Remdesivir

Abstract

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Generic Name: REMDESIVIR

Proprietary Name: Veklury (Gilead Sciences, Inc.)

Approval Rating: 1P

Therapeutic Class: Antiviral Agent

Similar Drugs: None

Sound-/Look-Alike Names: Velcade, Venofer

Indications

Remdesivir is indicated for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization in adults and pediatric patients 12 years and older and weighing at least 40 kg. Remdesivir should only be administered in a hospital or in a health care setting capable of providing acute care comparable to inpatient hospital care. ¹

An emergency use authorization (EUA) for remdesivir has been issued by the food And Drug Administration (FDA) to allow for emergency use for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing at least 3.5 kg.^2,3 All requirements of the EUA must be met prior to administration. ²

Clinical Pharmacology

Remdesivir is a nucleotide analog inhibitor of viral RNA-dependent RNA polymerase, with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome (MERS-CoV), and a variety of other coronaviruses, as well as other RNA virus families including paramyxoviruses, pneumoviruses, and filoviruses.^1,4-6 Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or cathepsin A, depending on the cell type. The nucleoside monophosphate is subsequently phosphorylated by cellular kinases to form a pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase. Incorporation into the RNA chain results in delayed chain termination (position i+3) during replication of the viral RNA. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, inhibiting viral RNA synthesis. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases, including human mitochondrial RNA polymerase. ¹

Remdesivir exhibited antiviral activity against a clinical isolate of SARS-CoV-2 in cultured primary human airway epithelial cells, with a 50% effective concentration (EC₅₀) of 9.9 nM after 48 hours of treatment. It inhibited replication of SARS-CoV-2 in the continuous human lung epithelial cell line Calu-3, with an EC₅₀ value of 280 nM after 72 hours of treatment. ¹ Additional clinical trial data are being assessed to determine the impact of remdesivir on viral shedding and viral load. ⁷

No clinical or cell culture data are available on the development of SARS-CoV-2 resistance to remdesivir, although introduction of F480L and V557L substitutions into SARS-CoV resulted in a 6-fold reduction in susceptibility to remdesivir in cell culture. ¹ An additional study is being conducted to identify remdesivir-resistant SARS-CoV-2 variants and characterize several independent isolates phenotypically and genotypically. ⁷

In an animal model, rhesus macaques treated with remdesivir early in infection did not show signs of respiratory disease, unlike vehicle control animals; macaques treated with remdesivir also showed reduced pulmonary infiltrates on radiographs and lower lung viral loads and reduced lung damage on necropsy. ⁸

Pharmacokinetics

Peak concentrations of remdesivir are reached within a median of 0.67 to 0.68 hours following a 30-minute intravenous (IV) infusion. Remdesivir plasma concentrations decline rapidly and are accompanied by appearance of the GS-704277 metabolite (peaks in 0.75 hours) and the nucleoside GS-441524 metabolite (peaks within 1.51-2 hours).^1,9 The GS-441524 metabolite is the predominant plasma metabolite. ⁹

Remdesivir is 88% to 93.6% bound to plasma proteins, while the metabolites are minimally plasma protein bound (1%-2%). ¹

The median plasma elimination half-life of remdesivir is 1 hour; median half-life of the GS-441524 metabolite is 27 hours, and that of the GS-704277 metabolite is 1.3 hours.^1,9 Remdesivir is metabolized via CES1 (80%), cathepsin A (10%), and CYP3A (10%) to 2 major metabolites. The GS-704277 metabolite undergoes further metabolism via HINT1, while the GS-441524 metabolite is not significantly metabolized but is primarily eliminated via glomerular filtration and active tubular secretion. The percentage of dose excreted in the urine is 10% for remdesivir, compared with 49% for the GS-441524 metabolite, and 2.9% for the GS-704277 metabolite. ¹

Pharmacokinetic differences in remdesivir exposure based on sex, race, age, renal function, and hepatic function have not been assessed. The pharmacokinetics of remdesivir have not been evaluated in pediatric patients or in patients with renal or hepatic impairment. ¹ Based on modeling and simulation, the recommended dosing regimen for patients 12 years and older and weighing at least 40 kg is expected to produce comparable steady-state plasma exposures of remdesivir and metabolites as observed in healthy adults. ¹ Studies will be conducted to identify remdesivir drug interactions and effects on the QTc interval, as well as to assess remdesivir pharmacokinetics and safety in pediatric patients; pregnant patients; subjects with moderate and severe hepatic impairment; and subjects with mild, moderate, and severe renal impairment. ⁷

Comparative Efficacy

Indication: Coronavirus Disease 2019

Guidelines

• Guideline: Infectious Diseases Society of America (IDSA) guidelines on the treatment and management of patients with COVID-19

• Reference: Bhimraj et al ¹⁰ (IDSA)

