The novel SARS-CoV-2 virus, cause of the COVID-19 pandemic, continues to plague the world. Despite prior signs of slowing infection rates in many countries, the number of global cases is approaching 10 million, and large numbers of new cases continue to be reported in the US, India, Brazil, and many other countries.

While the world eagerly awaits an effective vaccine, the current focus is on drug treatments. One such agent, the corticosteroid dexamethasone, has garnered considerable interest due to favourable findings from a recent study out of the UK. Remdesivir, interleukin-6 pathway inhibitors, hydroxychloroquine, and several other agents have also been described as possibly effective treatments. Unfortunately, patients requiring these treatments are often seriously ill and receiving multiple medications, a scenario that too often leads to serious drug interactions. This article discusses drug interaction considerations for these medications to help clinicians either avoid or to minimise the consequence of any such interactions to limit the risk of adverse outcomes.

Dexamethasone

A corticosteroid with numerous anti-inflammatory and immunoregulatory actions that may account for its beneficial effects in patients with COVID-19, dexamethasone's interaction considerations are relatively well-known. Potent CYP3A4 inducers or inhibitors may substantially alter dexamethasone concentrations, resulting in either diminished effects or a greater risk of toxicities.

Dexamethasone itself is a weak inducer of CYP3A4, with most data showing that it reduces the exposure of sensitive CYP3A4 substrates by approximately 20%. Despite this weak induction, the prescribing information for many drugs classify dexamethasone as a moderate CYP3A4 inducer, with some recommending avoidance of dexamethasone or dose adjustments with concurrent use.

Corticosteroids (high-dose, systemic use) and non-depolarising neuromuscular blocking agents each have an adverse effect on neuromuscular transmission. This combination may cause prolonged muscle weakness, neuropathy, myopathy, and/or paralysis. This has been observed most commonly in the ICU setting, particularly in patients requiring high-dose intravenous steroids and mechanical ventilation. Corticosteroids doses of more than 2mg/kg or 20mg/day of prednisone (for persons over 10kg) administered for two or more weeks are considered sufficiently immunosuppressive to warrant concerns about possibly reduced safety and effectiveness of vaccines, and particularly live organism vaccines.

The dexamethasone dose of 6mg daily recommended for COVID 19 treatment is equivalent to approximately 40mg/day of prednisone, but the recommended duration for COVID-19 is no more than 10 days, so the degree to which these immunosuppressive concerns are relevant is uncertain and likely to vary by patient. Corticosteroids also have a high risk of causing or worsening hyperglycaemia and may reduce the efficacy of antidiabetic agents.

Remdesivir

Remdesivir (GS-5734) is an investigational nucleotide analogue that has been made available in the US under an emergency use authorisation (EUA) to treat COVID-19 in adults and children hospitalised with severe disease.

One recent update to its EUA is an added warning about a potential drug interaction with hydroxychloroquine and chloroquine based on in-vitro data suggesting that chloroquine may antagonise the intracellular activation and antiviral activity of remdesivir. Concurrent use of remdesivir with either chloroquine or hydroxychloroquine is not recommended.

Most other drug interaction data is limited to in-vitro data. Remdesivir appears to be a substrate for the drug metabolising enzymes CYP2C8, CYP2D6, and CYP3A4, as well as a substrate for organic anion transporting polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters.

Additionally, remdesivir has been shown in-vitro to be capable of inhibiting CYP3A4, OATP1B1/1B3, bile salt export pump (BSEP), multidrug resistance-associated protein-4 (MRP4), and sodium/bile acid cotransporter (NTCP).

One case report describes a possible interaction with amiodarone resulting in hepatotoxicity that quickly resolved after remdesivir discontinuation. The authors attributed this to amiodarone inhibition of remdesivir efflux by P-gp, though whether this represents an interaction, an adverse reaction, or a complication of COVID-19 is uncertain. However, due to the lack of drug interaction studies in humans, such pharmacokinetic interactions cannot be completely ruled out, and it seems prudent to minimize the concurrent use of any nonessential medications whenever possible.

Interleukin-6 Pathway Inhibitors

Interleukin-6 (IL-6) pathway inhibitors such as tocilizumab, sarilumab and siltuximab are being studied for their ability to limit the cytokine response seen in some patients with COVID-19.

One unique drug interaction consideration with these drugs is that they may increase drug metabolism. Inflammation itself can impair hepatic drug metabolism, so drugs that substantially reduce systemic inflammation could cause a relative increase in drug metabolism.

Indeed, studies of IL-6 inhibitors have reported 36% to 57% reductions in exposure to some CYP3A4 substrates following just one dose. Exposure to CYP2D6 and CYP2C19 substrates has been reduced by 5% to 28%, respectively. Since these decreases are thought to represent a remediation of ongoing cytokine-associated effects, it is unclear if these effects would apply to all disease states – including COVID-19.  Additionally, these drugs impair immune function to such a degree that live vaccines should not be given to patients who are being treated with an IL-6 pathway inhibitor.

