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Drug Interactions between entrectinib and Lipitor

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

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Moderate

atorvastatin entrectinib

Applies to: Lipitor (atorvastatin) and entrectinib

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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  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):
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  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
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  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
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  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
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  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
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  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

entrectinib food

Applies to: entrectinib

GENERALLY AVOID: Grapefruit juice and Seville oranges may increase the plasma concentrations of entrectinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole. When a single 100 mg dose of entrectinib was administered with itraconazole, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Coadministration of entrectinib with a moderate CYP450 3A4 inhibitor is predicted to increase entrectinib Cmax and AUC by 2.9- and 3-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. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with entrectinib.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. "Product Information. Rozlytrek (entrectinib)." Genentech (2019):

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Moderate

atorvastatin food

Applies to: Lipitor (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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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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