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Drug Interactions between ivacaftor / lumacaftor and terfenadine

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

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Interactions between your drugs

Moderate

terfenadine ivacaftor

Applies to: terfenadine and ivacaftor / lumacaftor

MONITOR: Coadministration with ivacaftor may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these pathways due to inhibition by ivacaftor and its pharmacologically active M1 metabolite. The interaction has been studied with midazolam and digoxin, probe substrates for CYP450 3A4 ad P-gp, respectively. In study subjects, midazolam systemic exposure (AUC) increased by 1.5-fold when it was administered with ivacaftor, suggesting weak inhibition of CYP450 3A4 by ivacaftor. Likewise, digoxin AUC increased by 1.3-fold with ivacaftor, which is also consistent with weak inhibition of P-gp by ivacaftor.

MANAGEMENT: Caution is advised when ivacaftor is used with drugs that are substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ivacaftor is added to or withdrawn from therapy.

References

  1. "Product Information. Kalydeco (ivacaftor)." Vertex Pharmaceuticals (2012):

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Drug and food interactions

Major

terfenadine food

Applies to: terfenadine

CONTRAINDICATED: The consumption of grapefruit juice has been associated with significantly increased plasma concentrations of terfenadine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. Terfenadine in high serum levels has been associated with prolongation of the QT interval and development of torsade de pointes, a potentially fatal ventricular arrhythmia.

MANAGEMENT: Due to the risk of cardiotoxicity, patients receiving the drug should be advised to avoid consumption of grapefruit products. Loratadine, cetirizine, and fexofenadine may be safer alternatives in patients who may have trouble adhering to the dietary restriction.

References

  1. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr "Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin." Clin Pharmacol Ther 52 (1992): 231-8
  2. Zimmermann M, Duruz H, Guinand O, et al. "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J 13 (1992): 1002-3
  3. Mathews DR, McNutt B, Okerholm R, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 266 (1991): 2375-6
  4. Monahan BP, Ferguson CL, Killeavy ES, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 264 (1990): 2788-90
  5. Honig PK, Wortham DC, Zamani K, et al. "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA 269 (1993): 1513-8
  6. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P "Torsades de pointes after terfenadine-itraconazole interaction." BMJ 306 (1993): 186
  7. Cortese LM, Bjornson DC "Potential interaction between terfenadine and macrolide antibiotics." Clin Pharm 11 (1992): 675
  8. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP "Torsades-de-pointes induced by erythromycin and terfenadine." Am J Emerg Med 12 (1994): 636-8
  9. Zechnich AD, Haxby DG "Drug interactions associated with terfenadine and related nonsedating antihistamines." West J Med 164 (1996): 68-9
  10. Honig PK, Wortham DC, Lazarev A, Cantilena LR "Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine." J Clin Pharmacol 36 (1996): 345-51
  11. Woosley RL "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol 36 (1996): 233-52
  12. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL "Grapefruit juice alters terfenadine pharmacokinetics resulting in prolongation of repolarization on the electrocardiogram." Clin Pharmacol Ther 59 (1996): 383-8
  13. Hsieh MH, Chen SA, Chiang CE, et al. "Drug-induced torsades de pointes in one patient with congenital long QT syndrome." Int J Cardiol 54 (1996): 85-8
  14. 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
  15. Rau SE, Bend JR, Arnold JMO, Tran LT, Spence JD, Bailey DG "Grapefruit juice terfenadine single-dose interaction: Magnitude, mechanism, and relevance." Clin Pharmacol Ther 61 (1997): 401-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  17. Bailey DG, 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
View all 17 references

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Moderate

ivacaftor food

Applies to: ivacaftor / lumacaftor

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.

References

  1. "Product Information. Kalydeco (ivacaftor)." Vertex Pharmaceuticals (2012):
  2. "Product Information. Orkambi (ivacaftor-lumacaftor)." Vertex Pharmaceuticals (2015):
  3. "Product Information. Symdeko (ivacaftor-tezacaftor)." Vertex Pharmaceuticals (2022):
  4. "Product Information. Trikafta (elexacaftor/ivacaftor/tezacaftor)." Vertex Pharmaceuticals (2019):
View all 4 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.

Further information

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