• Comments: In patients with COVID-19 admitted to the hospital without the need for supplemental oxygen and oxygen saturation greater than 94% on room air, the panel suggests against the routine use of remdesivir. In hospitalized patients with severe COVID-19 (defined as patients with oxygen saturation of 94% or less on room air and those requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]), the guideline suggests remdesivir over no antiviral treatment (conditional recommendation; moderate certainty of evidence). In contingency or crisis capacity settings (ie, remdesivir supply is limited), remdesivir demonstrates the most benefit in those with severe COVID-19 on supplemental oxygen rather than on mechanical ventilation or ECMO. The recommended treatment duration is consistent with the product labeling: 5 days in patients on supplemental oxygen but not mechanical ventilation or ECMO, and 10 days for patients on mechanical ventilation or ECMO (conditional recommendation; low certainty of evidence). In hospitalized critically ill patients, the panel recommends dexamethasone rather than no dexamethasone (strong recommendation; moderate certainty of evidence). In hospitalized patients with severe but noncritical COVID-19, the panel suggests dexamethasone rather than no dexamethasone (conditional recommendation; moderate certainty of evidence). Based on hospitalization status and disease severity/oxygen requirements, the panel recommends against various therapies, including hydroxychloroquine, hydroxychloroquine plus azithromycin, lopinavir/ritonavir, glucocorticoids, famotidine, bamlanivimab. Given the rapidity of emerging literature, the IDSA recognized the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians, and other health-care professionals in their decisions about treatment and management of patients with COVID-19.

• Guideline: Coronavirus disease 2019 (COVID-19) treatment guidelines

• Reference: COVID-19 Treatment Guidelines Panel, 2020 (NIH) ¹¹

• Comments: The panel provides pharmacologic strategies for management of patients with different severities of disease. For patients with COVID-19 not hospitalized, no specific antiviral or immunomodulatory therapy is recommended; the panel recommends against use of dexamethasone (strong recommendation). For patients who are hospitalized but do not require supplemental oxygen, data are insufficient to recommend for or against routine use of remdesivir, but use may be appropriate for select patients, such as those at high risk for disease progression; the panel recommends against use of dexamethasone (strong recommendation). For patients with COVID-19 who are hospitalized and require supplemental oxygen but do not require oxygen via a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO, remdesivir (moderate recommendation) or remdesivir plus dexamethasone (moderate recommendation) is recommended; if remdesivir cannot be used, dexamethasone alone may be used (moderate recommendation). For patients who are hospitalized and require oxygen delivery through a high-flow device or noninvasive ventilation, dexamethasone (strong recommendation) or dexamethasone plus remdesivir (moderate recommendation) is recommended. For patients who are hospitalized and require invasive mechanical ventilation or ECMO, dexamethasone (strong recommendation) is recommended. The guidelines are published in electronic format that can be updated in step with the rapid pace and growing volume of information regarding the treatment of COVID-19.

• Guideline: A living WHO guideline on drugs for COVID-19

• Reference: Rochwerg et al ¹² (WHO)

• Comments: For patients with confirmed COVID-19 at any severity, it is suggested that remdesivir not be used (weak recommendation), based on low-quality evidence that demonstrated no important differences in outcome measurements, including mortality, need for mechanical ventilation, serious adverse events, viral clearance at 7 days, acute kidney injury, delirium, mean time to clinical improvement, and mean duration of hospitalization or mechanical ventilation. Corticosteroids (eg, dexamethasone) are recommended for patients with severe and critical COVID-19 (strong recommendation) but not for patients with nonsevere COVID-19 (weak recommendation). New recommendations to this living guideline are expected and will be published as updates to this guideline.

Studies

• Drug: Remdesivir versus Placebo

• Reference: Beigel et al ¹³ (Adaptive COVID-19 Treatment Trial [ACTT-1])

• Study Design: Phase 3, randomized, double-blind, placebo-controlled, multicenter study

• Study Funding: National Institute of Allergy and Infectious Diseases; National Institutes of Health; governments of Denmark, Japan, Mexico, and Singapore; Seoul National University Hospital; United Kingdom Medical Research Council.

• Patients: One thousand and sixty-two adult patients hospitalized with COVID-19 infection and with evidence of lower respiratory tract infection; 957 patients (90%) were categorized as having severe disease. Patients were considered to have severe disease if they required mechanical ventilation, if they required supplemental oxygen, if their oxygen saturation as measured by pulse oximetry was 94% or lower while breathing ambient air, or if they had tachypnea (respiratory rate of 24 breaths per minute or greater). Clinical status was assessed on an 8-category ordinal scale: 1 (not hospitalized and no limitation of activities); 2 (not hospitalized but with limitation of activities, home oxygen requirement, or both); 3 (hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care [used if hospitalization was extended for infection-control or other nonmedical reasons]); 4 (hospitalized and requiring ongoing medical care related to COVID-19 or other medical conditions, but not requiring supplemental oxygen); 5 (hospitalized and requiring any supplemental oxygen); 6 (hospitalized and requiring noninvasive ventilation or use of high-flow oxygen devices); 7 (hospitalized and receiving invasive mechanical ventilation or ECMO); and 8 (death). Mean patient age was 58.9 years, and 64.4% of patients were male; 53.3% were White, 21.3% were Black, 12.7% were Asian, 0.7% were American Indian or Alaska Native; and 23.5% were Hispanic or Latino. The majority of patients (79.8%) were enrolled in North America, followed by Europe (15.3%) and Asia (4.9%). The majority of patients (55.2%) had 2 or more coexisting conditions; the most common were hypertension (50.7%), obesity (45.4%), and type 2 diabetes (30.6%). The baseline ordinal scale score was 4 in 13% of patients, 5 in 41%, 6 in 18.2%, 7 in 26.8%, and missing in 1%.

• Intervention: Patients were randomized (1:1) to receive remdesivir (n = 541) or placebo (n = 521), with randomization stratified by study site and disease severity at enrollment. Remdesivir or matching placebo was administered IV as a 200 mg loading dose on day 1, followed by a 100 mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death. The median number of days between symptom onset and randomization was 9. All patients received supportive care according to the standard of care for the trial site. During the study, 35.6% of patients received hydroxychloroquine and 23% received a glucocorticoid.

