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Drug Interactions between Caduet and Ergocomp-PB

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

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Moderate

ergotamine PENTobarbital

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital) and Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ergot alkaloids, which are substrates of the isoenzyme.

MANAGEMENT: The potential for diminished pharmacologic effects of ergot alkaloids should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. Cerner Multum, Inc. "Australian Product Information." O 0
  3. "Product Information. Methergine (methylergonovine)." Novartis Pharmaceuticals (2010):

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Moderate

ergotamine amLODIPine

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital) and Caduet (amlodipine / atorvastatin)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may 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 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. No data are available for other, less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised during concomitant use of ergot derivatives with mild or moderate CYP450 3A4 inhibitors. Patients should be monitored for potential ergot toxicity including peripheral vasospasm, ischemia, thrombosis, tachycardia, and hypertension.

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. 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
  7. Horowitz RS, Dart RC, Gomez HF "Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction." Arch Intern Med 156 (1996): 456-8
  8. "Product Information. Migranal (dihydroergotamine nasal)." Novartis Pharmaceuticals PROD (2001):
  9. Rosenthal E, Sala F, Chichmanian RM, Batt M, Cassuto JP "Ergotism related to concurrent administration of ergotamine tartrate and indinavir." JAMA 281 (1999): 987
  10. Liaudet L, Buclin T, Jaccard C, Eckert P "Severe ergotism associated with interaction between ritonavir and ergotamine." Br Med J 318 (1999): 771
  11. 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
  12. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  13. 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
  14. Eadie MJ "Clinically significant drug interactions with agents specific for migraine attacks." Cns Drugs 15 (2001): 105-18
  15. Spiegel M, Schmidauer C, Kampfl A, Sarcletti M, Poewe W "Cerebral ergotism under treatment with ergotamine and ritonavir." Neurology 57 (2001): 743-4
  16. 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
  17. Montero A, Giovannoni AG, Tvrde PL "Leg ischemia in a patient receiving ritonavir and ergotamine." Ann Intern Med 130 (1999): 329
  18. Liaudet L "Severe ergotism associated with interaction between ritonavir and ergotamine." BMJ 318 (1999): 771
  19. Mortier E, Pouchet J, Vinceneux P, Lalande M "Ergotism related to interaction between nelfinavir and ergotamine." Am J Med 110 (2001): 594
  20. 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
  21. Ausband SC, Goodman PE "An unusual case of clarithromycin associated ergotism." J Emerg Med 4 (2001): 411-3
  22. Baldwin ZK, Ceraldi CC "Ergotism associated with HIV antiviral protease inhibitor therapy." J Vasc Surg 37 (2003): 676-8
  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. 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 25 references

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Moderate

PENTobarbital amLODIPine

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital) and Caduet (amlodipine / atorvastatin)

MONITOR: Barbiturates may increase the hepatic metabolism of some dihydropyridine calcium channel blockers by inducing CYP450 3A4 hepatic metabolism. The serum concentrations and effects of these calcium channel blockers may be significantly decreased.

MANAGEMENT: If concurrent administration cannot be avoided, the patient should be closely monitored for changes in pharmacologic effects whenever a barbiturate is initiated, discontinued or its dosage adjusted. An increased dosage of the calcium channel blocker may be necessary.

References

  1. Hamann SR, Blouin RA, Chang SL, et al. "Effects of hemodynamic changes on the elimination kinetics of verapamil and nifedipine." J Pharmacol Exp Ther 231 (1984): 301-5
  2. Schellens JH, Van Der Wart JH, Brugman M, Breimer D "Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design." J Pharmacol Exp Ther 249 (1989): 638-45
  3. Koleva MR, Stoychev TS "Effect of nifedipine, verapamil and diltiazem on the enzyme-inducing activity of phenobarbital and beta-naphthoflavone." Gen Pharmacol 26 (1995): 225-8

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Moderate

PENTobarbital atorvastatin

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital) and Caduet (amlodipine / atorvastatin)

