In this article, an infectious diseases pharmacist discusses five things to know about hydroxychloroquine (HCQ, Plaquenil).
Authored By: Timothy P. Gauthier, Pharm.D., BCPS
Last updated: 19 April 2020
Hydroxychloroquine (HCQ, Plaquenil) is a 4-aminoqunoline compound that is FDA-approved for the treatment of acute and chronic rheumatoid arthritis in adults, chronic discoid lupus erythematosus or systemic lupus erythematosus in adults, and uncomplicated malaria caused by Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, or Plasmodium vivax. The first approval of hydroxychloroquine listed on the FDA website is 1988.
As an infectious diseases pharmacist for the last 10+ years primarily focused on inpatient adults in the United States, I have rarely dealt with hydroxychloroquine as an anti-infective agent. That has of course changed now that the COVID-19 pandemic is having a massive impact locally and across the globe. Hydroxychloroquine has of course emerged as an important potential therapy and so I have been learning a lot about it as of late. With the goal of sharing some of the key things to know about hydroxychloroquine, this article was composed.
Issues with drug shortages, hoarding, and the price of hydroxychloroquine are not discussed here. Note that there is much to know about hydroxychloroquine and this is by no means an all-inclusive list. Also note that there are no FDA-approved medications for treatment of COVID-19 and this article does not endorse the use of hydroxychloroquine for COVID-19. These caveats considered, here are my top five things to know about hydroxychloroquine.
1. Hydroxychloroquine is a prescription medication that should only be taken under the supervision of a licensed healthcare prescriber
In today’s climate where people with little to no legitimate healthcare training or understanding of medical literature are endorsing wide-spread use of hydroxychloroquine, it seems prudent to start out with this point. There is monitoring that should be strongly considered prior to taking hydroxychloroquine and consideration should be given for factors such as comorbid conditions and potential drug-drug interactions.
To minimize the risk of toxicity, hydroxychloroquine (and any drug for that matter) should be used at the lowest effective dose and for the shortest necessary duration. Take note that with a half-life of up to 50 days, even a short course of hydroxychloroquine can lead to a prolonged period of exposure.
2. Hydroxychloroquine appears to have in vitro activity versus SARS-CoV-2 (the cause of COVID-19)
It has been reported that both chloroquine and hydroxychloroquine have activity versus SARS-CoV-2. Researchers investigating this activity in Vero cells (i.e., kidney epithelial cells from monkeys) infected with SARS-CoV-2 reported hydroxychloroquine was more active than chloroquine against SARS-CoV-2 in vitro, with an EC50 of 0.27 μM. EC50 stands for effective concentration 50%, meaning the concentration of a drug that provides half of the maximal response. Since hydroxychloroquine accumulates in lung tissues and potentially effective concentrations are achievable in humans at rational doses, the authors speculated that hydroxychloroquine could be an option for trading COVID-19 in vivo.
While it is great news to see evidence of anti-viral activity, it should be noted that in vitro activity (i.e., something found in a lab) does not always mean in vivo clinical utility (i.e., it may not be effective for treating humans with disease caused by this pathogen). Which brings us to our next point…
3. It is unclear if hydroxychloroquine has clinical utility for treating preventing COVID-19 in vivo
To date there are no adequately powered randomized controlled trials published to inform us on the utility of hydroxychloroquine for treating humans with COVID-19. There are only several hypothesis-generating publications with small sample sizes reporting on clinical outcomes of COVID-19 patients given hydroxychloroquine from which no firm conclusions can be drawn about it’s effectiveness.
There are several article investigating this topic that are available through preprint and have not undergone certification via peer review. As stated on the pre-print articles, it is not appropriate to be using these to guide clinical practice and pre-prints have not been vetted for adequacy via peer review.
The Infectious Diseases Society of America COVID-19 guideline and the Society of Critical Care Medicine COVID-19 guideline does not recommend hydroxychloroquine for COVID-19 outside a clinical trial. The American Thoracic Society (ATS) COVID-19 guideline makes no suggestion for or against hydroxychloroquine for (1) patients with COVID-19 well enough to be managed as outpatients or (2) hospitalized patients with COVID-19 who have no evidence of pneumonia. The ATS does suggest hydroxychloroquine be used on a case-by-case basis for patients who are hospitalized with COVID-19 and have evidence of pneumonia, although this comes with several caveats that they list in their document.
At this time the experts do not all agree on if or when to use hydroxychloroquine for COVID-19. We are also not sure about the best dose of hydroxychloroquine to use or whether it has a role for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). We need vetted and good quality data to guide us (which is hopefully coming out soon). In the meantime many clinicians are weighing the risk:benefit ratio in each specific patient case. The topic of risk brings me to the next section…
4. Hydroxychloroquine has been associated with cardiac toxicity
An article published in 2007 examining 85 outpatient without established cardiac disease on hydroxychloroquine for at least 1 year found these patients had PR intervals, QTc intervals, and heart rates consistent with the average person. A systematic review investigating cardiac complications of hydroxychloroquine published in 2018 was unable to quantify the risk due to the lack of observational studies and randomized controlled trials.
Hydroxychloroquine blocks the KCHH2-encoded hERG/Kv11.1 potassium channel and can potentially cause QTc prolongation that could in turn lead to torsades de pointes or drug induced sudden cardiac death. To this point a paper published just last week included data from the FDA Adverse Events Reporting System and found 222 post-marketing events of hydoxychloroquine causing ventricular tachycardia, ventricular fibrillation, torsades de pointes, or long QT syndrome. There were an additional 105 events of cardiac arrest identified.
The American College of Cardiology has released a statement related to the risk of cardiac toxicity related to hydroxychloroquine and suggests utilizing the Tisdale score to assist in stratifying risk. Two key modifiable risk factors are concomitant QT prolonging medications and electrolyte management. There is also a new article out co-authored by Dr. Tisdale (available here) which discusses this topic.
5. Hydroxychloroquine is very similar to chloroquine, but may be better tolerated
Chloroquine has been around for over 70 years (first FDA approved in 1948), so there is much more clinical experience with it as compared to hydroxychloroquine. Hydroxychloroquine is the hydroxy-analog of chloroquine. In general the two drugs have much in common, including spectrum of activity and a long half-life. They are also structurally similar, although an N-hydroxyethyl on hydroxychloroquine makes it more soluble than chloroquine.
Image sources: FDA Package Inserts
As you might imagine dosing is different for the two drugs. The major difference I have found reported between the two is that hydroxychloroquine has a better safety profile than chloroquine. In particular ocular toxicity appears to be more common with chloroquine. This article contrasts the drugs in the context of COVID-19.
ADDITIONAL REFERENCES & READINGS
Hydroxychloroquine Package Insert
Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients
Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial
Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
Hydroxychloroquine and chloroquine FDA Emergency Use Authorization
Could chloroquine /hydroxychloroquine be harmful in Coronavirus Disease 2019 (COVID-19) treatment?
Chloroquine and Hydroxychloroquine in the Era of SARS – CoV2: Caution on Their Cardiac Toxicity
Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19
Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH‐Deficient Patients
DISCLAIMER: The views expressed in this article represent that of the author and do not necessarily reflect the position or policy of any previous, current, or potential future employers or other organizations in which he serves.