• Results.

• Primary End Point(s):

  • ● Time to recovery (defined as the first day during the 28 days after enrollment on which a patient met criteria for category 1, 2, or 3 on the 8-category ordinal scale) was shorter in the remdesivir group than in the placebo group (median, 10 days vs 15 days; rate ratio for recovery, 1.29 [95% CI, 1.12-1.49]; P < .001). Among the 957 patients with severe disease at enrollment, median time to recovery was 11 days with remdesivir compared with 18 days with placebo (rate ratio for recovery, 1.31; 95% CI, 1.12-1.52).
• Secondary End Point(s):

  • ● Clinical status at day 15, as assessed on the 8-category ordinal scale, was more likely to be improved in the remdesivir group than in the placebo group (odds ratio [OR] for improvement, 1.5 [95% CI, 1.2-1.9]).
  • ● Time to improvement of 1 category on ordinal scale was shorter in the remdesivir group (median, 7 days vs 9 days; rate ratio for recovery, 1.23 [95% CI, 1.08-1.42]).
  • ● Time to improvement of 2 categories on ordinal scale was shorter in the remdesivir group (median, 11 days vs 14 days; rate ratio for recovery, 1.29 [95% CI, 1.12-1.48]).
  • ● Time to discharge or a National Early Warning Score of 2 or less maintained for 24 hours, whichever occurred first, was shorter in the remdesivir group (median, 8 days vs 12 days; rate ratio, 1.27 [95% CI, 1.1-1.46]).
  • ● Median number of days with supplemental oxygen among the 913 subjects receiving supplemental oxygen at enrollment, was lower in the remdesivir group (median, 13 days vs 21 days; difference, −8 days [95% CI, −11.8 to −4.2]). Percentage of patients not receiving oxygen at enrollment and requiring new use of oxygen did not differ (36% in the remdesivir group vs 44% in the placebo group; difference, −8 days [95% CI, −24 to 8]).
  • ● Median number of days of noninvasive ventilation or high-flow oxygen use in the 193 patients receiving these interventions at baseline was 6 in both groups.
  • ● Incidence of new noninvasive ventilation or high-flow oxygen use among the 573 patients not receiving noninvasive ventilation or high-flow oxygen at baseline was lower in the remdesivir group (17% vs 24%; difference, −7% [95% CI, −14% to −1%]).
  • ● Median number of days of mechanical ventilation or ECMO during study among the 285 patients receiving these interventions at baseline was 17 in the remdesivir group and 20 in the placebo group (difference, −3 days; 95% CI, −9.3 to 3.3).
  • ● Percentage of the 766 patients not receiving invasive ventilation or ECMO at enrollment and requiring new use of these interventions during the study was lower in the remdesivir group (13% vs 23%; difference, −10% [95% CI, −15% to −4%]).
  • ● Median duration of initial hospitalization (up to day 29) was 12 days in the remdesivir group and 17 days in the placebo group (difference, −5 days; 95% CI, −7.7 to −2.3); readmission occurred in 5% of patients in the remdesivir group and in 3% in the placebo group (difference, 2%; 95% CI, 0% to 4%).
  • ● Kaplan-Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (HR, 0.55 [95% CI, 0.36-0.83]).
  • ● Kaplan-Meier estimates of mortality by day 29 were 11.4% in the remdesivir group and 15.2% in the placebo group (HR, 0.73 [95% CI, 0.52-1.03]).

• Comments: Patients were enrolled at 60 sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore. The original primary end point, clinical status at day 15 as assessed on the 8-category ordinal scale, was switched to a secondary end point after 72 patients were enrolled and prior to any unblinding as evidence of COVID-19’s protracted course was evolving. While the primary end point, time to recovery, was shorter among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45 [95% CI, 1.18-1.79]), it was not significantly improved among patients with a baseline ordinal score of 4 or 6, for those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), or for those randomized more than 10 days after the onset of symptoms. Rate of recovery was improved when analysis was adjusted for baseline ordinal score as a covariate and for patients who underwent randomization during the first 10 days after symptom onset.

• Limitations: Too few patients were enrolled to determine efficacy by baseline clinical status and in other subgroup analyses.

• Reference: Wang et al ¹⁴

• Study Design: Phase 3, randomized, double-blind, multicenter study

• Study Funding: Chinese Academy of Medical Sciences Emergency Project of COVID-19; National Key Research and Development Project of China, Beijing Science and Technology Project

• Patients: Two hundred and thirty-seven adult patients hospitalized with laboratory-confirmed SARS-CoV-2 infection and who were within 12 days of symptom onset. Patients had radiologically confirmed pneumonia, and oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less. Exclusion criteria included hepatic cirrhosis, transaminases greater than 5 times the upper limit of normal (ULN), severe renal impairment, and pregnancy or breastfeeding. Clinical status was assessed on a 6-point ordinal scale: 1 (discharged or reaching discharge criteria); 2 (hospitalized but not requiring oxygen); 3 (hospitalized for oxygen therapy but not requiring high-flow or noninvasive ventilation); 4 (hospitalized for noninvasive ventilation or high-flow oxygen therapy); 5 (hospitalized for mechanical ventilation or ECMO); and 6 (death). Mean patient age was 66 years in the remdesivir group and 64 years in the placebo group; 56% of patients in the remdesivir group and 65% in the placebo group were male. Coexisting conditions included hypertension in 46% of the remdesivir group and 38% of the placebo group and diabetes in 25% of the remdesivir group and 21% of the placebo group. The majority of patients were in clinical status category 3 (82% in the remdesivir group and 83% in the placebo group), followed by category 4 (18% in the remdesivir group and 12% in the placebo group). The median time from symptom onset to start of therapy was 10 days.

