In this episode, I’ll discuss evaluating the unknown QTc/torsades risk of hydroxychloroquine and azithromycin.
In a small case-control study, the combination of hydroxychloroquine and azithromycin appeared to reduce nasopharyngeal carriage of the COVID-19 virus. In vitro studies also suggest that hydroxychloroquine would have efficacy against this virus.
While the French study is not without its limitations, and the level of evidence is low, there will no doubt be a great desire among clinicians to combine these two medications.
In the study, 6 of the patients had hydroxychloroquine 200 mg po three times daily for 10 days combined with azithromycin 500 mg on day one followed by 250 mg po daily for an additional 4 days.
The authors stated this was done under “daily electrocardiogram control.” No data on the QTc interval on these 6 patients was provided.
The actual QTc risk of this combination is unknown, so clinicians wishing to make a risk:benefit analysis must look to other sources of information. I am not able to find any data on the QTc related effects of combining hydroxychloroquine and azithromycin. I have contacted the corresponding author of the French study requesting QTc data on the 6 patients who received hydroxychloroquine+azithromycin and will post it here with permission if I receive it.
It is important to remember that the QTc is just a number on a piece of paper. The development of torsades is the clinically relevant outcome we are trying to avoid; just because a drug interaction may prolong the QTc does not mean that the patient will experience torsades.
Torsades has been reported with azithromycin and hydroxychloroquine separately, although the occurrence of torsades is likely rare with either medication.
Despite hydroxychloroquine being considered a safer version of chloroquine, there is considerable data on the combination of chloroquine and azithromycin.
Prescribing information for azithromycin describes a study where chloroquine was combined with azithromycin. The QTc was increased in a dose-dependent manner but the maximum mean increase was only 14 milliseconds.
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
The combination of chloroquine and azithromycin has also been used for protection against malaria and sexually transmitted infections in pregnancy and malaria resistant to chloroquine alone. QTc data does not seem to be available in these studies, likely because of the limited resource and outpatient treatment nature of the study populations.
In the absence of clinical data, my preferred reference for evaluating QTc risk is Hansten and Horn’s Top 100 Drug Interaction Handbook (this is an Amazon affiliate link). This book categorizes medications as to whether they prolong the QTc at therapeutic levels or at elevated levels.
Neither hydroxychloroquine or azithromycin are listed in this reference as medications that may produce a clinically relevant prolongation of the QTc at therapeutic OR elevated concentrations. This suggests that the QTc/torsades risk with this combination would be expected to be very low.
Even if both hydroxychloroquine and azithromycin were considered to produce a clinically relevant prolongation of the QTc at elevated concentrations, there is no pharmacokinetic interaction between the two medications. This would place the combination in risk management class 3 at the highest, which is often handled by considering QTc monitoring instead of changing therapy.
Patient-specific risk factors that increase the chance of torsades may warrant a higher degree of monitoring or even the use of hydroxychloroquine alone, but these decisions can only be made on a case-by-case basis.
The risk factors for torsades are both modifiable and non-modifiable.
Modifiable risk factors:
1. Hypomagnesemia
2. Hypokalemia
3. Bradycardia
Non-modifiable risk factors:
1. Hypertrophy
2. Heart failure
3. Female gender
4. Advanced age
5. QTc over 500 msec at baseline
Although the individual risk to a patient for QTc prolongation and torsades might be judged to be low with this combination, the scale at which we are likely going to see hydroxychloroquine and azithromycin used together will mean we are almost certain to see cases of torsades.
Each clinician will come to their own interpretation of the risk vs benefit of the combination of hydroxychloroquine and azithromycin. My personal interpretation is that while the benefits are largely unknown and based on in vitro data and a small case-control study, the risk of torsades is likely very low for most patients. As resources allow in inpatient settings, I would consider daily ECGs in patients receiving this combination especially if other risk factors for torsades are present. ECG monitoring is not feasible or realistic in outpatient settings, and in the setting of low-risk patients I would consider unmonitored outpatient use no different than when azithromycin or hydroxychloroquine are co-prescribed with other medications that have rare reports of QTc prolongation or torsades.
To those APPE students whose hospital rotation has been disrupted by recent events: One way I’d like to help is by providing free access to 8 essential training videos on topics that I discuss with students on my rotation. Get free 14-day access by going to pharmacyjoe.com/virtual.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
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