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Drug Interactions between astemizole and saquinavir

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

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Interactions between your drugs

Major

astemizole saquinavir

Applies to: astemizole and saquinavir

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 (39)
  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

Drug and food interactions

Major

astemizole food

Applies to: astemizole

GENERALLY AVOID: Some beverages such as tonic water contain varying amounts of quinine. Coadministration of a single 430 mg dose of quinine has been shown to increase plasma concentrations of astemizole and its metabolite, desmethylastemizole. Elevated levels of these agents may cause a prolongation of the electrocardiographic QT interval and potentially fatal ventricular arrhythmias. Although pharmacokinetic data have indicated that the amounts of quinine in beverages (up to 80 mg quinine in 32 oz of tonic water) are not sufficient to produce a significant effect, the potential for an interaction exists if large amounts of tonic water are ingested. Also, grapefruit juice has been shown to inhibit CYP450 enzymes, which may lead to increased serum astemizole concentrations. The risk of life-threatening ventricular arrhythmias may be increased.

MANAGEMENT: Patients should be counseled to limit consumption of quinine-containing beverages and avoid grapefruit juice while they are taking astemizole.

References (1)
  1. (2002) "Product Information. Hismanal (astemizole)." Janssen Pharmaceuticals
Moderate

saquinavir food

Applies to: saquinavir

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

References (6)
  1. (2001) "Product Information. Invirase (saquinavir)." Roche Laboratories
  2. Kupferschmidt HHT, Fattinger KE, Ha HR, Follath F, Krahenbuhl S (1998) "Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man." Br J Clin Pharmacol, 45, p. 355-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Eagling VA, Profit L, Back DJ (1999) "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol, 48, p. 543-52
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  6. Cerner Multum, Inc. "Australian Product Information."

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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