• Intervention: Patients were randomized (2:1) to receive remdesivir 200 mg IV on day 1 followed by 100 mg daily on days 2 through 10 (n = 158) or the same volume of placebo infusions for 10 days (n = 79). Randomization was stratified by level of respiratory support. Concomitant use of lopinavir/ritonavir, interferons, and corticosteroids was permitted; 66% of patients received corticosteroids during their hospital stay, and 39% had received corticosteroids before enrollment.

• Results.

• Primary End Point(s):

  • ● Time to clinical improvement (defined as a 2-point reduction from admission in clinical status on the 6-point ordinal scale or hospital discharge, whichever came first) within 28 days after randomization did not differ between the remdesivir and placebo groups in the intention-to-treat (ITT) analysis population (median, 21 days in the remdesivir group compared with 23 days in the placebo group; HR, 1.23 [95% CI, 0.87-1.75]). Results were similar in the per-protocol analysis (21 days vs 23 days; HR, 1.27 [95% CI, 0.89-1.8]). Among subjects treated within 10 days of symptom onset in the ITT population, median time to improvement was 18 days in the remdesivir group and 23 days in the placebo group (HR, 1.52; 95% CI, 0.95-2.43); however, the difference was not statistically significant.
• Secondary End Point(s):

  • Proportion of patients in each clinical category did not differ significantly between treatment groups at day 7 (OR, 0.69; 95% CI, 0.41-1.17), day 14 (OR, 1.25; 95% CI, 0.76-2.04), or day 28 (OR, 1.15; 95% CI, 0.67-1.96).
  • All-cause mortality at day 28 was 14% in the remdesivir group and 13% in the placebo group (difference, 1.1%; 95% CI, −8.1% to 10.3%).
  • ● Duration of invasive mechanical ventilation was 7 days in the remdesivir group and 15.5 days in the placebo group (difference, −4 days; 95% CI, −14 to 2).
  • Duration of oxygen support did not differ between groups (19 days with remdesivir and 21 days with placebo; difference, −2 days [95% CI, −6 to 1]).
  • Duration of hospital stay did not differ between groups (25 days with remdesivir and 24 days with placebo; difference, 0 days [95% CI, −4 to 4]).
• Other End Point(s):

  • ● Viral loads were similar to baseline and declined over time to a similar extent in both groups.

• Comments: Patients were enrolled at 10 hospitals in Wuhan, Hubei province, China.

• Limitations: The study was not adequately powered to detect assumed differences in clinical outcomes. Treatment was initiated late in the course of infection. Data were absent regarding infectious virus recovery or possible emergence of reduced susceptibility to remdesivir.

• Drug: Remdesivir

• Reference: Goldman et al ¹⁵ (GS-US-540-5773 trial)

• Study Design: Phase 3, randomized, open-label, multicenter study

• Study Funding: Gilead Sciences

• Patients: 397 patients 12 years and older with confirmed SARS-CoV-2 infection. Patients had radiologic evidence of pneumonia and had either oxygen saturation of 94% or less while breathing room air or were receiving supplemental oxygen. Exclusion criteria included mechanical ventilation or ECMO, signs of multiorgan failure, elevated transaminases greater than 5 times the ULN, estimated creatinine clearance (CrCl) less than 50 mL/minute, or concurrent use of other agents with putative antiviral activity (within 24 hours prior to start of trial treatment). Clinical status was assessed on a 7-point ordinal scale: 1 (death); 2 (hospitalized and receiving invasive mechanical ventilation or ECMO); 3 (hospitalized and receiving noninvasive ventilation or high-flow oxygen); 4 (hospitalized and requiring low-flow supplemental oxygen); 5 (hospitalized and not requiring supplemental oxygen, but requiring ongoing medical care [related or not related to COVID-19]); 6 (hospitalized and requiring neither supplemental oxygen nor ongoing medical care [other than that for the protocol for remdesivir administration]); and 7 (not hospitalized). Baseline demographic characteristics were similar between groups: Median patient age was 61 years in the 5-day group and 62 years in the 10-day group; 60% of subjects were male in the 5-day group and 68% were male in the 10-day group. The majority of patients were White (71% in the 5-day group and 70% in the 10-day group); 10% and 12%, respectively, were Black and 10% and 13%, respectively, were Asian. Coexisting conditions included hypertension (50% in both groups), diabetes (24% in the 5-day group and 22% in the 10-day group), hyperlipidemia (20% in the 5-day group and 25% in the 10-day group), and asthma (14% in the 5-day group and 11% in the 10-day group). The median duration of hospitalization before the first remdesivir dose was 2 days in both groups. Most patients had an ordinal scale score of 4 at baseline (56% in the 5-day group and 54% in the 10-day group); however, more patients in the 10-day group had a score of 2 or 3 (5% vs 2% and 30% vs 24%, respectively) and fewer had a score of 5 (11% vs 17%), demonstrating overall worse clinical status in the 10-day group (P = .02).

