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Drug Interactions between hydroxychloroquine and terfenadine

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

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Major

terfenadine hydroxychloroquine

Applies to: terfenadine and hydroxychloroquine

GENERALLY AVOID: Hydroxychloroquine (HCQ) can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such advanced age, congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In a retrospective study of electronic health records analyzing QTc prolongation risk in patients on HCQ alone or with other QT-prolonging drugs, a statistically significant QTc interval increase of 18 ms was observed in the HCQ monotherapy group. No significant QTc increase was found in patients taking HCQ with the evaluated QT-prolonging medications. However, this result may have been influenced by factors such as varying patient sensitivity to QT-prolonging drugs across treatment sites, and differences in HCQ exposure duration prior to QTc measurement in combination therapy cases. QT prolongation has also been reported with chloroquine, with an increased risk reported at higher doses.

MANAGEMENT: Coadministration of hydroxychloroquine or chloroquine with other drugs that can prolong the QT interval should generally be avoided, particularly in patients with baseline QT prolongation (e.g., QTc >=500 msec) or congenital long QT syndrome. Close monitoring of QTc interval, electrolyte levels, and renal and hepatic function is recommended if concomitant use is required, and benefits are anticipated to outweigh the risks. Electrolyte abnormalities should be corrected prior to initiating treatment with hydroxychloroquine. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Because both hydroxychloroquine and chloroquine are eliminated slowly from the body (e.g., terminal half-life of hydroxychloroquine is 40-50 days), potential drug interactions may persist for several weeks to months after their discontinuation.

References (28)
  1. (2022) "Product Information. Plaquenil (hydroxychloroquine)." Apothecon Inc
  2. (2005) "Product Information. Chloroquine Phosphate (chloroquine)." West Ward Pharmaceutical Corporation
  3. (2017) "Product Information. Hydroxychloroquine Sulfate (hydroxychloroquine)." Prasco Laboratories
  4. US Food and Drug Administration (2020) Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems. https://www.fda.gov/safety/medical-product-safety-information/h
  5. US Food and Drug Administration (2020) FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF HYDROXYCHLOROQUINE SULFATE SUPPLIED FROM THE STRATEGIC NATIONAL STOCKPILE FOR TREATMENT OF COVID-19 IN CERTAIN HOSPITALIZED PATIENTS. https://www.fda.gov/media/136537/download
  6. US Food and Drug Administration (2020) FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF CHLOROQUINE PHOSPHATE SUPPLIED FROM THE STRATEGIC NATIONAL STOCKPILE FOR TREATMENT OF COVID-19 IN CERTAIN HOSPITALIZED PATIENTS. https://www.fda.gov/media/136535/download
  7. National Institutes of Health (NIH) (2020) Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://covid19treatmentguidelines.nih.gov/
  8. Mercuro NJ, Yen CF, Shim DJ, et al. (2020) "Risk of QT interval prolongation associated with the use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19)" JAMA Cardiol, May 1:e201834, epub ahead of print
  9. Bonow RO, Hernandez AF, Turakhia M (2020) "Hydroxychloroquine, coronavirus disease 2019, and QT prolongation." JAMA Cardiol, May 1, epub ahead of print
  10. Bessiere F, Roccia H, Deliniere A, et al. (2020) "Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit." JAMA Cardiol, May 1, epub ahead of print
  11. Saleh M, Gabriels J, ChangD, et al. (2020) "The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection." Circ Arrhythm Electrophysiol, Apr 29, epub ahead of print
  12. Javelot H, El-Hage W, Meyer G, Becker G, Michel B, Hingray C (2020) "COVID-19 and (hydroxy)chloroquine-azithromycin combination: should we take the risk for our patients?" Br J Clin Pharmacol, Apr 29, epub ahead of print
  13. Sacher F, Fauchier L, Boveda S, et al. (2020) "Use of drugs with potential cardiac effect in the setting of SARS-CoV-2 infection." Arch Cardiovasc Dis, Apr 24, epub ahead of print
  14. Smit C, Peeters MYM, van den Anker JN, Knibbe CAJ (2020) "Chloroquine for SARS-CoV-2: Implications of its unique pharmacokinetic and safety properties." Clin Pharmacokinet, Ar 18, epub ahead of print
  15. Roden DM, Harrington RA, Poppas A, Russo AM (2020) "Considerations for drug interactions on QTc in exploratory COVID-19 (Coroanvirus disease 2019) treatment." Heart Rhythm, Apr 14, epub ahead of print
  16. Sapp JL, Alqarawi W, MacIntyre CJ, et al. (2020) "Guidance on minimizing risk of drug-induced ventricular arrhythmia during treatment of COVID-19: A statement from the Canadian Heart Rhythm Society." Can J Cardiol, Apr 8, epub ahead of print
  17. Kapoor A, Pandurangi U, Arora V, et al. (2020) "Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society." Indian Pacing Electorphysiol J, Apr 8, epub ahead of print
  18. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ (2020) "Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19)" Mayo Clin Proc, Apr 7, epub ahead of print
  19. Borba MGS, Val FFA, Sampaio VS, et al. (2020) "Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 1 (SARS-CoV-2) infection: A randomized clinical trial." JAMA Netw Open, Apr 1, epub ahead of print
  20. mitra RL, Greenstein SA, Epstein lm (2020) "An algorithm for managing QT prolongation in coronavirus disease 2019 (COVID-19) patients treated with either chloroquine or hydroxychloroquine in conjunction with azithromycin; Possible benefits of intravenous lidocaine." HeartRythm Case Rep, Apr 1, epub ahead of print
  21. (2024) "Product Information. Hydroxychloroquine Sulfate (hydroxychloroquine)." Dr. Reddy's Laboratories Inc
  22. (2023) "Product Information. Plaquenil (hydroxychloroquine)." Sanofi-Aventis Canada Inc
  23. (2024) "Product Information. Quinoric (hydroxychloroquine)." Bristol Laboratories Ltd
  24. (2024) "Product Information. Hydroxychloroquine (GH) (hydroxychloroquine)." Generic Health Pty Ltd
  25. (2023) "Product Information. HIDROXICLOROQUINA RATIOPHARM (hidroxicloroquina)." RATIOPHARM ESPANA S.A.
  26. Zapata LV, Boyce RD, Chou E, et al. (2024) QTc Prolongation with the use of hydroxychloroquine and concomitant arrhythmogenic medications: A retrospective study using electronic health records data https://pmc.ncbi.nlm.nih.gov/articles/PMC9167427/
  27. (2022) "Product Information. Avloclor (chloroquine)." Alliance Pharmaceuticals Ltd
  28. (2024) "Product Information. Chloroquine Phosphate (chloroquine)." Rising Pharmaceuticals

