- Remdesivir is approved for the treatment of coronavirus disease 2019 (COVID-19) in adult and pediatric patients (12 years of age and older, and who weigh at least 40kg) who:
- Require hospitalization
- Have positive results of direct SARS-CoV-2 viral testing, who are not hospitalized, have mild to moderate symptoms, and are at high risk for progression to severe COVID-19, including hospitalization or death
- Remdesivir is not FDA approved in children < 12 years of age, but remains authorized for use in the U.S. by the FDA under an Emergency Use Authorization (EUA) for treatment of suspected or laboratory-confirmed SARS-CoV-2 infection (COVID-19) in children who:
- Require hospitalization
- Have positive results of direct SARS-CoV-2 viral testing, who are not hospitalized, have mild to moderate symptoms, and are at high risk for progression to severe COVID-19, including hospitalization or death.
- Severe disease is defined as:
- Patients with SpO2 ≤ 94% on room air, OR
- Requiring supplemental oxygen, OR
- Requiring mechanical ventilation, OR
- Requiring extracorporeal membrane oxygenation (ECMO)
NON-FDA APPROVED USES
- Nonhospitalized patients who are at high risk for disease progression may be given a 3-day course of remdesivir (200 mg IV on day 1, then 100 mg IV on days 2 and 3).
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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, while there was no significant difference in the clinical outcomes in patients who were not on ECMO or on mechanical ventilation.
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 ≥ 5 times the upper limit of normal at baseline.
ADULT RENAL DOSING
DOSING IN HEMODIALYSIS
DOSING IN PERITONEAL DIALYSIS
DOSING IN RENAL REPLACEMENT THERAPY
Other Adult Renal Dosing Information
- Remdesivir has not been formally evaluated in patients with renal impairment.
- eGFR < 30 ml/min: not recommended due to concern for the accumulation of sulfobutylether-β-cyclodextrin (SBECD), the excipient in remdesivir in renal impairment (this is the same issue with voriconazole IV). However, many experts (including the JH ABX Guide) recommend use due to the lack of finding substantial toxicity to date when used (voriconazole or remdesivir).
USUAL PEDIATRIC DOSING
- Weight ≥3.5 kg - < 40 kg: 5 mg/kg/dose once (max 200 mg/dose), followed by 2.5 mg/kg/dose (max 100 mg/dose) IV Q24h for a total duration of up to 10 days.
- Weight ≥ 40 kg: 200 mg once, followed by 100 mg IV Q24h, for a total duration of up to 10 days.
Administration instructions: Infuse each dose over 30 to 120 minutes in total volume up to 250 ml of sodium chloride 0.9%. Flush line with at least 30 mL sodium chloride 0.9% after remdesivir infusion is complete. Do not administer simultaneously with any other medication or intravenous solutions.
Required labs: Baseline and daily hepatic function tests (ALT, AST, bilirubin, alkaline phosphatase), renal function tests (SCr, calculated CrCl), serum chemistries, hematology parameters. remdesivir should not be initiated in patients with ALT ≥ 5 times the upper limit of normal at baseline.
PEDIATRIC RENAL DOSING
Remdesivir has not been evaluated in patients with renal impairment.
eGFR < 30 ml/min: not recommended due to concern for the accumulation of sulfobutylether-β-cyclodextrin (SBECD), the excipient in remdesivir, in renal impairment.
- Do not use in term neonates ≥ 7 days with SCr ≥ 1 mg/dL unless the benefits outweigh the risks.
ADVERSE DRUG REACTIONS
- Generally well tolerated
- Adverse events up to 60% were reported in clinical trials; however, it is unclear if all were remdesivir-related.
- Adverse events were generally higher in patients receiving a 10-day duration of treatment compared to 5 days.
- In the ACTT-1 trial, remdesivir had similar rates of AEs compared to placebo.
- Remdesivir is contraindicated in patients with hypersensitivity to any ingredient of remdesivir.
- Constipation (6-14%)
- Nausea (5-10%)
- Vomiting (3%)
- Diarrhea (3%)
- Infusion-related reactions: hypotension, nausea, vomiting, diaphoresis, shivering
- Acute respiratory failure (6-11%)
- Hypoalbuminemia (13%)
- Hypokalemia (5-12%)
- Anemia (8-12%)
- Thrombocytopenia (10%)
- Increased bilirubin (10%)
- Transaminase elevations (4-7%)
- Remdesivir should be discontinued in patients who develop ALT ≥ 5 times the upper limit of normal during treatment.
- Or ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
- Remdesivir should be discontinued in patients who develop ALT ≥ 5 times the upper limit of normal during treatment.
- Prothrombin time (PT) elevation without a change in INR
- Rash -7%
- Renal: AKI (2-8%), decreased CrCl (3-12%). Rates are higher with a 10-day course compared to 5 days.
- Pyrexia (5%)
- Hypoglycemia (4%)
- Insomnia (5%)
- 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.
- There are no data in humans and the clinical relevance is unknown at this time, although experts do not expect a significant impact on remdesivir concentrations.
No clinical data are available on the development of SARS-CoV-2 resistance to remdesivir.