• Intervention: Patients were randomized (1:1) to receive IV remdesivir for either 5 days (n = 200) or 10 days (n = 197). Remdesivir was administered with a 200 mg loading dose on day 1, followed by 100 mg once daily on subsequent days. Supportive care at the discretion of the investigator was continued throughout the trial. An extension phase including 5600 additional patients, including a cohort receiving mechanical ventilation, is ongoing; results of the extension phase will be published separately.

• Results.

• Primary End Point(s):

  • ● Clinical improvement of at least 2 points on the 7-point ordinal scale at day 14 occurred in 64% of patients treated with the 5-day course and in 54% of those treated with the 10-day course. After adjustment for the imbalance in baseline clinical status, patients treated with the 10-day course had a distribution in clinical status at day 14 similar to that in patients treated with the 5-day course (P = .14).
• Secondary End Point(s):

  • ● Proportion of patients with adverse events that occurred on or after the first dose of remdesivir for up to 30 days after the last dose was similar in the 2 groups (70% in the 5-day group and 74% in the 10-day group).
• Other End Point(s):

  • ● Time to clinical improvement (defined as an improvement of at least 2 points from baseline on the 7-point ordinal scale) was 10 days in the 5-day group and 11 days in the 10-day group (difference, 0.79; 95% CI, 0.61-1.01).
  • ● Proportion of patients achieving recovery (defined as an improvement from a baseline ordinal scale score of 2 to 5 to a score of 6 or 7) was 64% in the 5-day group and 54% in the 10-day group (baseline-adjusted difference, −6.3%; 95% CI, −15.4% to 2.8%).
  • Median time to recovery was 10 days in the 5-day group and 11 days in the 10-day group (difference, 0.81 days; 95% CI, 0.64-1.04).
  • ● Proportion of patients achieving modified recovery (defined as improvement from a baseline ordinal scale score of 2 to 4 to a score of 5 to 7, or from a score of 5 to a score of 6 or 7) was 70% in the 5-day group and 59% in the 10-day group (difference, −6.7%; 95% CI, −15.3% to 1.9%).
  • ● Median time to modified recovery was 9 days in the 5-day group and 10 days in the 10-day group (difference, 0.82 days; 95% CI, 0.64-1.04).
  • ● By day 14, 8% of patients in the 5-day group and 11% in the 10-day group had died.
  • ● Among patients receiving mechanical ventilation or ECMO at day 5, 40% in the 5-day group died by day 14 compared with 17% in the 10-day group. Improved outcomes with treatment beyond 5 days were not observed in patients receiving noninvasive positive-pressure ventilation or high-flow oxygen, in patients receiving low-flow oxygen, or in patients breathing ambient air.

• Comments: Patients were enrolled at 55 hospitals in the United States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, and Taiwan. One primary assessment end point—proportion of patients with normalization of temperature at day 14—was changed after the start of enrollment but before any results were available to assessment of clinical status on the 7-point ordinal scale on day 14, a change made in response to evolving standards for assessment of COVID-19.

• Limitations: There was an imbalance in clinical severity between treatment groups at baseline. Interpretation of study results is limited by the lack of a randomized placebo control group and by the open-label design. The study was designed as an open-label trial for 2 reasons: the available supply of matched placebo vials had been allocated to other ongoing randomized, controlled clinical trials; and, given the stretched health care resources during the pandemic, patients were allowed to be discharged from the hospital as soon as medically indicated, regardless of whether they had completed the full assigned course of treatment with remdesivir. As a result, only 44% of patients in the 10-day treatment group completed the full course of therapy. Patients who were not discharged were presumably those with more severe illness, which may account for the different rates of adverse events in the 2 groups. Researchers could not obtain SARS-CoV-2 viral load results during and after treatment because of the variability in local access to testing and practices across the global sites.

• Results cannot be applied to patients receiving mechanical ventilation; further evaluation of this subgroup, and of other high-risk groups such as immunocompromised persons, is needed to determine the shortest effective duration of therapy.

• Drug: Remdesivir vs Standard Care

• Reference: Spinner et al ¹⁶ (GS-US-540-5774 trial)

• Study Design: Randomized, open-label, multicenter, phase 3 study

• Study Funding: Gilead Sciences

• Patients: Five hundred and ninety-six patients 12 years and older with confirmed SARS-CoV-2 infection and moderate COVID-19 pneumonia (pulmonary infiltrates and oxygen saturation greater than 94% on room air); of the 596 patients randomized, only 584 began the study. Patients requiring mechanical ventilation at screening or with transaminase levels greater than 5 times the ULN or CrCl less than 50 mL/minute were excluded. Clinical assessment used the same 7-point ordinal scale as the previously described study GS-US-540-5773. ¹⁵ Patients in the 3 groups were balanced in demographics and disease characteristics. Median patient age was 56 years in the 10-day group, 58 years in the 5-day group, and 57 years in the standard care group. The majority of subjects were male (61% in the 10-day group, 60% in the 5-day group, and 63% in the standard care group) and White (57% in the 10-day group, 59% in the 5-day group, and 58% in the standard care group), Black (20% in the 10-day group, 19% in the 5-day group, and 14% in the standard care group), or Asian (16% in the 10-day group, 18% in the 5-day group, and 19% in the standard care group). Overall, 56% of patients had cardiovascular disease, 42% had hypertension, 40% had diabetes, and 14% had asthma. Patients in all groups had been hospitalized a median of 2 days; the median duration of symptoms was 9 days in the standard care group and 8 days in the 2 remdesivir groups. Most patients had a clinical status score of 5 (84% in the 10-day group, 84% in the 5-day group, and 80% in the standard care group).