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 (17)
  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
Moderate

hydroxychloroquine food

Applies to: hydroxychloroquine

GENERALLY AVOID: Theoretically, grapefruit and grapefruit juice may increase the plasma concentrations of hydroxychloroquine or chloroquine and the risk of toxicities such as QT interval prolongation and ventricular arrhythmias. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Following coadministration with cimetidine, a weak to moderate CYP450 3A4 inhibitor, a 2-fold increase in chloroquine exposure occurred. Since chloroquine and hydroxychloroquine have similar structures and metabolic elimination pathways, a similar interaction may be observed with hydroxychloroquine. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

ADJUST DOSING INTERVAL: Administration with food or milk may reduce the incidence of hydroxychloroquine-related gastrointestinal adverse effects.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during hydroxychloroquine or chloroquine therapy. Hydroxychloroquine should be administered with food or milk to reduce the occurrence of gastrointestinal upset.

References (5)
  1. (2024) "Product Information. Hydroxychloroquine Sulfate (hydroxychloroquine)." Dr. Reddy's Laboratories Inc
  2. (2023) "Product Information. Plaquenil (hydroxychloroquine)." Sanofi-Aventis Canada Inc
  3. (2024) "Product Information. Quinoric (hydroxychloroquine)." Bristol Laboratories Ltd
  4. (2024) "Product Information. Hydroxychloroquine (GH) (hydroxychloroquine)." Generic Health Pty Ltd
  5. (2023) "Product Information. HIDROXICLOROQUINA RATIOPHARM (hidroxicloroquina)." RATIOPHARM ESPANA S.A.

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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