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Drug Interactions between atorvastatin and avacopan

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

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Moderate

atorvastatin avacopan

Applies to: atorvastatin and avacopan

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

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

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Drug and food interactions

Moderate

atorvastatin food

Applies to: 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 (1991) "Interaction between fibre and lovastatin." Lancet, 338, p. 706
  2. McMillan K (1996) "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm, 53, p. 2206-14
  3. (2001) "Product Information. Lipitor (atorvastatin)." Parke-Davis
  4. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M (1997) "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos, 25, p. 321-31
  5. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  6. Lilja JJ, Kivisto KT, Neuvonen PJ (1999) "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther, 66, p. 118-27
  7. Neuvonen PJ, Backman JT, Niemi M (2008) "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet, 47, p. 463-74
View all 7 references

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Moderate

avacopan food

Applies to: avacopan

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of avacopan. When a 30 mg capsule of avacopan was administered with a high-fat, high-calorie meal, avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 8% and 72%, respectively, while the time to reach peak concentration (Tmax) was delayed by approximately 4 hours (from 2.0 hours to 6.0 hours).

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of avacopan. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for itraconazole, a potent CYP450 3A4 inhibitor. When avacopan was administered with itraconazole (200 mg once daily for 4 days), avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.9-fold and 2.2-fold, respectively. 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. Increased exposure to avacopan may increase the risk and/or severity of serious adverse reactions such as hepatotoxicity and infections.

MANAGEMENT: To ensure maximal oral absorption, avacopan should be administered with food. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during avacopan therapy.

References

  1. (2021) "Product Information. Tavneos (avacopan)." ChemoCentryx, Inc.
  2. (2023) "Product Information. Tavneos (avacopan)." Vifor Fresenius Medical Care Renal Pharma UK Ltd

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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.

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