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Remdesivir

Last Updated: July 24, 2020

Remdesivir is an intravenous (IV) investigational nucleotide prodrug of an adenosine analog. Remdesivir binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription. It has demonstrated in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 In a rhesus macaque model of SARS-CoV-2 infection, remdesivir treatment was initiated soon after inoculation; remdesivir-treated animals had lower virus levels in the lungs and less lung damage than the control animals.2

Remdesivir has been studied in several clinical trials for the treatment of COVID-19. The recommendations from the COVID-19 Treatment Guidelines Panel (the Panel) are based on the results of these studies.

Remdesivir is available through the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for people with severe COVID-19.

Recommendation for Prioritizing Limited Supplies of Remdesivir

  • Because remdesivir supplies are limited, the Panel recommends prioritizing remdesivir for use in hospitalized patients with COVID-19 who require supplemental oxygen but who do not require oxygen delivery through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) (BI).

Recommendation for Patients With Mild or Moderate COVID-19

  • There are insufficient data for the Panel to recommend either for or against the use of remdesivir in patients with mild or moderate COVID-19.

Recommendations for Patients With COVID-19 Who Require Supplemental Oxygen

For Patients Who Do Not Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or ECMO

  • The Panel recommends using remdesivir for 5 days or until hospital discharge, whichever comes first (AI).
  • If a patient who is on supplemental oxygen while receiving remdesivir progresses to requiring delivery of oxygen through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO, the course of remdesivir should be completed.

For Patients Who Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or ECMO

  • Because there is uncertainty regarding whether starting remdesivir confers clinical benefit in these groups of patients, the Panel cannot make a recommendation either for or against starting remdesivir.

Duration of Therapy for Patients Who Have Not Shown Clinical Improvement After 5 Days of Therapy

  • There are insufficient data on the optimal duration of remdesivir therapy for patients with COVID-19 who have not shown clinical improvement after 5 days of therapy. In this group, some experts extend the total remdesivir treatment duration to up to 10 days (CIII).

Rationale

The recommendations for remdesivir are largely based on data from a multinational, randomized, placebo-controlled trial (the Adaptive COVID-19 Treatment Trial [ACTT-1]). This trial included 1,063 hospitalized patients with COVID-19 and evidence of lower respiratory tract infection who received IV remdesivir or placebo for 10 days (or until hospital discharge, whichever came first). Participants who received remdesivir had a shorter time to clinical recovery than those who received placebo (median recovery time was 11 days vs. 15 days, respectively).3

For Patients Who Do Not Require Supplemental Oxygen

In the preliminary subgroup analyses of ACTT-1, there was no observed benefit for remdesivir in people with COVID-19 who did not require supplemental oxygen; however, the number of people in this category was relatively small. Remdesivir is being evaluated in another clinical trial for the treatment of patients with moderate COVID-19; complete data from this trial are expected soon.

For Patients Who Require Supplemental Oxygen But Do Not Require Oxygen Delivery Through a High-Flow Device, Noninvasive Ventilation, Invasive Mechanical Ventilation, or ECMO

The preliminary analysis of ACTT-1 also reported that the participants with the clearest evidence of clinical benefit from starting remdesivir were those who required supplemental oxygen but who did not require oxygen delivery through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO at baseline (n = 421). In this subgroup, those who received remdesivir had a shorter time to recovery than those who received placebo (recovery rate ratio 1.47; 95% CI, 1.17–1.84); in a post-hoc analysis of deaths by Day 14, remdesivir appeared to confer a survival benefit (HR for death 0.22; 95% CI, 0.08–0.58).

For Patients Who Require Oxygen Delivery Through a High-Flow Device or Noninvasive Ventilation

In patients who required delivery of oxygen through a high-flow device or noninvasive ventilation at baseline (n = 197), there was no observed difference in the time to recovery between the remdesivir and placebo groups (recovery rate ratio 1.20; 95% CI, 0.79–1.81). In the post-hoc analysis of deaths by Day 14, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 1.12; 95% CI, 0.53–2.38). However, because the trial was not powered to detect differences in outcomes within these subgroups, there is uncertainty as to the effect of remdesivir on the course of COVID-19 in these patients.

For Patients Who Require Invasive Mechanical Ventilation or ECMO

In participants who were on invasive mechanical ventilation or ECMO at baseline (n = 272), there was no observed difference in the time to recovery between the remdesivir and placebo groups (recovery rate ratio 0.95; 95% CI, 0.64–1.42). In the post-hoc analysis of deaths by Day 14, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 1.06; 95% CI, 0.59–1.92).

