Hydroxychloroquine and Potential Drug Interactions in Older Adults.

Dear Editor,

Hydroxychloroquine has in vitro activity against severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other coronaviruses. It is currently under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and treatment of patients with mild, moderate, and severe coronavirus disease 2019 (COVID-19). There are no currently available data from Randomized Clinical Trials to inform clinical guidance on the use, dosing, interactions, or duration of hydroxychloroquine for prophylaxis or treatment of COVID-19 infection. Recently, Gautret and cols have reported that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin (drug interaction). Preliminary results have confirmed that viral positivity in respiratory secretions was significantly decreased at day 6 in hydroxychloroquine treated COVID-19 patients versus those with supportive care, supporting the current choice of hydroxychloroquine as first-line treatment.2, 3 Despite of limited studies, nowadays, hydroxychloroquine is recommended for hospitalized patients confirmed COVID-19 patients, with mild-to moderate disease, age >65 years and/or underlying end organ dysfunction (lung, heart, liver, etc.), diabetes, coronaropathy, chronic obstructive pulmonary disease, arterial hypertension or severe disease.

General guiding principles are based on these considerations, however, the therapeutic window is quite narrow (cardiotoxicity/arrhythmia), requiring caution for use at higher cumulative dosages, taking also into account that therapy will be required mostly in older patients and/or in case of severe disease. In addition, the slow elimination and the variable pharmacokinetics of hydroxychloroquine frequently lead to delayed actions and a variable clinical response. It is possible that this variability arises partly from drug-drug interactions (DDIs) and genetic differences in the capacity to metabolize hydroxychloroquine, as has been shown for many other drugs.

Contradictory results of the inhibitory effect of HCQ on cytochrome-P450 isoenzyme 2D6 (CYP2D6) activity in vivo have been published in humans. Generally, all drugs metabolized by CYP2D6 may inhibit each other's metabolism. Because of the great variety of drugs metabolized by CYP2D6 (antiarrhythmics, antihypertensives, β-adrenoceptor antagonists, monoamine oxidase inhibitors, morphine derivatives, antipsychotics and antidepressants), characterization of potential interacting drugs affecting the activity of this enzyme is clinically important and can improve the safety of drug treatment. On the other hand, the P-glycoprotein (P-gp) transport system is an efflux transporter found most notably in gut luminal and blood-brain barrier endothelial cells. Hydroxychloroquine is an inhibitor of this transporter/pump presenting also as a possible interaction.

Keeping in mind that hydroxychloroquine use is recommended in elderly patients, the number of DDIs should be monitored. Polypharmacy prevalence in elderly people is about 50% and is associated with an increased risk of DDIs, which impact on patient health and effectiveness of drugs including hydroxychloroquine. In addition, combinations of hydroxychloroquine with other QT-prolonging medications can increase the risk of developing a toxic arrhythmia such as ventricular fibrillation.7, 8, 9, 10

We have developed a retrospective analytical study about most common medical prescription in older adults and potential drug interactions with hydroxychloroquine. We have analyzed chronic medication data about 377 older adults recruited between October 2016 and May 2019 in the North of Spain (Soria) for previous studies. Potential drug interactions with hydroxychloroquine were identified and classified according to information published by Liverpool Drug Interactions Group or Drugbank database. Data were analyzed using relative (percentage) frequencies of the classes of each variable to characterize the sample studied.

We have checked forty-seven drugs and elaborated a table of most common drugs in the aforementioned population and should be monitored in the patients treated with hydroxychloroquine. Of total, we have included information about twelve DDIs (See Table 1 ). Following recommendations, five drugs should not be coadministered with hydroxychloroquine and seven may require close monitoring. Rifampicin, phenobarbital, phenytoin and carbamazepin could reduce the exposure of hydroxychloroquine. Anticonvulsans, carbamazepine, phenytoin, phenobarbital induce many cytochrome-P450 and glucuronyl transferase enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes with the attendant risk of related adverse effects.12, 13 We have only found one study about hydroxychloroquine and rifampicin interactions, a case report about a women who due to the drug interaction, suffered from toxicoderma and causing a systemic autoimmune disease due to the drug interaction.

Table 1

Main Potential Hydroxychloroquine Drug Interactions in Older Adults.

Drug	ATC	Effects*	Should not Be Coadministered	Potential Interaction: May Require Close Monitoring, Alteration of Drug Dosage or Timing of Administration	Potential Interaction Likely to Be of Weak Intensity. Additional Action/monitoring or Dosage Adjustment Is Unlikely to Be Required	Altered QT/PR	Frequency (%)
Amiodarone	C01BD01	↑	X			X	3.27
Rifampicin	J04AB02	⇓	X				3.4
Phenobarbital	N03AA02	⇓	X				17.4
Phenytoin	N03AB02	⇓	X				1.4
Carbamazepine	N03AF01	⇓	X				1.4
Digoxin	C01AA05	↑		X			1.8
Citalopram	N06AB04	↔		X		X	0.4
Dabigatran	B01AE07	↑		X			5.4
Hydroxyzine	N05BB51	↔		X		X	2.18
Nortriptyline	N06AA10	↑		X		X	0.8
Salmeterol	R03AC12	↔		X		X	0.36
Apixaban	B01AF02	↑			X		2.9

Abbreviations: ATC, Anatomical Therapeutic Chemical code.

↑potencial increased exposure of the comedication.

↓potencialdecreased exposure of the comedication.

⇑potencial increased exposure of coronavirus disease 2019 drug.

⇓potencialdecreased exposure of coronavirus disease 2019 drug.

↔ No significant effect.

On the other hand, amiodarone coadministered with hydroxychloroquine could increase the effect of the antiarrhythmic medication. Among its adverse effects, pulmonary toxicity causing interstitial pneumonitis is the most dangerous without a causal treatment option. Moreover, Miranda-Aquino reported that the long QT syndrome was present when amiodarone and hydroxychloroquine interacted.

Seven consumed drugs in older adults could cause potential interactions with hydroxychloroquine which may require close monitoring, alteration of drug dosage or timing of administration. Hydroxychloroquine coadministered with digoxin, dabigatran, nortryptiline or apixaban could increase the effect of the comedication, so similar to an overdose. Dabigatran and apixaban are direct oral anticoagulants, substrates of P-gp and inhibitors of this enzyme that may increase bleeding risk. The dose of the oral anticoagulants could be reduced to compensate for the potential interaction. Ido Leden and cols. observed that the digoxin concentration in plasma was reduced in spite of increased administration when hydroxychloroquine was coadministered. In addition, citalopram, hydroxyzine, nortriptyline, salmeterol may require close monitoring, alteration of drug dosage or timing of administration due to their relationship with QT prolongation associated with DDIs in older adults.19, 20

Despite of limitations, the selection criteria used to classify drugs aimed to be useful in the screening process for potential DDIs during prescribing hydroxychloroquine in older adults. There are numerous hydroxychloroquine drug interactions that are currently known and that are potential, use of these agents with other drug therapy requires consideration for patient safety. Elderly patients are considered to be at increased risk for a more frequent and more severe COVID-19 clinical course, clinicians should be especially cognizant of these potential DDIs.

In conclusion, concomitant administration of hydroxychloroquine increases the bioavailability of several drugs in older adults and could getting worse this situation. Medication errors are known to compromise patient safety. The clinical significance of the interaction of hydroxychloroquine with several drugs and as well as the potential interactions of hydroxychloroquine with other substrates of CYP2D6 would need to be evaluated.