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of atorvastatin and its active metabolites, all of which are substrates of the isoenzyme. When atorvastatin (40 mg/day) was coadministered for 28 days with the potent CYP450 3A4 inducer phenytoin (4 mg/kg/day) in healthy volunteers (n=44), atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by an average of 24% and 54%, respectively. The Cmax of two active metabolites, 2-hydroxy- and 4-hydroxyatorvastatin, also decreased by an average of 22% and 52%, respectively, while AUC decreased by an average of 53% and 44%, respectively. Consistent with the observed pharmacokinetic interaction, there have been isolated reports of reduced efficacy of atorvastatin in the presence of phenytoin, followed by improved cholesterol levels after discontinuation of phenytoin. In another study, coadministration of the mixed CYP450 3A4 inducer/inhibitor efavirenz (600 mg once daily for 15 days) with atorvastatin (10 mg daily during the last 4 days of efavirenz) in 14 healthy volunteers resulted in median decreases of 43% in atorvastatin AUC and 34% in total active atorvastatin (parent drug + active metabolites) AUC. However, the median LDL decrease was not significantly different during coadministration with efavirenz compared to atorvastatin administered alone (-29 versus -22, respectively). Atorvastatin did not affect the AUC of efavirenz. In a study of patients with non-small cell lung cancer receiving the CYP450 3A4 inducer bexarotene (400 mg/m2 orally once a day) plus either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, treatment with atorvastatin or fenofibrate was given to manage bexarotene-induced hyperlipidemia. Investigators reported that bexarotene decreased mean atorvastatin systemic exposure (dose-corrected AUC) by approximately 50%, whereas atorvastatin had no significant effect on bexarotene plasma concentrations. In 16 study subjects administered etravirine with atorvastatin 40 mg once a day, atorvastatin AUC decreased by 37%, while Cmax and AUC of 2-hydroxy-atorvastatin increased by 76% and 27%, respectively. Atorvastatin did not significantly affect the pharmacokinetics of etravirine.

MANAGEMENT: The potential for diminished pharmacologic effects of atorvastatin should be considered during coadministration with CYP450 3A4 inducers. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. Otherwise, pharmacologic response to atorvastatin should be closely monitored, and the dosage adjusted as necessary. A statin that is not metabolized by CYP450 3A4 such as fluvastatin, pitavastatin, pravastatin, or rosuvastatin may also be substituted for atorvastatin when used with certain enzyme inducers.

References

  1. "Product Information. Lipitor (atorvastatin)." Parke-Davis PROD (2001):
  2. Murphy MJ, Dominiczak MH "Efficacy of statin therapy: possible effect of phenytoin." Postgrad Med J 75 (1999): 359-60
  3. Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al. "Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study." J Acquir Immune Defic Syndr 39 (2005): 307-12
  4. Khandwala HM "Lipid lowering inefficacy of high-dose statin therapy due to concurrent use of phenytoin." South Med J 99 (2006): 1385-7
  5. Bullman J, Nicholls A, Van Landingham K, et al. "Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers." Epilepsia 52 (2011): 1351-8
View all 5 references

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Moderate

amLODIPine atorvastatin

Applies to: Caduet (amlodipine / atorvastatin) and Caduet (amlodipine / atorvastatin)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by the isoenzyme. Lovastatin and simvastatin are particularly susceptible because of their low oral bioavailability, but others such as atorvastatin and cerivastatin may also be affected. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Clinically significant interactions have been reported with potent CYP450 3A4 inhibitors such as macrolide antibiotics, azole antifungals, protease inhibitors and nefazodone, and moderate inhibitors such as amiodarone, cyclosporine, danazol, diltiazem and verapamil.

MANAGEMENT: Caution is recommended if atorvastatin, cerivastatin, lovastatin, simvastatin, or red yeast rice (which contains lovastatin) is prescribed with a CYP450 3A4 inhibitor. It is advisable to monitor lipid levels and use the lowest effective statin dose. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. Fluvastatin, pravastatin, and rosuvastatin are not expected to interact with CYP450 3A4 inhibitors.