Overall, a review of the final data set, which included 28-day mortality, showed that this data set was consistent with the published preliminary data (the unpublished data was provided to the Panel by the ACTT-1 study team [written communication, July 2020]).

For patients with COVID-19 who required delivery of oxygen through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO, there was no observed difference between the remdesivir and placebo groups in the time to recovery or the mortality rate. However, because the trial was not powered to detect differences in outcomes within these subgroups, there is uncertainty as to whether starting remdesivir confers clinical benefit in these patients. For this reason, the Panel cannot make a recommendation either for or against starting remdesivir in these patients. Because the supply of remdesivir is limited, the Panel recommends prioritizing the drug for use in those for whom efficacy has been demonstrated (i.e., in hospitalized patients who require supplemental oxygen but who do not require oxygen delivery through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO).

Duration of Therapy

Data from a multinational, open-label trial of hospitalized patients with severe COVID-19 showed that remdesivir treatment for 5 or 10 days had similar clinical benefit.4 The optimal duration of therapy for patients who do not improve after 5 days of receiving remdesivir is unclear. In the absence of data, some experts consider extending the total treatment duration of remdesivir to up to 10 days in patients who do not improve after 5 days of remdesivir therapy.5

See Remdesivir: Selected Clinical Data for more information.

Monitoring, Adverse Effects, and Drug-Drug Interactions

Remdesivir can cause gastrointestinal symptoms (e.g., nausea, vomiting), elevated transaminase levels, and an increase in prothrombin time (without a change in the international normalized ratio).

Clinical drug-drug interaction studies of remdesivir have not been conducted. Remdesivir levels are unlikely to be substantially altered by cytochrome P450 (CYP) 2C8, CYP2D6, or CYP3A4 enzymes, or by P-glycoprotein (P-gp) or organic anion-transporting polypeptide (OATP) drug transporters.

Remdesivir may be administered with weak to moderate inducers or with strong inhibitors of CYP450, OATP, or P-gp. Strong induction may modestly reduce remdesivir levels. The clinical relevance of lower remdesivir levels is unknown.6 Based on information provided by Gilead Sciences (written communication, July 2020), the use of remdesivir with drugs that are strong inducers (e.g., rifampin) is not recommended.

Minimal to no reduction in remdesivir exposure is expected when remdesivir is coadministered with dexamethasone, according to information provided by Gilead Sciences (written communication, July 2020). Chloroquine or hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.7

Because the remdesivir formulation contains renally cleared sulfobutylether-beta-cyclodextrin sodium, patients with an estimated glomerular filtration rate (eGFR) of <50 mL/min are excluded from some clinical trials (some trials have an eGFR cutoff of <30 mL/min).

Considerations in Pregnancy

  • Use remdesivir in pregnant patients only when the potential benefit justifies the potential risk to the mother and the fetus.5
  • The safety and effectiveness of remdesivir for the treatment of COVID-19 have not been evaluated in pregnant patients. Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.
  • Remdesivir is available through the FDA EUA for adults and children and through compassionate use programs for pregnant women and children with COVID-19.
  • Ninety-eight female participants received remdesivir as part of a randomized controlled trial for the treatment of Ebola virus infection; six of these participants had a positive pregnancy test. The obstetric and neonatal outcomes were not reported in the study.8

Considerations in Children

  • The safety and effectiveness of remdesivir for the treatment of COVID-19 have not been evaluated in pediatric patients.
  • Remdesivir is available through an FDA EUA for adults and children and through compassionate use programs for children with COVID-19. A clinical trial is currently evaluating the pharmacokinetics of remdesivir in children (ClinicalTrials.gov identifier NCT04431453).
  • In the same randomized controlled trial for the treatment of Ebola virus infection discussed above, 41 pediatric patients received remdesivir. These patients included neonates and children aged <18 years.8 The safety and clinical outcomes for children were not reported separately in the published results for the trial. One neonate received remdesivir for the treatment of vertically transmitted Ebola virus infection and recovered.9

Clinical Trials

Multiple clinical trials that are evaluating remdesivir are currently underway or in development. Please check ClinicalTrials.gov for the latest information.

References

  1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
  2. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32516797.
  3. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32445440/.
  4. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919.
  5. Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of Veklury (remdesivir). 2020. Available at: https://www.fda.gov/media/137566/download. Accessed August 25, 2020.
  6. Gilead Sciences. Remdesivir (GS-5734) investigator’s brochure. Edition 5. February 21, 2020.
  7. Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-interaction-may-reduce. Accessed August 25, 2020.
  8. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31774950.
  9. Dornemann J, Burzio C, Ronsse A, et al. First newborn baby to receive experimental therapies survives Ebola virus disease. J Infect Dis. 2017;215(2):171-174. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28073857.