• Intervention: Patients were randomized 1:1:1 to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was administered as 200 mg IV on day 1, followed by 100 mg daily on subsequent days. Frequent concomitant medications included corticosteroids (15% in the 10-day group, 17% in the 5-day group, and 19% in the standard care group), azithromycin (21% in the 10-day group, 18% in the 5-day group, and 31% in the standard care group), hydroxychloroquine/chloroquine (11% in the 10-day group, 8% in the 5-day group, and 45% in the standard care group), and lopinavir/ritonavir (6% in the 10-day group, 5% in the 5-day group, and 22% in the standard care group). An extension phase allowed up to 1000 additional patients to be enrolled in the remdesivir arm; results of the extension phase will be published in a subsequent report.

• Results.

• Primary End Point(s):

  • Clinical status on day 11 (as assessed on 7-point ordinal scale) was better in the 5-day remdesivir group than in the standard care group (OR, 1.65 [95% CI, 1.09-2.48]; P = .02), but did not differ significantly between the 10-day remdesivir group and the standard care group (P = .18).
• Secondary End Point(s):

  • ● Proportion of patients experiencing adverse events was 51% in the 5-day group, 59% in the 10-day group, and 47% in the standard care group. The difference between the 10-day group and standard care group was significant (difference, 12% [95% CI, 1.6%-21.8%]; P = .02).
• Other End Point(s):

  • ● No differences were observed between the 5-day and 10-day remdesivir groups and the standard care group for any of the following exploratory end points: time to 2-point or greater improvement in clinical status, time to 1-point or greater improvement in clinical status, time to recovery, time to modified recovery, and time to discontinuation of oxygen support.
  • ● Kaplan-Meier estimates of all-cause mortality at 28 days were 1% (95% CI, 0%-2.6%) for the 5-day group (P = .43 vs standard care), 2% (95% CI, 0% to 3.6%) for the 10-day group (P = .72 vs standard care), and 2% (95% CI, 0.1%-4.1%) for the standard care group.
  • ● Post hoc sensitivity analyses of the primary end point adjusting for day 1 clinical status score and symptom duration, imputing missing patients as dead, and using the ITT population produced significant results for the 5-day course compared with standard care, but no difference between the 10-day course and standard care.

• Comments: Patients were enrolled at 105 hospitals in the United States, Europe, and Asia. The original primary end point—proportion of patients discharged by day 14 of the study—was changed to clinical status on day 11, because hospital discharge rates varied greatly across regions and the ordinal scale became standard for interventional COVID-19 studies.

• Limitations: The study used an open-label design. Virologic outcomes such as effect of remdesivir on SARS-CoV-2 viral load were not assessed. Other laboratory parameters that may have aided in identifying additional predictors of outcomes were not routinely collected. The ordinal scale used to evaluate outcomes was not ideal for detecting differences in patients with moderate COVID-19, especially for a clinical situation in which discharge decisions could be driven by factors other than clinical improvement.

• Drug: Antiviral Therapy (eg, Remdesivir) plus Standard of Care versus Standard of Care

• Reference: WHO Solidarity trial consortium, 2020 (SOLIDARITY trial and DisCoVeRy add-on trial)^17,18

• Study Design: Phase 3, adaptive, randomized, open-label, multicenter study

• Study Funding: World Health Organization

• Patients: Eleven thousand two hundred sixty-six adult patients hospitalized with COVID-19 and in need of oxygen therapy (pulmonary infection with oxygen saturation of 94% or less on room air or acute respiratory failure requiring supplemental oxygen, high-flow oxygen devices, noninvasive ventilation, and/or mechanical ventilation). Clinical status was assessed on a 7-point ordinal scale: 1 (not hospitalized and no limitation on activities); 2 (not hospitalized but activities limited); 3 (hospitalized but not requiring supplemental oxygen); 4 (hospitalized and requiring supplemental oxygen); 5 (hospitalized on noninvasive ventilation or high-flow oxygen devices); 6 (hospitalized on invasive mechanical ventilation or ECMO); and 7 (death). Baseline characteristics by random allocation to remdesivir were as follows: 961 patients in the remdesivir group and 952 in its control group were younger than 50 years, 1282 patients in the remdesivir group and 1287 patients in its control group were 50 to 69 years of age, and 500 patients in the remdesivir group and 469 patients in its control group were 70 years or older; 63% of patients were male; 60% were randomized on hospitalization day 0 or 1; and 25% had diabetes.

• Intervention: Patients were randomized (1:1:1:1:1) to standard of care (n = 4088) or standard of care plus remdesivir (n = 2750), lopinavir/ritonavir (n = 1411), interferon (n = 2063 [651 to interferon beta-1a plus lopinavir/ritonavir and 1412 to interferon beta-1a plus local standard of care), or hydroxychloroquine (n = 954) depending on drug availability. The remdesivir dose was 200 mg IV on day 1 and then 100 mg daily for 9 days. Controls for those randomly allocated to one particular drug were patients who could by chance have been randomly allocated to that drug, but instead got allocated standard of care. If more than one study drug was available for a particular study entrant, allocation to standard of care would put that patient into the control group for each of them. Hence, there is partial overlap between the 4 control groups. Randomization was stratified by region and severity of illness. The remdesivir assessment group included 2743 patients treated with remdesivir and 2708 controls.