References

  1. Spach DH, Bauwens JE, Clark CD, Burke WG "Rhabdomyolysis associated with lovastatin and erythromycin use." West J Med 154 (1991): 213-5
  2. Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3
  3. Corpier CL, Jones PH, Suki WN, et al. "Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients." JAMA 260 (1988): 239-41
  4. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA "Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation." N Engl J Med 318 (1988): 47-8
  5. Norman DJ, Illingworth DR, Munson J, Hosenpud J "Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin." N Engl J Med 318 (1988): 46-7
  6. "Product Information. Mevacor (lovastatin)." Merck & Co., Inc PROD (2002):
  7. "Product Information. Zocor (simvastatin)." Merck & Co., Inc PROD (2001):
  8. Dallaire M, Chamberland M "Severe rhabdomyolysis in a patient receiving lovastatin, danazol and doxycycline." Can Med Assoc J 150 (1994): 1991-4
  9. Campana C, Iacona I, Regassi MB, et al. "Efficacy and pharmacokinetics of simvastatin in heart transplant recipients." Ann Pharmacother 29 (1995): 235-9
  10. Lees RS, Lees AM "Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole." N Engl J Med 333 (1995): 664-5
  11. Zhou LX, Finley DK, Hassell AE, Holtzman JL "Pharmacokinetic interaction between isradipine and lovastatin in normal, female and male volunteers." J Pharmacol Exp Ther 273 (1995): 121-7
  12. Neuvonen PJ, Jalava KM "Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 60 (1996): 54-61
  13. Horn M "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol 132 (1996): 1254
  14. "Product Information. Lipitor (atorvastatin)." Parke-Davis PROD (2001):
  15. Jacobson RH, Wang P, Glueck CJ "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296
  16. Jody DN "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296-7
  17. "Product Information. Baycol (cerivastatin)." Bayer PROD (2001):
  18. Grunden JW, Fisher KA "Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin." Ann Pharmacother 31 (1997): 859-63
  19. Wong PW, Dillard TA, Kroenke K "Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy." South Med J 91 (1998): 202-5
  20. Neuvonen PJ, Kantola T, Kivisto KT "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin Pharmacol Ther 63 (1998): 332-41
  21. Agbin NE, Brater DC, Hall SD "Interaction of diltiazem with lovastatin and pravastatin." Clin Pharmacol Ther 61 (1997): 201
  22. Kivisto KT, Kantola T, Neuvonen PJ "Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin." Br J Clin Pharmacol 46 (1998): 49-53
  23. Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on the pharmacokinetics of atorvastatin." Clin Pharmacol Ther 64 (1998): 58-65
  24. Kantola T, Kivisto KT, Neuvonen PJ "Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations." Clin Pharmacol Ther 64 (1998): 177-82
  25. Azie NE, Brater DC, Becker PA, Jones DR, Hall SD "The interaction of diltiazem with lovastatin and pravastatin." Clin Pharmacol Ther 64 (1998): 369-77
  26. Lomaestro BM, Piatek MA "Update on drug interactions with azole antifungal agents." Ann Pharmacother 32 (1998): 915-28
  27. Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on cerivastatin pharmacokinetics." Eur J Clin Pharmacol 54 (1999): 851-5
  28. Malaty LI, Kuper JJ "Drug interactions of HIV protease inhibitors." Drug Safety 20 (1999): 147-69
  29. Siedlik PH, Olson SC, Yang BB, Stern RH "Erythromycin coadministration increases plasma atorvastatin concentrations." J Clin Pharmacol 39 (1999): 501-4
  30. Barry M, Mulcahy F, Merry C, Gibbons S, Back D "Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection." Clin Pharmacokinet 36 (1999): 289-304
  31. Rodriguez JA, CrespoLeiro MG, Paniagua MJ, Cuenca JJ, Hermida LF, Juffe A, CastroBeiras A "Rhabdomyolysis in heart transplant patients on HMG-CoA reductase inhibitors and cyclosporine." Transplant Proc 31 (1999): 2522-3
  32. Gruer PJK, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA "Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin." Am J Cardiol 84 (1999): 811-5
  33. Gilad R, Lampl Y "Rhabdomyolysis induced by simvastatin and ketoconazole treatment." Clin Neuropharmacol 22 (1999): 295-7
  34. Gullestad L, Nordal KP, Berg KJ, Cheng H, Schwartz MS, Simonsen S "Interaction between lovastatin and cyclosporine A after heart and kidney transplantation." Transplant Proc 31 (1999): 2163-5
  35. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE "Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients." Br J Clin Pharmacol 48 (1999): 610-5
  36. Maltz HC, Balog DL, Cheigh JS "Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine." Ann Pharmacother 33 (1999): 1176-9
  37. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  38. Jardine A, Holdaas H "Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience." J Clin Pharm Ther 24 (1999): 397-408
  39. Mousa O, Brater DC, Sundblad KJ, Hall SD "The interaction of diltiazem with simvastatin." Clin Pharmacol Ther 67 (2000): 267-74
  40. Westphal JF "Macrolide - induced clinically relevant drug interactions with cytochrome P-450 (CYP) 3A4: an update focused on clarithromycin, azithromycin, and dirithromycin." Br J Clin Pharmacol 50 (2000): 285-95
  41. Kusus M, Stapleton DD, Lertora JJL, Simon EE, Dreisbach AW "Rhabdomyolysis and acute renal failure in a cardiac transplant recipient due to multiple drug interactions." Am J Med Sci 320 (2000): 394-7
  42. Lee AJ, Maddix DS "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin." Ann Pharmacother 35 (2001): 26-31
  43. Yeo KR, Yeo WW "Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes." Br J Clin Pharmacol 51 (2001): 461-70
  44. Arnadottir M, Eriksson LO, Thysell H, Karkas JD "Plasma concentration profiles of simvastatin 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin." Nephron 65 (1993): 410-3
  45. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F "New insights into the pharmacodynamic and pharmacokinetic properties of statins." Pharmacol Ther 84 (1999): 413-28
  46. Garnett WR "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm 52 (1995): 1639-45
  47. Omar MA, Wilson JP "FDA adverse event reports on statin-associated rhabdomyolysis." Ann Pharmacother 36 (2002): 288-95
  48. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. "Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047." AIDS 16 (2002): 569-577
  49. Amsden GW, Kuye O, Wei GC "A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers." J Clin Pharmacol 42 (2002): 444-9
  50. Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70
  51. Thompson M, Samuels S "Rhabdomyolysis with simvastatin and nefazodone." Am J Psychiatry 159 (2002): 1607
  52. Huynh T, Cordato D, Yang F, et al. "HMG coA reductase-inhibitor-related myopathy and the influence of drug interactions." Intern Med J 32(9-10) (2002): 486-90
  53. Paoletti R, Corsini A, Bellosta S "Pharmacological interactions of statins." Atheroscler Suppl 3 (2002): 35-40
  54. Sipe BE, Jones RJ, Bokhart GH "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction." Ann Pharmacother 37 (2003): 808-11
  55. de Denus S, Spinler SA "Amiodarone's role in simvastatin-associated rhabdomyolysis." Am J Health Syst Pharm 60 (2003): 1791; author reply 1791-2
  56. Skrabal MZ, Stading JA, Monaghan MS "Rhabdomyolysis associated with simvastatin-nefazodone therapy." South Med J 96 (2003): 1034-5
  57. Andreou ER, Ledger S "Potential drug interaction between simvastatin and danazol causing rhabdomyolysis." Can J Clin Pharmacol 10 (2003): 172-4
  58. Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG "Rhabdomyolysis in association with simvastatin and amiodarone." Ann Pharmacother 38 (2004): 978-81
  59. Jacobson TA "Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors." Am J Cardiol 94 (2004): 1140-6
  60. Chouhan UM, Chakrabarti S, Millward LJ "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother 39 (2005): 1760-1
  61. Karnik NS, Maldonado JR "Antidepressant and statin interactions: a review and case report of simvastatin and nefazodone-induced rhabdomyolysis and transaminitis." Psychosomatics 46 (2005): 565-8
  62. Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74
  63. "Product Information. Qelbree (viloxazine)." Supernus Pharmaceuticals Inc (2021):
View all 63 references