Remdesivir is an adenosine nucleotide prodrug that is metabolized to active form nucleoside triphosphate metabolite, which acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, inhibiting viral replication.
Metabolism and Excretion
- ~ 74% of remdesivir is recovered in feces and 18% in urine. The majority (49%) of the dose recovered in urine is metabolite GS-441524, and 10% was recovered as remdesivir.
- AUC0-24 = 4.8 μM•h for remdesivir and AUC0-24 =7.7 μM•h for the nucleoside metabolite after for 200 mg of remdesivir was administered to healthy human subjects.
- Cmax = 5440 ng/ml for remdesivir and Cmx=152 ng/ml for the metabolite GS-441524 after 200 mg dose.
The free fraction in humans was 12.1%.
Cmax, Cmin, and AUC
- Remdesivir exhibits linear PK profile.
- Remdesivir: ~1 h
- Metabolite GS-441524: ~25 h
DOSING FOR DECREASED HEPATIC FUNCTION
- The PK of remdesivir has not been evaluated in patients with hepatic impairment. It is not known if a dosage adjustment is needed in patients with hepatic impairment. Remdesivir should not be used in patients with ALT ≥ 5 times the upper limit of normal.
- Remdesivir should be used in pregnancy only if the benefits outweigh the risk to the mother and fetus. In nonclinical reproductive toxicity studies, no adverse effects on embryofetal development were observed when remdesivir was administered to pregnant animals at systemic exposure of the predominating circulating metabolite of remdesivir at 4 times the exposure in humans.
- In Ebola clinical trial, six out of 98 females who had received remdesivir had a positive pregnancy test. However, obstetric and neonatal outcomes were not reported in the study.
BREAST FEEDING COMPATIBILITY
No data on remdesivir excretion in human breast milk. In animal studies, remdesivir and its metabolites have been detected in nursing mothers.
- Remdesivir is approved for the treatment of 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
- Remdesivir is not FDA approved in children < 12 years of age, but remains authorized for use in the U.S. by the FDA under an Emergency Use Authorization (EUA) for treatment of suspected or laboratory-confirmed SARS-CoV-2 infection (COVID-19) in children hospitalized with severe diseases.
- Recent data (PINETREE) support the use of remdesivir 3-day therapy based on a study of unvaccinated, nonhospitalized 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 was seen to achieve an 87% reduction in risk for hospitalization or death within 28d compared to placebo.
- The efficacy of remdesivir has been evaluated in two randomized clinical trials. Preliminary results of the largest RTC (N=1059), NIAID ACTT-1, 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 starting 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 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.
- 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 as well as 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 discontinued treatment due to adverse events (10% vs. 4%) compared to 5-day treatment.
- Other viruses
- In animal studies when remdesivir was used as prophylaxis, it prevented MERS-CoV clinical disease, reduced MERS-CoV levels, and lung injury.
- Remdesivir has been tested in humans for the treatment of Ebola virus infection, in a large study of 681 patients, remdesivir (n=175) was inferior to human monoclonal antibodies (REGN-EB3 and MAb114).
- In a mouse model, remdesivir was effective when tested as a treatment for SARS-CoV-1.
Basis for recommendation
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020. [PMID:32445440]
Comment: In this final report, double-blind, randomized, placebo-controlled trial, IV remdesivir was compared to placebo for the treatment of hospitalized adults with severe Covid-19 lower respiratory tract infection. Remdesivir was given for a total of 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 in 163 of the 516 patients who received a placebo (31.6%).
- 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. [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 severity of the disease in the 10-day group (p=0.02). There was no difference in the clinical status at day 14 between 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 who had symptoms < 10 days before receiving remdesivir (62% vs. 49%). There was no difference in mortality or length of hospital stay between two groups. The most common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT (7%).
- Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2021. [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.
- Garibaldi BT, Wang K, Robinson ML, et al. Real-World Effectiveness Of Remdesivir In Adults Hospitalized With Covid-19: A Retrospective, Multicenter Comparative Effectiveness Study. Clin Infect Dis. 2021. [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.
- 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]
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 discretion of the clinician, and there was no placebo arm. Also, RDV did not appear to have a great effect on the need for ventilation or hospital LOS.
- 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.
- 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]
In this randomized, double-blind, placebo-controlled trial (n=237) in China, a remdesivir 10-day course was compared to placebo for the treatment of severe COVID-19 pneumonia (O2 saturation ≤ 94% or PaO2/FiO2 ratio of ≤300 mm Hg). The median time to starting 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 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.
- 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.
- 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 in combination with interferon beta had superior activity against MERS-CoV to lopinavir/ritonavir in vitro. Furthermore, when remdesivir was given to mice as prophylaxis and treatment of MERS-CoV, and 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 reduced viral loads, but had no impact on improving the clinical status of mice.
- 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, or 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 with respect to mortality. At that point, patients were re-assigned only to the MAb114 and REGN-EB3 and remdesivir arm was terminated. Mortality at 28-days in 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 was not related to the underlying Ebola virus disease.
- VEKLURY (remdesivir) for injection [package insert]. Foster City, CA. Gilead Sciences, Inc.;2020 https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf (accessed 1/13/22)
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