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FAQs - Chloroquine and Hydroxychloroquine > What kind of monitoring should be done for people taking chloroquine or hydroxychloroquine for COVID-19?

What kind of monitoring should be done for people taking chloroquine or hydroxychloroquine for COVID-19?

posted on 7:13 PM, April 14, 2020
  • ECGs AND BASELINE LABORATORY STUDIES: For either chloroquine or hydroxychloroquine, a baseline ECG should be obtained prior to initiation of treatment, in addition to baseline renal and hepatic function, in order to assist in assessing potential risk of treatment.
  • CARDIAC MONITORING DURING TREATMENT: A baseline ECG should be obtained when using either drug, and monitoring “during treatment” is recommended. No specific timing interval is necessarily correct; this should be guided by the clinical scenario. Clinical signs and symptoms of cardiac dysfunction (such as cardiomyopathy) may increase the risk of cardiac dysfunction and/or dysrhythmia. Previous studies describe peak QT prolongation at peak serum concentration (Mzayek 2007, Pukrittayakamee 2014). For chloroquine, Tmax is expected at 2 hours after oral dosing; for hydroxychloroquine, peak concentrations are described between 2.4 – 3.74 hours. Note that due to distribution properties these pharmacokinetic parameters may not necessarily describe maximal cardiac concentrations of the drug. QTc intervals measured at steady-state drug concentration – estimated at 5 drug half-lives – would not be feasible due to the short treatment regimens for COVID-19 in relation to drug elimination half-lives: 5 to 50 days for chloroquine, and 7 to 50 days for hydroxychloroquine. (Micromedex)
  • SHOULD CHLOROQUINE OR HYDROXYCHLOROQUINE THERAPY BE STOPPED IF THE QTc INTERVAL IS PROLONGED? QTc prolongation > 60ms over baseline, or > 500ms absolute, is associated with increased risk of torsades de pointes (Trinkley 2013) and may necessitate cessation or withholding of therapy depending on estimated risk/benefit. When continuing therapy in the presence of borderline or increased QTc intervals, co-administration of other QT-prolonging drugs should be minimized and modifiable risk factors should be addressed, such as electrolyte abnormalities (potassium, magnesium, calcium) or drug-induced bradycardia. By way of perspective, prescribed treatment regimens for COVID-19 are more comparable to the daily malarial treatment regimens or dosing for rheumatoid arthritis or systemic lupus erythematosus than to once-weekly malarial prophylactic regimens. QTc prolongation in these settings has been described: chloroquine therapy for antimalarial purposes is described as increasing the QTc between 12-26 msec; (Ursing 2016) QTc prolongation in hydroxychloroquine therapy is described as 25 msec (range -66 - 143, Negoescu 2013). Some of these patients had multiple QTc interval prolonging risk factors. The American College of Cardiology has recently (March 29, 2020) posted a statement (https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19) with recommendations including the use of a dysrhythmia score (Tisdale score) to rank patients’ risk of drug-associated QTc prolongation.
  • CAN BLOOD CONCENTRATIONS OF CHLOROQUINE OR HYDROXYCHLOROQUINE BE USED TO GUIDE THERAPY? There is no specific guidance provided on the FDA EUA regarding use of therapeutic drug monitoring via blood concentration. This has not been described yet in the context of COVID-19. On a practical basis, most clinical laboratories do not have equipment to determine chloroquine or hydroxychloroquine concentrations, and most reference laboratories would not be able to provide results in a clinically relevant timeframe. While therapeutic measurements are available for these drugs in other prescribing situations as noted below, these are most appropriate for chronic therapy, not short-term therapy as anticipated if these drugs are used for COVID-19. In addition, steady state concentrations would not be achieved for weeks due to the long terminal half-lives of both drugs. As is noted under the drug-drug interactions FAQ, the prolonged elimination of chloroquine or hydroxychloroquine may therefore impact the kinetics of subsequent therapeutic drug administration, even after the chloroquine or hydroxychloroquine has been discontinued. As points of reference for situations where blood concentrations are available, therapeutic concentrations for other conditions include:
    • For chloroquine, therapeutic levels of 0.2-0.4mcg/mL are cited for Rheumatoid Arthritis treatment, and 10-20ng/mL for antimalarial purposes (Ette 1986).
    • For hydroxychloroquine, therapeutic levels (500-2000ng/mL) are cited for Systemic Lupus Erythematosus, and discussed for certain indications in rheumatologic conditions (Durcan 2015)

 

References:

Ette EI, Essien EE, Brown-Awala A. Pharmacokinetics of chloroquine: saliva and plasma levels relationship. Eur J Drug Metab Pharmacokinet 1986: 2:275-281.

Durcan L, Clarke WA et al. Hydroxychloroquine blood levels in Systemic Lupus Erythematosus: clarifying dosing controversies and improving adherence. J Rheumatol 2015;42(11): 2092-7.

Chloroquine. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/ . Updated April 8, 2020. [Accessed April 8, 2020].

Hydroxychloroquine. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/ . Updated April 8, 2020. [Accessed April 8, 2020].

Mzayek F, Deng H et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials 2007;2:e6.

Negoescu A, Thronback A, et al. Long QT and Hydroxychloroquine; a poorly recognized problem in rheumatology patients. Abstract: 2013 ACR/ARHP annual meeting. October 2013, San Diego, CA. 

Pukrittayakamee S, Tarning J et al. Pharmacokinetic interactions between Primaquine and Chloroquine. Antimicrobial Agents Chemother. 2014;58 (6); 3354-3359.

Trinkley K, Page RL. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Cur Med Research Opinion 2013;29 (12): 1719-1726.

Ursing J, Rombo L, et al. High-dose chloroquine for uncomplicated plasmodium falciparum malaria is well tolerated and causes similar QT interval prolongation as standard-dose chloroquine in children. Antimicrobial Agents Chemother 2020;64 (3): e01846-19.

U.S. Food and Drug Administration. EUA Chloroquine Phosphate Health Care Provider Fact Sheet, version date 4/3/2020. U.S. Food and Drug Administration. Silver Spring, MD. Retrieved from: https://www.fda.gov/media/136535/download [last accessed 4/9/2020]

U.S. Food and Drug Administration. EUA Hydroxychloroquine Sulfate Health Care Provider Fact Sheet, version date 4/3/2020. U.S. Food and Drug Administration. Silver Spring, MD. Retrieved from: https://www.fda.gov/media/136537/download [last accessed 4/9/2020]