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Drug and food interactions

Major

PENTobarbital food

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

References

  1. Gupta RC, Kofoed J "Toxological statistics for barbiturates, other sedatives, and tranquilizers in Ontario: a 10-year survey." Can Med Assoc J 94 (1966): 863-5
  2. Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS "Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats." Am J Med 51 (1971): 346-51
  3. Saario I, Linnoila M "Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving." Acta Pharmacol Toxicol (Copenh) 38 (1976): 382-92
  4. Stead AH, Moffat AC "Quantification of the interaction between barbiturates and alcohol and interpretation of fatal blood concentrations." Hum Toxicol 2 (1983): 5-14
  5. Seixas FA "Drug/alcohol interactions: avert potential dangers." Geriatrics 34 (1979): 89-102
View all 5 references

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Moderate

ergotamine food

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

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

atorvastatin food

Applies to: Caduet (amlodipine / atorvastatin)

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of atorvastatin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 40 mg dose of atorvastatin was coadministered with 240 mL of grapefruit juice, atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 16% and 37%, respectively. Greater increases in Cmax (up to 71%) and/or AUC (up to 2.5 fold) have been reported with excessive consumption of grapefruit juice (>=750 mL to 1.2 liters per day). Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

MANAGEMENT: Patients receiving therapy with atorvastatin should limit their consumption of grapefruit juice to no more than 1 liter per day. Patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, patients should either refrain from the use of oat bran and pectin or, if concurrent use cannot be avoided, to separate the administration times by at least 2 to 4 hours.

