INDICATIONS

FORMS

*Prices represent the specified cost per unit and "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Hospitalized Patients (typically 5-day course)

200 mg IV once, followed by 100 mg IV q24h for 4 days (duration can be extended for additional 5 days if no clinical response) or 10 days for patients requiring mechanical ventilation and/or ECMO.

• In an open-label study, serious adverse events were observed at a higher rate in patients receiving 10-day treatment compared to 5-day treatment. At the same time, there was no significant difference in the clinical outcomes in patients who were not on ECMO or mechanical ventilation.
• Most patients hospitalized for COVID-19 pneumonia should also receive RDV in conjunction with dexamethasone. See the COVID-19 module for additional details on management.

Mild-Moderate COVID-19 (usually ambulatory patients, 3-day course)

200 mg IV once, followed by 100mg IV q24h for 2 days

Administration instructions: Infuse each dose over 30 to 120 minutes in total volume up to 250 ml of 0.9% normal saline.

Required labs: All patients must have creatinine clearance calculated and liver enzymes obtained before initiation of therapy.

• Daily LFT monitoring is also required.
• Remdesivir should not be initiated in patients with ALT ≥ 10 times the upper limit of normal at baseline.

ADULT RENAL DOSING

PEDIATRIC DOSING

ADVERSE DRUG REACTIONS

DRUG INTERACTIONS

• In vitro, remdesivir is a substrate of CYP2C8, CYP2D6, and CYP3A4; substrate of organic anion transporting polypeptides 1B1 (OAPT1B1); and substrate of P-glycoprotein (P- gp) transporters. It is also an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP.
  • Experts do not expect a significant impact on remdesivir concentrations.
• Chloroquine or hydroxychloroquine
  • Coadministration is not recommended based on tissue culture data displaying potential antagonism, which may lead to a decrease in the antiviral activity of RDV.

SPECTRUM

Remdesivir showed in vitro activity against SARS-CoV-2 in animal models and in vitro and in vivo activity against MERS-CoV and SARS-CoV-1. EC₅₀ for SARS-CoV2 was 0.77 μM in one in vitro study.

RESISTANCE

No clinical data are available on the development of SARS-CoV-2 resistance to remdesivir.

PHARMACOLOGY

COMMENTS

• Remdesivir is approved for treating coronavirus disease 2019 (COVID-19), requiring hospitalization in adult and pediatric patients (12 years of age and older and who weigh at least 40kg).
  
  • There are two formulations: solution formulation and lyophilized powder formulation.
• The PINETREE trial supports the use of remdesivir 3-day therapy based on a study of unvaccinated, non-hospitalized patients with less than 7 days of symptoms and at least one risk factor (age ≥ 60 yrs, obesity, hypertension, cardiovascular disease, cerebrovascular disease, diabetes, immune compromise, chronic kidney or liver disease, current cancer or sickle cell disease) for progression to severe disease. Remdesivir achieved an 87% reduction in risk for hospitalization or death within 28d compared to placebo.
• GFR assessment is no longer required before dosing RDV as now FDA-approved regardless of renal status.

COVID-19

• The efficacy of remdesivir has been evaluated in two randomized clinical trials. Preliminary results of the largest RTC (N=1059), NIAID ACTT-1[2], suggest a shorter time (by 5 days) to recovery in patients receiving remdesivir compared to placebo (median time, 10 vs. 15 days; HR 1.32; 95% CI 1.12 to 1.55, p< 0.001).
  • There was no significant difference in mortality between remdesivir and placebo (7.1% vs. 11.9%; HR for death, 0.70; 95% CI, 0.47 to 1.04).
  • The median time from symptom onset to randomization was 9 days.
• In a second double-blind, placebo-controlled clinical trial from China that included hospitalized patients with severe COVID-19 pneumonia, no difference in time to clinical improvement was observed in patients receiving remdesivir compared to placebo.
  • The median time to start the study drug from symptom onset was 10 days. Late administration of the drug could be one of the main reasons for the failure of remdesivir to demonstrate improvement in clinical symptoms, as observed in the NIAID ACTT-1 clinical trial as well as the small sample size that did not have the power to detect a difference in clinical outcome. Remdesivir did not show a significant impact on viral load.
• The duration of remdesivir treatment was evaluated in the randomized, open-label study of patients with COVID-19 pneumonia. This study did not find a significant difference in the clinical status at 14 days after adjusting for baseline differences among the two groups. It is important to note that intubated patients or those on ECMO and those with multiorgan failure were excluded from the study. Patients who received 10-day treatment were more likely to experience serious adverse events (35% vs. 21%) and discontinue treatment due to adverse events (10% vs. 4%) compared to 5-day treatment.
• A Phase 2/3, open-label, single-arm clinical trial in 53 pediatric patients demonstrated similar results and adverse effects as seen in adults when given remdesivir for up to 10 days. PK data were also similar.
• Other viruses
  • In animal studies, when remdesivir was used as prophylaxis, it prevented MERS-CoV clinical disease, reduced MERS-CoV levels, and lung injury[13][14].
  • Remdesivir has been tested in humans for treating Ebola virus infection; in a large study of 681 patients, remdesivir (n=175) was inferior to human monoclonal antibodies (REGN-EB3 and MAb114)[15].
  • In a mouse model, remdesivir was effective when tested as a treatment for SARS-CoV-1.

