - ergotamine drug interaction." Aust N Z J Med 30 (2000): 635-6
  15. Eadie MJ "Clinically significant drug interactions with agents specific for migraine attacks." Cns Drugs 15 (2001): 105-18
  16. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W "Cerebral ergotism under treatment with ergotamine and ritonavir." Neurology 57 (2001): 743-4
  17. Vila A, Mykietiuk A, Bonvehi P, Temporiti E, Uruena A, Herrera F "Clinical ergotism induced by ritonavir." Scand J Infect Dis 33 (2001): 788-9
  18. Montero A, Giovannoni AG, Tvrde PL "Leg ischemia in a patient receiving ritonavir and ergotamine." Ann Intern Med 130 (1999): 329
  19. Liaudet L "Severe ergotism associated with interaction between ritonavir and ergotamine." BMJ 318 (1999): 771
  20. Mortier E, Pouchet J, Vinceneux P, Lalande M "Ergotism related to interaction between nelfinavir and ergotamine." Am J Med 110 (2001): 594
  21. Blanche P, Rigolet A, Gombert B, Ginsburg C, Salmon D, Sicard D "Ergotism related to a single dose of ergotamine tartrate in an AIDS patient treated with ritonavir." Postgrad Med J 75 (1999): 546-7
  22. Ausband SC, Goodman PE "An unusual case of clarithromycin associated ergotism." J Emerg Med 4 (2001): 411-3
  23. Tribble MA, Gregg CR, Margolis DM, Amirkhan R, Smith JW "Fatal ergotism induced by an HIV protease inhibitor." Headache 42 (2002): 694-5
  24. "Product Information. Cafergot (caffeine-ergotamine)." Novartis Pharmaceuticals (2004):
  25. "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation (2006):
  26. Cerner Multum, Inc. "Australian Product Information." O 0
  27. Srisuma S, Lavonas EJ, Wananukul W "Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors." Clin Toxicol (Phila) (2014): 1-4
View all 27 references

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Drug and food interactions

Moderate

itraconazole food

Applies to: Onmel (itraconazole)

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

References

  1. Van Peer A, Woestenborghs R, Heykants J, et al. "The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects." Eur J Clin Pharmacol 36 (1989): 423-6
  2. Wishart JM "The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal infection." J Am Acad Dermatol 17 (1987): 220-3
  3. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  4. Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers." Antimicrob Agents Chemother 37 (1993): 778-84
  5. Zimmermann T, Yeates RA, Albrecht M, Laufen H, Wildfeuer A "Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in japanese subjects." Int J Clin Pharmacol Res 14 (1994): 87-93
  6. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals (2022):
  7. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H "Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects." Int J Clin Pharmacol Ther 36 (1998): 306-8
  8. Barone JA, Moskotitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L "Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers." Pharmacotherapy 18 (1998): 295-301
  9. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M "Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers." Ther Drug Monit 21 (1999): 304-9
  10. Katz HI "Drug interactions of the newer oral antifungal agents." Br J Dermatol 141 (1999): 26-32
View all 10 references

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Moderate

ergotamine food

Applies to: Wigraine (caffeine / ergotamine)

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

References

  1. Edgar B, Bailey D, Bergstrand R, et al. "Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics on felodipine and its potential clinical relevance." Eur J Clin Pharmacol 42 (1992): 313-7
  2. Jonkman JH, Sollie FA, Sauter R, Steinijans VW "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther 49 (1991): 248-55
  3. Bailey DG, Arnold JM, Munoz C, Spence JD "Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin." Clin Pharmacol Ther 53 (1993): 637-42
  4. Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
  5. Sigusch H, Hippius M, Henschel L, Kaufmann K, Hoffmann A "Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation." Pharmazie 49 (1994): 522-4
  6. Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD "Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics." Clin Pharmacol Ther 54 (1993): 589-94
  7. Yamreudeewong W, Henann NE, Fazio A, Lower DL, Cassidy TG "Drug-food interactions in clinical practice." J Fam Pract 40 (1995): 376-84
  8. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
  9. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther 58 (1995): 127-31
  10. Min DI, Ku YM, Geraets DR, Lee HC "Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers." J Clin Pharmacol 36 (1996): 469-76
  11. Majeed A, Kareem A "Effect of grapefruit juice on cyclosporine pharmacokinetics." Pediatr Nephrol 10 (1996): 395
  12. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DS "Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice." Br J Clin Pharmacol 42 (1996): p662
  13. Josefsson M, Zackrisson AL, Ahlner J "Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers." Eur J Clin Pharmacol 51 (1996): 189-93
  14. Kantola T, Kivisto KT, Neuvonen PJ "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 63 (1998): 397-402
  15. Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A "Interaction between grapefruit juice and diazepam in humans." Eur J Drug Metab Pharmacokinet 23 (1998): 55-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  17. Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in humans." Clin Pharmacol Ther 64 (1998): 248-56
  18. Garg SK, Kumar N, Bhargava VK, Prabhakar SK "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy." Clin Pharmacol Ther 64 (1998): 286-8
  19. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther 64 (1998): 477-83
  20. Fuhr U, Maier-Bruggemann A, Blume H, et al. "Grapefruit juice increases oral nimodipine bioavailability." Int J Clin Pharmacol Ther 36 (1998): 126-32
  21. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther 66 (1999): 118-27
  22. Eagling VA, Profit L, Back DJ "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol 48 (1999): 543-52
  23. Damkier P, Hansen LL, Brosen K "Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine." Br J Clin Pharmacol 48 (1999): 829-38
  24. Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BCC "The effects of grapefruit juice on sertraline metabolism: An in vitro and in vivo study." Clin Ther 21 (1999): 1890-9
  25. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  26. Gunston GD, Mehta U "Potentially serious drug interactions with grapefruit juice." S Afr Med J 90 (2000): 41
  27. Takanaga H, Ohnishi A, Maatsuo H, et al. "Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model." Br J Clin Pharmacol 49 (2000): 49-58
  28. Libersa CC, Brique SA, Motte KB, et al. "Dramatic inhibition of amiodarone metabolism induced by grapefruit juice." Br J Clin Pharmacol 49 (2000): 373-8
  29. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77
  30. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, Golik A, Scapa E "Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers." Ther Drug Monit 23 (2001): 369-73
  31. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol 44 (1993): 295-8
  32. Flanagan D "Understanding the grapefruit-drug interaction." Gen Dent 53 (2005): 282-5; quiz 286
View all 32 references

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Moderate

ergotamine food

Applies to: Wigraine (caffeine / ergotamine)

MONITOR: Nicotine may cause vasoconstriction in some patients and potentiate the ischemic response to ergot alkaloids.

MANAGEMENT: Caution may be advisable when ergot alkaloids are used in combination with nicotine products. Patients should be advised to seek immediate medical attention if they experience potential symptoms of ischemia such as coldness, pallor, cyanosis, numbness, tingling, or pain in the extremities; muscle weakness; severe or worsening headache; visual disturbances; severe abdominal pain; chest pain; and shortness of breath.

References

  1. "Product Information. Migranal (dihydroergotamine nasal)." Novartis Pharmaceuticals PROD (2001):
  2. "Product Information. Cafergot (caffeine-ergotamine)." Novartis Pharmaceuticals (2004):
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  4. Cerner Multum, Inc. "Australian Product Information." O 0
View all 4 references

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Minor

caffeine food

Applies to: Wigraine (caffeine / ergotamine)

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.

References

  1. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
  2. Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WR "Influence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamics." Pharmacotherapy 16 (1996): 1046-52

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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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