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Drug Interactions between Prevymis and terfenadine

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

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Moderate

terfenadine letermovir

Applies to: terfenadine and Prevymis (letermovir)

MONITOR: Coadministration with letermovir may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, CYP450 3A4, and/or organic anion transporting polypeptide protein (OATP) 1B1 and 1B3. Letermovir has been shown to be a reversible inhibitor of CYP450 2C8 in vitro, although its effect on CYP450 2C8 substrates has not been evaluated clinically. Letermovir is also a time-dependent inhibitor and inducer of CYP450 3A4 in vitro. According to the product labeling, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 1.7- and 2.3-fold, respectively, when a single 2 mg oral dose of midazolam was coadministered with letermovir 480 mg orally once daily. The Cmax did not change when midazolam 1 mg was administered intravenously with letermovir 240 mg orally once daily, but AUC increased by 1.5-fold and concentration at 24 hours postdose (C24hr) increased by 2.7-fold. The increased AUC of midazolam, a CYP450 3A4 probe substrate, indicates that net effect of letermovir on the isoenzyme is moderate inhibition. In addition, letermovir is an inhibitor of the hepatic uptake transporters, OATP 1B1 and 1B3. When a single 20 mg dose of atorvastatin, a CYP450 3A4 and OATP1B1/1B3 substrate, was coadministered with letermovir 480 mg orally once daily, atorvastatin Cmax, AUC and C24hr increased by an average of 2.2-, 3.3- and 3.6-fold, respectively. Additional use of cyclosporine is likely to further increase the magnitude of these interactions, since it is an inhibitor of CYP450 3A4 and a strong inhibitor of OATP 1B1 and 1B3.

MANAGEMENT: Caution is advised when letermovir is used concurrently with drugs that are substrates of CYP450 2C8, CYP450 3A4, and/or OATP 1B1 and 1B3, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever letermovir is added to or withdrawn from therapy. Moreover, clinicians should be aware that the magnitude of CYP450 3A- and OATP1B1/3-mediated drug interactions with coadministered drugs may be different when letermovir is used with cyclosporine. The combined effect of the two drugs on CYP450 3A4 may be similar to that of a strong CYP450 3A4 inhibitor, hence clinicians should refer to the prescribing information for dosing recommendations of the CYP450 3A4 substrate with a strong CYP450 3A4 inhibitor. Similarly, letermovir and cyclosporine may demonstrate some additive effects on OATP1B1 inhibition, although cyclosporine by itself is already a strong OATP1B1/3 inhibitor.

References

  1. (2017) "Product Information. Prevymis (letermovir)." Merck & Co., Inc

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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 (1992) "Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin." Clin Pharmacol Ther, 52, p. 231-8
  2. Zimmermann M, Duruz H, Guinand O, et al. (1992) "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J, 13, p. 1002-3
  3. Mathews DR, McNutt B, Okerholm R, et al. (1991) "Torsades de pointes occurring in association with terfenadine use." JAMA, 266, p. 2375-6
  4. Monahan BP, Ferguson CL, Killeavy ES, et al. (1990) "Torsades de pointes occurring in association with terfenadine use." JAMA, 264, p. 2788-90
  5. Honig PK, Wortham DC, Zamani K, et al. (1993) "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA, 269, p. 1513-8
  6. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P (1993) "Torsades de pointes after terfenadine-itraconazole interaction." BMJ, 306, p. 186
  7. Cortese LM, Bjornson DC (1992) "Potential interaction between terfenadine and macrolide antibiotics." Clin Pharm, 11, p. 675
  8. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP (1994) "Torsades-de-pointes induced by erythromycin and terfenadine." Am J Emerg Med, 12, p. 636-8
  9. Zechnich AD, Haxby DG (1996) "Drug interactions associated with terfenadine and related nonsedating antihistamines." West J Med, 164, p. 68-9
  10. Honig PK, Wortham DC, Lazarev A, Cantilena LR (1996) "Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine." J Clin Pharmacol, 36, p. 345-51
  11. Woosley RL (1996) "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol, 36, p. 233-52
  12. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL (1996) "Grapefruit juice alters terfenadine pharmacokinetics resulting in prolongation of repolarization on the electrocardiogram." Clin Pharmacol Ther, 59, p. 383-8
  13. Hsieh MH, Chen SA, Chiang CE, et al. (1996) "Drug-induced torsades de pointes in one patient with congenital long QT syndrome." Int J Cardiol, 54, p. 85-8
  14. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DS (1996) "Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice." Br J Clin Pharmacol, 42, p662
  15. Rau SE, Bend JR, Arnold JMO, Tran LT, Spence JD, Bailey DG (1997) "Grapefruit juice terfenadine single-dose interaction: Magnitude, mechanism, and relevance." Clin Pharmacol Ther, 61, p. 401-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  17. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 17 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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