Basis for recommendation

1. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022;386(4):305-315.  [PMID:34937145]

   Comment: The PINETREE study compared 3 days of outpatient RDV infusion (200 mg day 1 and 100 mg on days 2 and 3) to placebo among ambulatory patients ≥12 years old who had ≥1 risk factor for severe COVID-19 and ≤7 days of symptoms. Characteristics among the 279 RDV and 283 placebo patients were balanced with a mean age of 50, 50% women, and 61% with diabetes mellitus as the primary risk for severe COVID-19. The primary outcome was COVID-19-related hospitalization or death 28 days after enrollment. In the RDV arm, 2 (0.7%) participants had a COVID-19-related hospitalization compared to 15 (5.3%) in the placebo arm (p=0.008), for a relative risk reduction of 87%. There were no deaths in either arm. Adverse events were similar in both arms.
   

2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020;383(19):1813-1826.  [PMID:32445440]

   Comment: In this final report, a double-blind, randomized, placebo-controlled trial, IV remdesivir, was compared to placebo for treating hospitalized adults with severe Covid-19 lower respiratory tract infection. Remdesivir was given for 10 days (200 mg on day 1, followed by 100 mg daily for up to 9 days). In the analysis of 1059 patients (538 in remdesivir and 521 in placebo), the median time to recovery was significantly shorter remdesivir group compared to placebo, 10 days vs. 15 days respectively, the rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P< 0.001, by a log-rank test). Most patients had one or two pre-existing conditions, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number from symptom onset to randomization was 9 days. The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and 163 of the 516 patients who received a placebo (31.6%).
   

3. 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;383(19):1827-1837.  [PMID:32459919]

   Comment: In this randomized, open-label, phase III trial, remdesivir 5 days (n=200) vs. 10 days (n=197) course was compared in hospitalized patients (≥12 y/o) SARS-CoV-2 pneumonia with oxygen saturation of ≤ 94% while they were breathing ambient air or were receiving supplemental oxygen. Intubated patients or those on ECMO, as well as those with multiorgan failure, were excluded. More patients at baseline had a higher disease severity in the 10-day group (p=0.02). There was no difference in the clinical status at day 14 between the two groups after adjustment for bassline clinical status (p=0.14). The median time to clinical improvement was 10 days in both groups. Discharge rates were higher in patients with symptoms < 10 days before receiving remdesivir (62% vs. 49%). There was no difference in mortality or length of hospital stay between the two groups. The most common adverse events were nausea (9%), worsening respiratory failure (8%), and elevated ALT (7%).
   

4. NIH COVID-19 Treatment Guidelines. Therapeutic Management of Hospitalized Adults With COVID-19. https://www.covid19treatmentguidelines.nih.gov/management/clinical-managem... (accessed 7/26/23, last updated 7/26/23).

   Comment:
   The current placement of RDV, including revised recommendations regarding use in reduced GFR states per FDA prescribing information.
   
   
   

5. NIH COVID-19 Treatment Guidelines. Therapeutic Management of Hospitalized Adults With COVID-19. https://www.covid19treatmentguidelines.nih.gov/management/clinical-managem... (accessed 7/26/23, last updated 7/26/23).

   Comment:
   The current placement of RDV, including revised recommendations regarding the use in reduced GFR states per FDA prescribing information.
   
   
   

References

6. Lee TC, Murthy S, Del Corpo O, et al. Remdesivir for the treatment of COVID-19: a systematic review and meta-analysis. Clin Microbiol Infect. 2022;28(9):1203-1210.  [PMID:35598856]

   Comment: Analysis of 8 RCTs suggested a 23% mortality reduction in those receiving RDV vs placebo for those who did not require supplement oxygen but not benefit for those who had it started while on iMV or ECMO.
   

7. Garibaldi BT, Wang K, Robinson ML, et al. Real-World Effectiveness of Remdesivir in Adults Hospitalized With Coronavirus Disease 2019 (COVID-19): A Retrospective, Multicenter Comparative Effectiveness Study. Clin Infect Dis. 2022;75(1):e516-e524.  [PMID:34910128]

   Comment: A retrospective study using a large data set and careful matching within the cohort found that those receiving RDV were more likely to gain clinical improvement by d28 if on no or low-flow oxygen. Although the study had no overall mortality benefit, it did find it to be so in the no or low-flow oxygen groups, suggesting earlier administration is necessary for this antiviral.
   

8. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022;399(10339):1941-1953.  [PMID:35512728]

   Comment: The final SOLIDARITY analysis that concludes no mortality benefit in this early, non-placebo-controlled trial is presented here. The authors also include a meta-analysis of RDV showing benefits among SOLIDARITY, ACTT-1 and Wuhan trials. This also showed no mortality benefit statistically ort effect on patients with COVID-19 who are already being ventilated. Among other hospitalized patients, it has a negligible effect on death or progression to ventilation (or both).
   

9. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221.  [PMID:34534511]

   Comment: This European trial did not show benefit if RDV was received > 7d after the onset of symptoms with either d15 or d28 as endpoints for clinical status assessment. The difference with ACTT-1 was likely based on DisCoVeRy having a larger proportion of patients on steroids and requiring oxygen (so more advanced in disease course). Missing from the abstract was that RDV in DisCoVeRy In DisCoVeRy in the subset of participants without mechanical ventilation or ECMO significantly delayed the need for new mechanical ventilation or ECMO, or death--which was in keeping with ACTT-1
   

10. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511.  [PMID:33264556]

    Comment:
    The WHO-sponsored large trial did not show a mortality benefit, although this four-arm trial lacked a placebo. It is unclear if subgroups may benefit. Patients could be moved to another group at the clinician’s discretion, and there was no placebo arm. Also, RDV did not appear to have a great effect on the need for ventilation or hospital LOS.
    

11. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32275812]

    Comment: Report of compassionate use of remdesivir in 53 patients with severe COVID-19; 75% received the full 10-day course of remdesivir. At baseline, 57% of patients were receiving mechanical ventilation and 8% were on ECMO. During the follow-up period (median of 18 days), 68% of patients showed improvement in oxygen support (57% of ventilated patients were extubated), 47% were discharged and 13% died. Adverse events were reported in 60% of patients, with 23% experiencing serious adverse events.
    

12. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.  [PMID:32423584]

    Comment:
    In this randomized, double-blind, placebo-controlled trial (n=237) in China, a remdesivir 10-day course was compared to a placebo for the treatment of severe COVID-19 pneumonia (O2 saturation ≤ 94% or PaO2/FiO2 ratio of ≤300 mm Hg). The median time to start the study drug from symptom onset was 10 days. 28% of patients in the remdesivir arm also received lopinavir/ritonavir. Remdesivir use did not result in a significant clinical improvement 28 days after randomization compared to placebo. Patients who received remdesivir within 10 days of symptom onset in the ITT population had a numerically faster time to clinical improvement than those receiving a placebo. However, this was not statistically significant (18 vs. 23 days). Viral load decreases over time were similar in both groups. Adverse events were reported in 66% of patients receiving remdesivir and 64% receiving placebo.
    

13. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771-6776.  [PMID:32054787]

    Comment: In the rhesus macaque (non-human primate model), remdesivir given 24h before inoculation with MERS-CoV as a prophylactic agent was effective in preventing MERS-CoV−induced clinical disease (including the formation of lesions formed in the lungs) and inhibiting MERS-CoV replication in respiratory tissues. Remdesivir was also given as treatment 12 h post-inoculation in the same primate model and was effective in reducing clinical signs, including the severity of the lung lesions and viral replication.
    

14. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222.  [PMID:31924756]

    Comment: This study demonstrates that remdesivir, combined with interferon beta, had superior activity against MERS-CoV to lopinavir/ritonavir in vitro. Furthermore, when remdesivir was given to mice to prevent and treat MERS-CoV, it demonstrated clinical improvement and reduced viral loads. On the other hand combination of lopinavir/ritonavir with interferon beta was not as effective as remdesivir and reduced viral loads but had no impact on improving the clinical status of mice.
    

15. Mulangu S, Dodd LE, Davey RT, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381(24):2293-2303.  [PMID:31774950]

    Comment: A total of 681 patients with Ebola virus were randomly assigned in a 1:1:1:1 ratio to 1) triple monoclonal antibody ZMapp, 2) remdesivir, or 3) a single monoclonal antibody MAb114, or 4) the triple monoclonal antibody REGN-EB3. At the interim analysis, data showed the superiority of MAb114 and REGN-EB3 to ZMapp and remdesivir concerning mortality. At that point, patients were re-assigned only to the MAb114 and REGN-EB3 and the remdesivir arm was terminated. Mortality at 28 days in the remdesivir arm was 53.1% vs. 49.7% in ZMapp vs. 35.1% in Mab114 vs. 33.5% in REGN-EB3.A total of 9 adverse events occurred in the remdesivir arm that were unrelated to the underlying Ebola virus disease.
    Rating: Important
    

16. A Phase 2/3 Single-Arm, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Remdesivir (GS-5734™) in Participants From Birth to < 18 Years of Age With COVID-19. ClinicalTrials.gov. Gilead Sciences. Identifier NCT04431453, https://clinicaltrials.gov/ct2/show/NCT04431453

    Comment: A phase 2/3, single-arm, open-label trial enrolling 53 pediatric patients who received remdesivir for up to 10 days. Outcomes were similar to those seen in the adult population, with no differences in the incidence of adverse effects or pharmacokinetic parameters. This data led to the FDA lowering the age/weight criteria for remdesivir approval.
    

17. VEKLURY (remdesivir) for injection [package insert]. Foster City, CA. Gilead Sciences, Inc. https://www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklu... (accessed 7/26/23)

    Comment:
    As an FDA-approved drug, PI information, is for both outpatient and inpatient use.