• Results.

• Primary End Point(s):

  • ● Overall mortality, initiation of ventilation, and duration of hospital stay (SOLIDARITY trial end point): Remdesivir did not reduce in-hospital mortality (death rate ratio, 0.95 [95% CI, 0.81-1.11]; P = .5), initiation of mechanical ventilation (295 patients receiving remdesivir vs 284 patients receiving control), or hospitalization duration compared with standard of care. Mortality also did not differ with remdesivir compared with its control when analyzed by ventilator status (ventilated vs not ventilated) or when assessed as a composite end point with initiation of ventilation.
  • ● Clinical status at day 15 on the 7-point ordinal scale (DisCoVeRy add-on study end point): Results are not available.
• Secondary End Point(s):

  • ● Other outcomes for the add-on study for which results are not yet reported include the following:
  • ● Time to improvement of 1 category on ordinal scale from admission.
  • ● Time to discharge or to a National Early Warning Score of 2 or less maintained for 24 hours, whichever occurs first.
  • ● Oxygen supplementation–free days in the first 28 days.
  • ● Ventilator-free days in the first 28 days.
  • ● Incidence and duration of new mechanical ventilation use.
  • ● Duration of hospitalization.

• Comments: Patients are enrolled at 405 hospitals in 30 countries; the DisCoVeRy add-on study was conducted only in Europe (mostly France).

• Limitations: Final results are not yet available. Patients were not enrolled in the United States.

Contraindications, Warnings, and Precautions

Contraindications

Remdesivir is contraindicated in patients with a history of clinically significant hypersensitivity reactions to remdesivir or to any component of the formulation (betadex sulfobutyl ether sodium and possibly hydrochloric acid and/or sodium hydroxide). ¹

Warnings and Precautions

Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed during and following remdesivir administration. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slowing of the infusion rate, with a maximum infusion time of up to 120 minutes, may be considered to prevent these signs and symptoms. Patients should be monitored closely for signs and symptoms of hypersensitivity during and following remdesivir administration. If clinically significant signs and symptoms of hypersensitivity occur, remdesivir administration should be immediately discontinued and appropriate treatment initiated. ¹

Transaminase elevations have been observed in healthy volunteers who received remdesivir as well as in patients with COVID-19 treated with remdesivir. Transaminase elevations have also been reported as a clinical feature of COVID-19, making discernment of the contribution of remdesivir to transaminase elevations in patients with COVID-19 difficult. Hepatic laboratory testing should be conducted in all patients prior to initiating therapy with remdesivir and during treatment as clinically appropriate. Discontinuation of remdesivir should be considered if ALT levels increase to greater than 10 times the ULN or if ALT elevation is accompanied by signs or symptoms of liver inflammation. ¹

Coadministration of chloroquine phosphate or hydroxychloroquine sulfate with remdesivir is not recommended. Cell culture data demonstrated an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir. ¹

Renal function should be evaluated prior to initiating therapy with remdesivir and while receiving remdesivir as clinically appropriate. The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment; however, patients with an estimated glomerular filtration rate (eGFR) of 30 mL/minute or greater have received remdesivir for the treatment of COVID-19 with no dosage adjustment. The excipient betadex sulfobutyl ether sodium is renally cleared and accumulates in patients with renal impairment; therefore, administration of remdesivir is not recommended in patients with eGFR less than 30 mL/minute. ¹

There are no adequate and well-controlled studies of remdesivir in pregnant women; data from case reports and compassionate use are insufficient to evaluate drug-associated risk. In nonclinical reproductive toxicity studies, no adverse effects on embryo-fetal development were observed at systemic exposures (AUC) of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose. Pregnant women hospitalized with COVID-19 are at risk for serious morbidity and mortality. ¹ A study is being conducted to evaluate the pharmacokinetics and safety of remdesivir in pregnant patients with COVID-19. ⁷

There are no data regarding the presence of remdesivir in human milk, or its effects on breastfeeding infants or milk production. The benefits of breastfeeding should be considered along with the mother’s clinical need for remdesivir and any potential adverse effects on the breastfeeding child from remdesivir or the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow recommendations to avoid exposing the infant to COVID-19. ¹

Safety and effectiveness of remdesivir in the treatment of COVID-19 have been established in pediatric patients 12 years and older and weighing at least 40 kg. Safety and effectiveness of remdesivir have not been established in pediatric patients younger than 12 years or weighing less than 40 kg. ¹ A study is being conducted to evaluate the safety, tolerability, pharmacokinetics, and treatment response to remdesivir in pediatric patients from birth to younger than 18 years with COVID-19. ⁷ An EUA allows for emergency use for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing at least 3.5 kg.^2,3

Adverse Reactions

The most common adverse reactions observed with remdesivir (incidence of at least 5%) have included nausea, increased ALT, and increased AST. Less frequent adverse reactions have included hypersensitivity reactions, generalized seizure, and rash. In a placebo-controlled trial (ACTT-1), severe reactions (grade 3 or higher) occurred in 8% of patients treated with remdesivir and in 9% treated with placebo. Serious reactions occurred in 0.4% of patients treated with remdesivir and in 0.6% treated with placebo; serious reactions in the remdesivir group were seizure and infusion-related reaction. Adverse reactions leading to discontinuation of treatment occurred in 2% of remdesivir-treated patients and in 3% of placebo-treated patients; these reactions in the remdesivir group included seizure, infusion-related reaction, increased transaminases, increased ALT and AST, decreased GFR, and acute kidney injury. Adverse reactions reported in open-label trials were similar to those observed in the placebo-controlled trial. ¹

Grade 3 and 4 laboratory abnormalities observed in the phase 3, placebo-controlled ACTT-1 trial are summarized in Table 1. ¹

Table 1.

Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Subjects Receiving Remdesivir in the Placebo-Controlled ACTT-1 Trial. ¹

Laboratory abnormality	Remdesivir 10-day regimen (n = 532) (%)	Placebo (n = 516) (%)
eGFR decreased	18	24
CrCl decreased	18	20
Hemoglobin decreased	15	22
Creatinine increased	15	16
Glucose increased	12	13
Lymphocytes decreased	11	18
Prothrombin time increased	9	4
AST increased	6	8
ALT increased	3	6
Bilirubin increased	2	5

Drug Interactions

Concomitant use of chloroquine phosphate or hydroxychloroquine sulfate with remdesivir is not recommended, due to antagonistic effects observed in cell culture. ¹

No formal drug interaction studies have been conducted in humans. In vitro, remdesivir is a substrate of CYP3A4 and OATP1B1 and P-gp transporters and an inhibitor of CYP3A4, OATP1B1, OATP1B3, and MATE1. The GS-704277 metabolite is a substrate for OATP1B1 and OATP1B3. The clinical significance of these in vitro observations is unknown. ¹

Recommended Monitoring

Baseline and during remdesivir administration when clinically appropriate: Hepatic function tests (ALT, AST, bilirubin, alkaline phosphatase, prothrombin time); renal function tests (serum creatinine, CrCl); signs/symptoms of infusion reaction. Prothrombin time should also be assessed. ¹

Dosing

Prior to initiating therapy and as clinically indicated during therapy, eGFR and hepatic laboratory testing and prothrombin time should be assessed. ¹

The recommended remdesivir dosage for adults and pediatric patients 12 years and older and weighing at least 40 kg is a single loading dose of 200 mg on day 1 via IV infusion, followed by once-daily maintenance doses of 100 mg from day 2 via IV infusion. Therapy should be continued for 5 days in patients not requiring invasive mechanical ventilation and/or ECMO but may be extended up to an additional 5 days if a patient does not exhibit clinical improvement, for a total treatment duration of 10 days. The recommended treatment duration in patients requiring invasive mechanical ventilation and/or ECMO is 10 days. ¹

Remdesivir is not recommended in patients with eGFR less than 30 mL/minute. ¹

Remdesivir must be diluted prior to IV infusion and must be prepared and administered under the supervision of a health care provider. The lyophilized powder must be reconstituted with sterile water for injection and then diluted in a 100 mL or 250 mL sodium chloride 0.9% infusion bag. The injection solution must be diluted in a 250 mL sodium chloride 0.9% infusion bag. Refer to product labeling for reconstitution and dilution instructions. Remdesivir should be administered via IV infusion over 30 to 120 minutes. ¹

The EUA provides for emergency use of remdesivir lyophilized powder for treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing at least 3.5 kg. The recommended dosage for pediatric patients weighing 3.5 to less than 40 kg is a single loading dose of 5 mg/kg on day 1 followed by 2.5 mg/kg once daily from day 2. The recommended dosage for pediatric patients younger than 12 years and weighing 40 kg or more is a single loading dose of 200 mg on day 1 followed by once-daily maintenance doses of 100 mg from day 2. ² Infusions should be administered over 30 to 120 minutes, and the recommended duration of therapy is the same as for patients 12 years and older.^1,2 Use is not recommended in pediatric patients older than 28 days with eGFR less than 30 mL/minute or in full-term neonates at least 7 to 28 days of age with serum creatinine 1 mg/dL or greater. ²

Product Availability and Storage

Remdesivir was approved by the FDA on October 22, 2020. ⁷ It is available as a 100 mg single-dose vial containing sterile, preservative-free lyophilized powder and as a 100 mg per 20 mL (5 mg/mL) single-dose vial containing a sterile, preservative-free solution for injection. ¹

The vials containing lyophilized powder should be stored below 30°C (86°F) until required for use. Once reconstituted, vials should be used immediately to prepare the diluted solution. The vials containing 100 mg per 20 mL of injection solution should be refrigerated at 2 to 8°C (36 to 46°F). Diluted remdesivir solution in infusion bags may be stored for up to 24 hours at room temperature (20 to 25°C [68 to 77°F]) prior to administration or for 48 hours refrigerated (2 to 8°C [36 to 46°F]). ¹

Drug Safety/REMS

No REMS is required for remdesivir. ⁷

Conclusion

Remdesivir is an antiviral that is FDA approved for the treatment of COVID-19 requiring hospitalization in adults and pediatric patients 12 years and older and weighing at least 40 kg. An EUA also provides for emergency use in hospitalized pediatric patients weighing at least 3.5 kg. Remdesivir has been shown to improve clinical recovery time in patients with severe disease; impact on survival has not been shown. Guideline recommendations regarding remdesivir use vary by organization and are evolving as new data become available. Additional studies are necessary to further identify the patient populations most likely to benefit from therapy, optimal timing for the initiation of therapy, and the role of remdesivir in conjunction with other therapeutics, including dexamethasone and monoclonal antibodies.