Hydroxychloroquine

The role of hydroxychloroquine in treatment of COVID-19 has become less clear with the removal of the EUA for its use in COVID-19 infections by the US FDA.

In addition to its interaction with remdesivir, the major drug interaction concern with hydroxychloroquine is its ability to prolong the QT interval, possibly increasing the risk for arrhythmias, a risk that may be greater in patients being treated for COVID-19.

There is little published data supporting significant QT prolongation with hydroxychloroquine when used for conditions other than COVID-19, mostly consisting of case reports in patients with other risk factors. However, publications have described potential cardiac risks of hydroxychloroquine in patients with COVID-19, particularly when combined with azithromycin, which itself is categorised as a moderate risk QT-prolonging drug.

Guidelines recommend that patients with COVID-19 being treated with hydroxychloroquine discontinue any non-critical drugs that can prolong the QT interval and receive close monitoring for significant QT prolongation, particularly when used with other QT-prolonging agents.

Hydroxychloroquine can also significantly reduce blood glucose concentrations, which could be a concern for patients receiving other blood glucose-lowering medications. This has been reported in both diabetic and non-diabetic patients, and hydroxychloroquine labeling states that patients should be warned about this risk and signs/symptoms of hypoglycaemia.

Other potential treatments

Anakinra

An IL-1 receptor antagonist, anakinra causes notable immunosuppression, raising concerns about the safety and effectiveness of vaccines, as well as with concomitant use of other immunosuppressants.

Baricitinib

Baricitinib is a Janus Kinase inhibitor with anti-inflammatory actions. The drug is a substrate of OAT3, and use with potent OAT3 inhibitors like probenecid may significantly increase baricitinib exposure. Baricitinib dose reductions are recommended if used with probenecid. Additionally, like anakinra, it has immunosuppressive effects and associated interaction concerns regarding other immunosuppressants and live vaccines.

Chloroquine

Chloroquine should not be used with remdesivir and also has the potential to cause dangerous QT interval prolongation (with more clinical evidence of harm than is available for hydroxychloroquine). Chloroquine also has been shown to lower blood glucose, similar to the effect seen with hydroxychloroquine.

Colchicine

Significant drug interactions exist, with reports of gastrointestinal symptoms, haematologic abnormalities, neuropathies, and even death, when colchicine was combined with inhibitors of CYP3A4 and P-gp. Some combinations require dose adjustment while others are contraindicated, especially in patients with diminished kidney or liver function. Additionally, use of colchicine with statins or fibrates increases the risk for muscle toxicities, including rhabdomyolysis.

Convalescent plasma; anti-COVID-19 human or equine antibodies

Immunoglobulins have very few drug interactions, so anti-COVID-19 antibodies from recovered patients do not have significant drug interaction concerns. However, because several different antibodies are often present in immunoglobin products or plasma, such antibodies may inactivate live vaccines and diminish vaccine effectiveness.

Darunavir/cobicistat; Lopinavir/ritonavir

These anti-HIV protease inhibitors have many significant drug interaction concerns, primarily related to their ability to strongly inhibit CYP3A4 and drug transporters such as P-gp, BCRP, and OATP1B1.  These medications are also substrates for CYP3A4, so use with strong enzyme inducers such as the rifamycins or enzyme-inducing antiepileptic drugs may reduce the concentrations and effectiveness of these protease inhibitors.

Favipiravir

Most drug interaction concerns with the RNA polymerase inhibitor favipiravir are of uncertain clinical significance. One case report describes significant QT-prolongation, but the patient had several other risk factors for QT interval prolongation raising important questions about the role of favipiravir. Additionally, a single-dose controlled study reported no significant QT prolongation.  Favipiravir is also a weak CYP2C8 inhibitor, but significant interactions are unlikely.

Interferons

Several different interferons have been mentioned as possible treatments based on their in-vitro activity against SARA-CoV and MERS-CoV. Interferons have been associated with increased hematologic and other side effects when combined with zidovudine, and alpha interferons are both potentially myelosuppressive and weak CYP1A2 inhibitors. Interferons have relatively few other significant drug interaction concerns.

Umifenovir

Umifenovir (also widely referred to in publications as Arbidol) appears to inhibit viral entry but may also have other antiviral actions. Umifenovir is a substrate for CYP3A4 and FMO3 in vitro, suggesting that use with CYP3A4 inhibitors and inducers may lead to potentially significant decreases or increases in umifenovir exposure.

Drug treatment of COVID-19 has changed throughout this pandemic and will continue to evolve as additional data emerges. As shown by the new warning about the use of remdesivir with hydroxychloroquine or chloroquine, our understanding of the drug interaction potential with these medications will likewise continue to grow. At present, however, caution and close monitoring is advisable when adding or discontinuing any medication, and clinicians are encouraged to report suspected interactions that they observe involving these medications.

Dr Daniel S. Streetman is the manager of referential content in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health.

Dr. Carrie W. Nemerovski is a senior clinical content specialist in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health.