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Drug Interactions between dasabuvir / ombitasvir / paritaprevir / ritonavir and terfenadine

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

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Interactions between your drugs

Major

terfenadine ritonavir

Applies to: terfenadine and dasabuvir / ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration with protease inhibitors (PIs), particularly ritonavir, may significantly increase the plasma concentrations of astemizole and terfenadine. The mechanism is PI inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of both astemizole and terfenadine. Although the interaction has not been specifically studied with any of the available PIs, high plasma levels of astemizole and terfenadine (e.g., due to overdose or interaction with other potent 3A4 inhibitors such as macrolide antibiotics and azole antifungal agents) have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of astemizole and terfenadine, use of these agents in patients treated with protease inhibitors is considered contraindicated. Loratadine, cetirizine, or fexofenadine may be safer alternatives during therapy with PIs.

References

  1. Eller MG, Okerholm RA (1991) "Pharmacokinetic interaction between terfenadine and ketoconazole." Clin Pharmacol Ther, 49, p. 130
  2. 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
  3. 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
  4. Mathews DR, McNutt B, Okerholm R, et al. (1991) "Torsades de pointes occurring in association with terfenadine use." JAMA, 266, p. 2375-6
  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. Craft TM (1986) "Torsade de pointes after astemizole overdose." Br Med J, 292, p. 660
  8. Snook J, Boothman-Burrell D, Watkins J, Colin-Jones D (1988) "Torsade de pointes ventricular tachycardia associated with astemizole overdose." Br J Clin Pract, 42, p. 257-9
  9. Saviuc P, Danel V, Dixmerias F (1993) "Prolonged QT interval and torsade de pointes following astemizole overdose." J Toxicol Clin Toxicol, 31, p. 121-5
  10. Hasan RA, Zureikat GY, Nolan BM (1993) "Torsade de pointes associated with astemizole overdose treated with magnesium sulfate." Pediatr Emerg Care, 9, p. 23-5
  11. Crane JK, Shih HT (1993) "Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine." Am J Med, 95, p. 445-6
  12. Biglin KE, Faraon MS, Constance TD, Lieh-Lai M (1994) "Drug-induced torsades de pointes: a possible interaction of terfenadine and erythromycin." Ann Pharmacother, 28, p. 282
  13. Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR (1993) "Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics." J Clin Pharmacol, 33, p. 1201-6
  14. Rao KA, Adlakha A, Vermaansil B, Meloy TD, Stanton MS (1994) "Torsades de pointes ventricular tachycardia associated with overdose of astemizole." Mayo Clin Proc, 69, p. 589-93
  15. Kivisto KT, Neuvonen PJ, Klotz U (1994) "Inhibition of terfenadine metabolism - pharmacokinetic and pharmacodynamic consequences." Clin Pharmacokinet, 27, p. 1-5
  16. Smith SJ (1994) "Cardiovascular toxicity of antihistamines." Otolaryngol Head Neck Surg, 111 Suppl, p. 348-54
  17. 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
  18. (2001) "Product Information. Invirase (saquinavir)." Roche Laboratories
  19. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical
  20. (2001) "Product Information. Crixivan (indinavir)." Merck & Co., Inc
  21. Ng PW, Chan WK, Chan TYK (1996) "Torsade de pointes during the concomitant use of terfenadine and cimetidine." Aust N Z J Med, 26, p. 120-1
  22. Heidemann SM, Sarnaik AP (1996) "Arrhythmias after astemizole overdose." Pediatr Emerg Care, 12, p. 102-4
  23. Woosley RL (1996) "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol, 36, p. 233-52
  24. Hey JA, Delprado M, Egan RW, Kreutner W (1996) "Terfenadine, astemizole, and ebastine produce QTc interval prolongation in an experimental model predictive of adverse clinical ECG effects." Ann Allergy Asthma Immunol, 76, p. 476
  25. Vorperian VR, Zhou ZF, Mohammad S, Hoon TJ, Studenik C, January CT (1996) "Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole." J Am Coll Cardiol, 28, p. 1556-61
  26. Tsai WC, Tsai LM, Chen JH (1997) "Combined use of astemizole and ketoconazole resulting in torsade de pointes." J Formos Med Assoc, 96, p. 144-6
  27. (2001) "Product Information. Viracept (nelfinavir)." Agouron Pharma Inc
  28. Ament PW, Paterson A (1997) "Drug interactions with the nonsedating antihistamines." Am Fam Physician, 56, p. 223
  29. Jurima-Romet M, Crawford K, Cyr T, Inaba T (1994) "Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals." Drug Metab Dispos, 22, p. 849-57
  30. Rankin AC (1997) "Non-sedating antihistamines and cardiac arrhythmia." Lancet, 350, p. 1115-6
  31. Gonzalez MA, Estes KS (1998) "Pharmacokinetic overview of oral second-generation H-1 antihistamines." Int J Clin Pharmacol Ther, 36, p. 292-300
  32. (2001) "Product Information. Agenerase (amprenavir)." Glaxo Wellcome
  33. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  34. (2001) "Product Information. Fortovase (saquinavir)." Roche Laboratories
  35. Mangum EM, Graham KK (2001) "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy, 21, p. 1352-63
  36. DuBuske LM (1999) "Second-generation antihistamines: the risk of ventricular arrhythmias." Clin Ther, 21, p. 281-95
  37. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb
  38. (2003) "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline
  39. (2006) "Product Information. Prezista (darunavir)." Ortho Biotech Inc
View all 39 references

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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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Moderate

ritonavir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical

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Moderate

paritaprevir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.

References

  1. (2022) "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC

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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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