References

  1. Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706
  2. McMillan K "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm 53 (1996): 2206-14
  3. "Product Information. Lipitor (atorvastatin)." Parke-Davis PROD (2001):
  4. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos 25 (1997): 321-31
  5. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  6. 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
  7. Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74
View all 7 references

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Moderate

amLODIPine food

Applies to: Caduet (amlodipine / atorvastatin)

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

References

  1. Sternbach H "Fluoxetine-associated potentiation of calcium-channel blockers." J Clin Psychopharmacol 11 (1991): 390-1
  2. Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lamas GA "Ethanol intoxication complicating intravenous nitroglycerin therapy." Ann Intern Med 101 (1984): 498-9
  3. Feder R "Bradycardia and syncope induced by fluoxetine." J Clin Psychiatry 52 (1991): 139
  4. Ellison JM, Milofsky JE, Ely E "Fluoxetine-induced bradycardia and syncope in two patients." J Clin Psychiatry 51 (1990): 385-6
  5. Rodriguez de la Torre B, Dreher J, Malevany I, et al. "Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients." Ther Drug Monit 23 (2001): 435-40
  6. Cerner Multum, Inc. "Australian Product Information." O 0
  7. Pacher P, Kecskemeti V "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des 10 (2004): 2463-75
  8. Andrews C, Pinner G "Postural hypotension induced by paroxetine." BMJ 316 (1998): 595
View all 8 references

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Moderate

belladonna food

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

References

  1. Linnoila M "Drug effects on psychomotor skills related to driving: interaction of atropine, glycopyrrhonium and alcohol." Eur J Clin Pharmacol 6 (1973): 107-12

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Moderate

amLODIPine food

Applies to: Caduet (amlodipine / atorvastatin)

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

References

  1. Henry M, Kay MM, Viccellio P "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med 3 (1985): 334-6
  2. Moller IW "Cardiac arrest following intravenous verapamil combined with halothane anaesthesia." Br J Anaesth 59 (1987): 522-6
  3. Oszko MA, Klutman NE "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm 6 (1987): 448-9
  4. Schoen MD, Parker RB, Hoon TJ, et al. "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol 67 (1991): 300-4
  5. O'Quinn SV, Wohns DH, Clarke S, Koch G, Patterson JH, Adams KF "Influence of calcium on the hemodynamic and anti-ischemic effects of nifedipine observed during treadmill exercise testing." Pharmacotherapy 10 (1990): 247
  6. Woie L, Storstein L "Successful treatment of suicidal verapamil poisoning with calcium gluconate." Eur Heart J 2 (1981): 239-42
  7. Morris DL, Goldschlager N "Calcium infusion for reversal of adverse effects of intravenous verapamil." JAMA 249 (1983): 3212-3
  8. Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E "Treatment of severe left ventricular dysfunction with calcium chloride in patients receiving verapamil." J Clin Pharmacol 27 (1987): 407-9
  9. Luscher TF, Noll G, Sturmer T, Huser B, Wenk M "Calcium gluconate in severe verapamil intoxication." N Engl J Med 330 (1994): 718-20
  10. Bar-Or D, Gasiel Y "Calcium and calciferol antagonise effect of verapamil in atrial fibrillation." Br Med J (Clin Res Ed) 282 (1981): 1585-6
  11. Lipman J, Jardine I, Roos C, Dreosti L "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med 8 (1982): 55-7
  12. McMillan R "Management of acute severe verapamil intoxication." J Emerg Med 6 (1988): 193-6
  13. Perkins CM "Serious verapamil poisoning: treatment with intravenous calcium gluconate." Br Med J 2 (1978): 1127
  14. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M "Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning." Clin Toxicol 17 (1980): 395-400
View all 14 references

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Moderate

ergotamine food

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

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

amLODIPine food

Applies to: Caduet (amlodipine / atorvastatin)

The consumption of grapefruit juice may slightly increase plasma concentrations of amlodipine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Data have been conflicting and the clinical significance is unknown. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

References

  1. Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
  2. 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
  3. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  4. Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL "Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine." Br J Clin Pharmacol 50 (2000): 455-63
  5. Josefsson M, Ahlner J "Amlodipine and grapefruit juice." Br J Clin Pharmacol 53 (2002): 405; discussion 406
  6. Kane GC, Lipsky JJ "Drug-grapefruit juice interactions." Mayo Clin Proc 75 (2000): 933-42
View all 6 references

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Minor

caffeine food

Applies to: Ergocomp-PB (belladonna / caffeine / ergotamine / pentobarbital)

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

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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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